Citations

Head and neck cancer is the sixth leading cancer by incidence worldwide. Unfortunately, drug resistance and relapse are the principal limitations of clinical oncology for many patients, and the failure of conventional treatments is an extremely demoralizing experience. It is therefore crucial to find new therapeutic targets and drugs to enhance the cytotoxic effects of conventional treatments without potentiating or offsetting the adverse effects. Melatonin has oncostatic effects, although the mechanisms involved and doses required remain unclear. The purpose of this study is to determine the precise underlying mitochondrial mechanisms of melatonin, which increase the cytotoxicity of oncological treatments, and also to propose new melatonin treatments in order to alleviate and reverse radio- and chemoresistant processes. We analyzed the effects of melatonin on head and neck squamous cell carcinoma (HNSCC) cell lines (Cal-27 and SCC-9), which were treated with 0.1, 0.5, 1, and 1.5 mM melatonin combined with 8 Gy irradiation or 10 μM cisplatin. Clonogenic and MTT assays, as well as autophagy and apoptosis, involving flow cytometry and western blot, were performed in order to determine the cytotoxic effects of the treatments. Mitochondrial function was evaluated by measuring mitochondrial respiration, mtDNA content (RT-PCR), and mitochondrial mass (NAO). ROS production, antioxidant enzyme activity, and GSH/GSSG levels were analyzed using a fluorometric method. We show that high concentrations of melatonin potentiate the cytotoxic effects of radiotherapy and CDDP in HNSCC, which are associated with increased mitochondrial function in these cells. In HNSCC, melatonin induces intracellular ROS, whose accumulation plays an upstream role in mitochondria-mediated apoptosis and autophagy. Our findings indicate that melatonin, at high concentrations, combined with cisplatin and radiotherapy to improve its effectiveness, is a potential adjuvant agent.

Background: Two-stage exchange is the most common form of treatment of chronic infection following total hip arthroplasty (THA). We examined the prevalence of, and risk factors associated with, hip instability following 2-stage exchange as well as the fate of reimplanted hip prostheses that dislocated. Methods: Data on 515 2-stage exchange THAs performed between 2000 and 2014 at a single institution were retrospectively reviewed. Risk factors for instability as well as postoperative reoperations and revisions were analyzed. The impact of dislocation on these outcomes was evaluated as well. The mean age at the time of reimplantation was 65 years, and the mean duration of follow-up was 5 years (range, 2 to 15 years). Results: Dislocation occurred in 52 hips following reimplantation (cumulative probability = 8.9% at 1 year). There was a higher risk of instability in women (hazard ratio [HR] = 1.8, p = 0.038) and in those who had a history of dislocation prior to the 2-stage revision (HR = 5.1, p < 0.001). Younger age, body mass index, number of previous operations, spacer type, surgical approach, use of a constrained liner, femoral head diameter, and persistent or recurrent infection were not found to be significant risk factors. Patients with an absent or ununited greater trochanter or abductor deficiency also had a higher rate of dislocation (HR = 30, p < 0.001), as did patients who underwent reimplantation with a megaprosthesis (HR = 6.0, p < 0.001). The risk of additional reoperations (HR = 121, p < 0.001) and revision surgery (HR = 13, p < 0.001) was significantly higher in patients who experienced a dislocation after the 2-stage exchange. Conclusions: Dislocation after 2-stage exchange THA continues to be a major concern, with the 1-year cumulative probability found to be 9% in the present study. Female sex, a history of dislocation, an absent or ununited greater trochanter or abductor deficiency, and reimplantation with a megaprosthesis were identified as risk factors for dislocation. There is a remarkable 121-fold increase in the rate of reoperations and a 13-fold increase in the rate of revisions in hips that dislocated after 2-stage exchange THA. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Background: For patients undergoing 2-stage exchange for the treatment of periprosthetic joint infection (PJI) following total knee arthroplasty, the long-term risk of reinfection and mechanical failure and long-term clinical outcomes are not well known. The purpose of our study was to determine the long-term clinical results of 2-stage exchange for PJI following total knee arthroplasty. Methods: We identified 245 knees that had undergone total knee arthroplasty and were subsequently treated with 2-stage exchange due to infection during the period of 1991 to 2006; the cohort had no prior treatment for PJI. Major, or 4 of 6 minor, Musculoskeletal Infection Society (MSIS) diagnostic criteria were fulfilled by 179 (73%) of the knees. The cumulative incidence of reinfection and of aseptic revision, accounting for the competing risk of death, were calculated. Risk factors for reinfection were evaluated using Cox proportional hazards regression. Knee Society Score (KSS) values were calculated. The mean age at spacer insertion was 68 years; 50% of the patients were female. The mean follow-up was 14 years (range, 2 to 25 years) following reimplantation. Results: The cumulative incidence of reinfection was 4% at 1 year, 14% at 5 years, 16% at 10 years, and 17% at 15 years. Factors that were predictive of reinfection included a body mass index of ≥30 kg/m 2 (hazard ratio [HR], 3.1; p < 0.01), previous revision surgery (HR, 2.8; p < 0.01), and a McPherson host grade of C (HR, 2.5; p = 0.04). The cumulative incidence of aseptic revision for loosening was 2% at 5 years, 5% at 10 years, and 7% at 15 years. Femoral (HR, 5.0; p = 0.04) and tibial (HR, 6.7; p < 0.01) bone-grafting at reimplantation were predictive of aseptic failure. The most common complications were wound-healing issues, requiring reoperation in 12 (5%) of the knees. The rate of death at 2 years following reimplantation was 11%. The mean KSS improved from 45 at PJI diagnosis to 76 at 10 years following reimplantation (p < 0.01). Conclusions: Long-term reinfection rates following 2-stage exchange for PJI after total knee arthroplasty were similar to those of shorter-term reports and were maintained out to 15 years. Mechanical failure rates were low if bone loss was addressed at the time of reimplantation. Improvements in clinical outcomes were maintained at long-term follow-up. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Aims Concurrent hip and spine pathologies can alter the biomechanics of spinopelvic mobility in primary total hip arthroplasty (THA). This study examines how differences in pelvic orientation of patients with spine fusions can increase the risk of dislocation risk after THA. Patients and Methods We identified 84 patients (97 THAs) between 1998 and 2015 who had undergone spinal fusion prior to primary THA. Patients were stratified into three groups depending on the length of lumbar fusion and whether or not the sacrum was involved. Mean age was 71 years (40 to 87) and 54 patients (56%) were female. The mean body mass index (BMI) was 30 kg/m2 (19 to 45). Mean follow-up was six years (2 to 17). Patients were 1:2 matched to patients with primary THAs without spine fusion. Hazard ratios (HR) were calculated. Results Dislocation in the fusion group was 5.2% at one year versus 1.7% in controls but this did not reach statistical significance (HR 1.9; p = 0.33). Compared with controls, there was no significant difference in rate of dislocation in patients without a sacral fusion. When the sacrum was involved, the rate of dislocation was significantly higher than in controls (HR 4.5; p = 0.03), with a trend to more dislocations in longer lumbosacral fusions. Patient demographics and surgical characteristics of THA (i.e. surgical approach and femoral head diameter) did not significantly impact risk of dislocation (p > 0.05). Significant radiological differences were measured in mean anterior pelvic tilt between the one-level lumbar fusion group (22°), the multiple-level fusion group (27°), and the sacral fusion group (32°; p < 0.01). Ten-year survival was 93% in the fusion group and 95% in controls (HR 1.2; p = 0.8). Conclusion Lumbosacral spinal fusions prior to THA increase the risk of dislocation within the first six months. Fusions involving the sacrum with multiple levels of lumbar involvement notably increased the risk of postoperative dislocation compared with a control group and other lumbar fusions. Surgeons should take care with component positioning and may consider higher stability implants in this high-risk cohort.

Background: Limited data exist that show the long-term risks of reinfection and mechanical failure with a contemporary 2-stage exchange protocol for periprosthetic joint infection following total hip arthroplasty. The purpose of this study was to determine the long-term reinfection and mechanical failure rates of 2-stage exchange for periprosthetic joint infection after total hip arthroplasty. Methods: We identified 164 hips (162 patients) with infection after total hip arthroplasty between 1991 and 2006 treated with a 2-stage exchange protocol with no prior treatment for periprosthetic joint infection. With regard to Musculoskeletal Infection Society diagnostic criteria, at least 1 major criterion or 4 of 6 minor criteria were fulfilled in 129 hips (79%). The cumulative incidence with a competing risk of death was calculated for reinfection, aseptic revisions, and all-cause revisions. The risk factors for reinfection were evaluated using Cox proportional hazards regression. Harris hip scores were calculated. The mean age at the time of spacer insertion was 68 years, and 35% of the patients were female. Excluding the patients with <2 years of follow-up, the mean follow-up was 12 years (range, 2 to 21 years). Results: The cumulative incidence of recurrence of infection was 10% at 1 year, 14% at 5 years, and 15% at 10 and 15 years. Seventeen patients (11%) used chronic antibiotic suppression (>6 months), with 7 (41%) of these having recurrent infection at the time of the latest follow-up. Use of chronic antibiotic suppression was the only predictive factor for reinfection (hazard ratio, 4.5 [95% confidence interval (CI), 1.9 to 10.9]; p = 0.001). The cumulative incidence of aseptic femoral and acetabular revisions was 2.6% at 5 years and 3.3% at 10 and 15 years. The cumulative incidence of all-cause revisions was 15% at 5 years and 16% at 10 and 15 years. Dislocation was the most common complication, with 28 dislocations occurring in 20 patients (12%). The mean Harris hip score improved from 52 points prior to spacer insertion to 70 points at 15 years after reimplantation (p < 0.01). Conclusions: The rate of recurrence of infection of 15% for up to 15 years after total hip arthroplasty was similar to previous shorter-term reports of 2-stage exchange for periprosthetic joint infection. Surgeons should anticipate mitigating instability after reimplantation. Implant survivorship free of aseptic loosening and clinical outcomes were preserved for the long term. The role of chronic antibiotic suppression in the long-term treatment of periprosthetic joint infection requires further investigation. Level of Evidence: Therapeutic Level IV . See Instructions for Authors for a complete description of levels of evidence.

Abstract In this cohort of 51 patients managed with retained “destination spacers” after the resection of infected joint prostheses, the presence of preoperative sinus drainage was significantly associated with reinfection. Chronic antimicrobial suppression after destination-spacer retention did not significantly prevent reinfections.

Docetaxel is a commonly used chemotherapeutic agent in a variety of cancer treatment regimens. We present a case of apparent docetaxel-induced Stevens-Johnson syndrome (SJS) in a patient recently treated for metastatic prostate cancer. This medication is not classically associated with the development of SJS but in our case, along with a number of other case reports, and a single phase II clinical trial, an association was recognized. We encourage clinicians who employ the use of this medication to be aware of this relationship.

263 Background: DNA repair genomic alterations (GAs) have been identified in 12% of Intrahepatic cholangiocarcinoma (IHCCA), 26% of extrahepatic CCA (EHCCA) and 8% of gallbladder cancer (GBC) patients (pts) ( Cancer 2016;122:3838–3847). Recently, the Cancer Genome Atlas (TCGA) has described more than 20 mutated DNA repair genes, many of which were not previously represented in prior reports. DNA repair GAs including MSI are associated with higher tumor mutational burden (TMB). Our study aim is to identify variations in the frequency of DNA repair GAs in IHCCA, EHCCA, and GBC. Methods: Hybrid capture-based next-generation sequencing of 422 fixed formalin paraffin embedded (FFPE) tissue blocks of BTC including; 270 IHCCA, 60 EHCCA, and 92 GBC was performed. We included 20 DNA repair genes and classified them as "direct" DNA repair genes ( ATM, ATR, BRCA1, BRCA2, FANCA, FANCD2, MLH1, MSH2, MSH6, PALB2, POLD1, POLE, PRKDC, RAD50, SLX4) and "caretaker" genes that induce genomic instability ( BAP1, CDK12, MLL3, TP53, BLM). We calculated TMB on 1.1 Mb of sequenced DNA in 205 tissue specimens [138 IHCCA, 23 EHCCA, and 44 GBC] and classified into three groups; high (TMB-H; ≥ 20 mut/Mb), intermediate (TMB-I; 6-19mut/Mb) and low (TMB-L; < 6mut/Mb). Results: A distinct pattern of DNA repair GAs in each tumor type was detected. (Table 1). DNA repair GAs were more commonly noted in both EHCCA and GB (63%) as compared with IHCAA (45.2%) (p= .002). Direct DNA repair GAs were highest within EHCCA (25%), while indirect DNA GAs were predominant in GBC (59.8%) (p= 0.04 and 0.001, respectively). The frequency of TMB-H and TMB-I differed significantly between BTC subtypes. Pts with EHCCA and GBC had significantly higher TMB-H and TMB-I versus IHCCA. Conclusions: The frequency of DNA repair GA’s is higher in EHCCA and GBC as compared with IHCCA. These results may have implications for clinical trials with DNA repair inhibitors and immune checkpoint blockers. [Table: see text]

AbstractBackgroundMobilization regimen choice is a significant contributing factor for successful hematopoietic progenitor cell (HPC) collection by leukocytapheresis and reaching the target CD34+ cell dose. How mobilization regimen affects collection efficiency and the quality of products collected using the Spectra Optia apheresis instrument is not fully known.MethodsWe evaluated the impact of granulocyte‐colony stimulating factor (GCSF) and GCSF/plerixafor mobilization regimens on CE and product composition. We studied 373 leukocytapheresis HPC collections for 147 autologous transplants from January 1, 2010 to December 31, 2014. Patients were categorized in two groups; good mobilizers, mobilized with GCSF only (GM) and poor mobilizers, mobilized with GCSF and Plerixafor (PM).ResultsOverall, compared with PM group, total nucleated cell (TNC) yield was significantly lower in GM group (P = <.001). In contrast, median percent mononuclear cell (MNC) collected from GM (86.5%) was significantly higher than products collected from PM group (79.5%; P < .001). Compared with GM group, CD34+ cell CE was about 10% lower in PM group (P < .008). In addition, daily CD34+ cell/Kg yield was significantly higher in GM (2.08 × 10/Kg) compared with PM group (1.64 x 10/Kg, P = .019). Overall, the median number of collections per patient was two for GM and three for PM (P = .004).ConclusionProducts collected from PM group contained higher TNC content relative to GM group but had lower MNC enrichment, CD34+ cell CE and daily CD34+ cell yield per Kg.