PT-112 Induces Mitochondrial Stress and Immunogenic Cell Death, Targeting Tumor Cells with Mitochondrial Deficiencies.

PT-112 is a novel pyrophosphate-platinum conjugate, with clinical activity reported in advanced pretreated solid tumors. While PT-112 has been shown to induce robust immunogenic cell death (ICD) in vivo but only minimally bind DNA, the molecular mechanism underlying PT-112 target disruption in cancer cells is still under elucidation. The murine L929 in vitro system was used to test whether differential metabolic status alters PT-112's effects, including cell cytotoxicity. The results showed that tumor cells presenting mutations in mitochondrial DNA (mtDNA) (L929dt and L929dt cybrid cells) and reliant on glycolysis for survival were more sensitive to cell death induced by PT-112 compared to the parental and cybrid cells with an intact oxidative phosphorylation (OXPHOS) pathway (L929 and dtL929 cybrid cells). The type of cell death induced by PT-112 did not follow the classical apoptotic pathway: the general caspase inhibitor Z-VAD-fmk did not inhibit PT-112-induced cell death, alone or in combination with the necroptosis inhibitor necrostatin-1. Interestingly, PT-112 initiated autophagy in all cell lines, though this process was not complete. Autophagy is known to be associated with an integrated stress response in cancer cells and with subsequent ICD. PT-112 also induced a massive accumulation of mitochondrial reactive oxygen species, as well as changes in mitochondrial polarization-only in the sensitive cells harboring mitochondrial dysfunction-along with calreticulin cell-surface exposure consistent with ICD. PT-112 substantially reduced the amount of mitochondrial CoQ10 in L929 cells, while the basal CoQ10 levels were below our detection limits in L929dt cells, suggesting a potential relationship between a low basal level of CoQ10 and PT-112 sensitivity. Finally, the expression of HIF-1α was much higher in cells sensitive to PT-112 compared to cells with an intact OXPHOS pathway, suggesting potential clinical applications.

Phase I study of PT-112, a novel pyrophosphate-platinum immunogenic cell death inducer, in advanced solid tumours.

Background: PT-112, the first pyrophosphate-platinum conjugate, causes immunogenic cell death in experimental models, leading to recruitment of tumour-infiltrating lymphocytes. PT-112 also associates with bone (osteotropism), likely driven by its pyrophosphate moiety. This is the first-in-human study of PT-112 monotherapy, exploring its safety and efficacy in a patient population where standard of care therapies were exhausted and novel treatment options are needed. Methods: Patients with progressing, advanced solid tumours received PT-112 intravenously (1 h) on days 1, 8, 15 of a 28-day cycle in an open-label, multi-centre 3 + 3 dose-escalation trial, conducted at four US research sites. The primary objective was to assess safety and pharmacokinetics, and to identify a recommended phase 2 dose (RP2D). Eligibility criteria included: age ≥18 years, Eastern Collaborative Oncology Group (ECOG) Performance Status of 0-1, and disease evaluable by Response Evaluation Criteria in Solid Tumours (RECIST) v1·1 or by informative tumour markers. Patients receiving ≥1 dose of PT-112 were included in the safety and pharmacokinetic analyses, with the exploratory efficacy analysis including patients receiving ≥1 dose at 125 mg/m2. This study is registered at ClinicalTrials.gov, number NCT02266745, with the dose-escalation portion of the study closed. Findings: Between July 7th, 2014 and September 18th, 2018, 66 heavily pre-treated patients (median 4 prior lines, IQR 2-6) were enrolled and treated across 11 doses (12-420 mg/m2). Treatment-related adverse events included fatigue (23 patients, 35%), nausea (16 patients, 24%), and peripheral neuropathy (14 patients, 21%). Grade 3 events were experienced by 18 patients (27%), with no grade 4-5 events observed. The recommended phase 2 dose was determined to be 360 mg/m2. Nine (17%) of the 54 efficacy evaluable patients achieved progression-free survival ≥6 months. Durable partial responses were induced in non-small cell lung cancer (NSCLC), small cell lung cancer (SCLC), and thymoma. Radiographic and serum marker reductions were observed among ten patients with metastatic castration resistant prostate cancer, four of whom survived two years or longer. Interpretation: PT-112 is safe and well-tolerated in a heavily pre-treated population. Prolonged responses were noted against thymoma and lung cancer, along with radiographic and serum marker improvement in prostate cancer. Given the heterogeneous patient population, subsequent studies will be needed to characterize the risk/benefit ratio in more homogenous settings. Further development of PT-112 is ongoing, as single-agent and in combination with immune checkpoint inhibition. Funding: Funding was provided by Promontory Therapeutics Inc.

Primary THA Using Thin Polyethylene Liners and Large Femoral Heads: A Minimum 5-Year Follow-Up.

BACKGROUND: Large femoral head sizes are commonly used in total hip arthroplasty (THA) to minimize the risk of instability. With small acetabular cup-size, large femoral head diameter often results in the use of thin polyethylene liners. The purpose of this study was to evaluate clinical and radiographic results of large femoral heads against thin polyethylene liners with minimum 5-year follow-up. METHODS: This was a retrospective review identifying 58 primary THAs utilizing thin polyethylene inserts from one manufacturer (X3 polyethylene, Stryker, Mahwah, NJ) and large femoral heads (36 mm or greater) with minimum 5-year follow-up. A total of 3 patients were deceased and 11 lost to follow-up, leaving 44 patients for review. All patients were female with mean age 65.7 (range 26-85) and mean body mass index (BMI) 29.9 (range 19.6-45.4). Average length of follow-up was 8.5 years (range 5.1-11.3). Outcome measures included survivorship, complications, PROMs and radiographic analysis. RESULTS: There were four revisions: two aseptic loosening, one prosthetic joint infection, and one recurrent dislocation. Average HOOS-Jr, FJS-12, and patient satisfaction using Likert score was 94.3/100, 92.9/100, and 4.69/5.00, respectively, with 94% of patients reporting being satisfied or very satisfied. Radiographic analysis at average of 8.5 years demonstrated well-fixed implants without evidence of progressive radiolucent lines, osteolysis, or failure of the polyethylene liner. Survivorship using failure of the thin polyethylene liner as the endpoint was 100% at an average of 8.5 years. CONCLUSION: Thin polyethylene liners used with large femoral head sizes in small acetabular cups demonstrated excellent results at average 8.5-year follow-up with no cases of liner fracture or osteolysis.

Variation in levels of luteinizing hormone and reproductive photoresponsiveness in a population of white-footed mice (Peromyscus leucopus).

Natural genetic variation in reproduction and life history strategies is a manifestation of variation in underlying regulatory neuronal and endocrine systems. A test of the hypothesis that genetic variation in luteinizing hormone (LH) level could be related to a life history trait, seasonal reproduction, was conducted on artificial selection lines from a wild-source population of white-footed mice (Peromyscus leucopus). Variation exists in the degree of suppression of reproduction by winter short-day photoperiods (SD) in wild-source individuals and in the laboratory population. In this population, most individuals from a photoperiod-responsive (R) artificial selection line are strongly suppressed reproductively in SD, while most individuals from a photoperiod-nonresponsive (NR) artificial selection line are only weakly reproductively suppressed in SD. We assayed levels of LH to test for genetic variation between lines that could contribute to variation in reproductive status in SD. Females from both lines were raised in long-day photoperiods (LD) or SD, ovariectomized under isoflurane anesthesia, and given estradiol implants. Levels of LH were significantly higher in the NR line than in the R line, indicating genetic variation for levels of LH. Levels of LH were higher in LD than in SD, indicating that levels of LH were sensitive to photoperiod treatment even with a controlled level of estradiol negative feedback. The results indicate that there is genetic variation in levels of LH that could be functionally important both in the laboratory in SD and in the wild population in winter. Thus genetic variation in levels of LH is a plausible causal factor determining winter reproductive phenotype in the wild population.

Acetabular component revision using a porous tantalum biomaterial: a case series.

Biologic ingrowth can be difficult to achieve in acetabular component revision, especially in cases with significant bone loss. The purpose of this study was to review our clinical results of acetabular component revisions in patients with significant bone loss using a porous tantalum biomaterial. This is a retrospective review of 25 patients. There were 16 females and 9 males with a mean age of 71.7 +/- 10.54 years. The mean follow up was 39 +/- 11.09 months (range, 28-55 months). All patients in this series had combined segmental and cavitary bone loss, Paprosky type 2 or type 3. Of 22 patients in this series, 21 had a well-fixed and functioning implant at latest follow up. All 21 patients developed ingrowth along the tantalum surface despite compromised host bone. There were no cases of dislocation or aseptic loosening. Porous tantalum appears to be a promising material for use in revision hip arthroplasty to facilitate biologic ingrowth in patients with acetabular bone loss.

Determining the relationship of the axillary nerve to the shoulder joint capsule from an arthroscopic perspective.

BACKGROUND: The axillary nerve is out of the field of view during shoulder arthroscopy, but certain procedures require manipulation of capsular tissue that can threaten the function or integrity of the nerve. We studied fresh cadavers to identify the course of the axillary nerve in relation to the glenoid rim from an intra-articular perspective and to determine how close the nerve travels in relation to the glenoid rim and the inferior glenohumeral ligament. METHODS: We dissected nine whole-body fresh-tissue shoulder joints and exposed the axillary nerve through a window in the inferior glenohumeral ligament. Then we cut coronal sections through the glenoid fossa of ten unembalmed, frozen shoulder specimens after the axillary nerve had been stained with Evans blue dye. All specimens were studied with the joint secured in the lateral decubitus position used for shoulder arthroscopy. RESULTS: Microsurgical dissection through the inferior glenohumeral ligament from within the joint capsule revealed the axillary nerve as it traversed the quadrangular space. In each dissection, the teres minor branch was the closest to the glenoid rim. The coronal sectioning of the unembalmed shoulder specimens demonstrated that the closest point between the axillary nerve and the glenoid rim was at the 6 o'clock position on the inferior glenoid rim. At this position, the average distance between the axillary nerve and the glenoid rim was 12.4 mm. The axillary nerve lay, throughout its course, at an average of 2.5 mm from the inferior glenohumeral ligament. CONCLUSIONS: We used two novel approaches to map the axillary nerve from an intra-articular perspective. Our analysis of the position of the nerve with use of these methods provides the shoulder arthroscopist with essential information regarding the location, route, and morphology of the nerve as it passes inferior to the glenoid rim and shoulder capsule.