Do breast cancer patients have increased risk of complications after primary total hip and total knee arthroplasty?

Aims: Breast cancer survivors have known risk factors that might influence the results of total hip arthroplasty (THA) or total knee arthroplasty (TKA). This study evaluated clinical outcomes of patients with breast cancer history after primary THA and TKA. Methods: Our total joint registry identified patients with breast cancer history undergoing primary THA (n = 423) and TKA (n = 540). Patients were matched 1:1 based upon age, sex, BMI, procedure (hip or knee), and surgical year to non-breast cancer controls. Mortality, implant survival, and complications were assessed via Kaplan-Meier methods. Clinical outcomes were evaluated via Harris Hip Scores (HHSs) or Knee Society Scores (KSSs). Mean follow-up was six years (2 to 15). Results: Breast cancer patient survival at five years was 92% (95% confidence interval (CI) 89% to 95%) after THA and 94% (95% CI 92% to 97%) after TKA. Breast and non-breast cancer patients had similar five-year implant survival free of any reoperation or revision after THA (p ≥ 0.412) and TKA (p ≥ 0.271). Breast cancer patients demonstrated significantly lower survival free of any complications after THA (91% vs 96%, respectively; hazard ratio = 2 (95% CI 1.1 to 3.4); p = 0.017). Specifically, the rate of intraoperative fracture was 2.4% vs 1.4%, and venous thromboembolism (VTE) was 1.4% and 0.5% for breast cancer and controls, respectively, after THA. No significant difference was noted in any complications after TKA (p ≥ 0.323). Both breast and non-breast cancer patients experienced similar improvements in HHSs (p = 0.514) and KSSs (p = 0.132). Conclusion: Breast cancer survivors did not have a significantly increased risk of mortality or reoperation after primary THA and TKA. However, there was a two-fold increased risk of complications after THA, including intraoperative fracture and VTE.

Knee Arthroscopy Following Total Knee Arthroplasty is Not Associated With an Elevated Risk of Infection.

BACKGROUND: Recent literature has suggested that knee arthroscopy (KA) following ipsilateral primary total knee arthroplasty (TKA) may be associated with an increased risk of periprosthetic joint infection (PJI). However, prior studies on this subject have relied on insurance databases or have lacked control groups for comparison. This study aimed to evaluate the risk of PJI in patients undergoing ipsilateral KA after primary TKA at a single institution. METHODS: Our total joint registry was queried to identify 167 patients (178 knees) who underwent ipsilateral KA for any indication other than infection following primary TKA (KA + TKA group). The average time from TKA to KA was 2.1 ± 2.3 years. The average follow-up from primary TKA and from KA was 8.4 ± 5.4 years and 6.3 ± 5.4 years, respectively. The mean patient age was 63 ± 11 years, the mean body mass index was 31 ± 5, and 64% were women. The most common indications for KA were patellar clunk or patellofemoral synovial hyperplasia (66%) and arthrofibrosis (16%). Patients in the KA + TKA group were matched to 523 patients who underwent TKA without subsequent KA (TKA group) based on age, sex, date of surgery, and body mass index. The primary outcome measure was survivorship free from PJI. RESULTS: There was no statistical difference in the overall rate of PJI between the KA + TKA group (n = 2, 1.1%) compared to the TKA group (n = 3, 0.6%) (hazard ratio 2.0, 95% confidence interval 0.3 to 12.0, P = .4). At 5 and 10 years after TKA, there was no difference in survivorship free of PJI between the 2 groups (P = .8 and P = .3, respectively). CONCLUSIONS: A PJI is a rare complication of KA after TKA. The rate of PJI in patients undergoing KA following TKA is not significantly increased. LEVEL OF EVIDENCE: III.

INPP5A phosphatase is a synthetic lethal target in GNAQ and GNA11-mutant melanomas.

Activating mutations in GNAQ/GNA11 occur in over 90% of uveal melanomas (UMs), the most lethal melanoma subtype; however, targeting these oncogenes has proven challenging and inhibiting their downstream effectors show limited clinical efficacy. Here, we performed genome-scale CRISPR screens along with computational analyses of cancer dependency and gene expression datasets to identify the inositol-metabolizing phosphatase INPP5A as a selective dependency in GNAQ/11-mutant UM cells in vitro and in vivo. Mutant cells intrinsically produce high levels of the second messenger inositol 1,4,5 trisphosphate (IP3) that accumulate upon suppression of INPP5A, resulting in hyperactivation of IP3-receptor signaling, increased cytosolic calcium and p53-dependent apoptosis. Finally, we show that GNAQ/11-mutant UM cells and patients' tumors exhibit elevated levels of IP4, a biomarker of enhanced IP3 production; these high levels are abolished by GNAQ/11 inhibition and correlate with sensitivity to INPP5A depletion. Our findings uncover INPP5A as a synthetic lethal vulnerability and a potential therapeutic target for GNAQ/11-mutant-driven cancers.

Environmental DNA-based biomonitoring of Cuban Crocodylus and their accompanying vertebrate fauna from Zapata Swamp, Cuba.

Crocodylians globally face considerable challenges, including population decline and extensive habitat modification. Close monitoring of crocodylian populations and their habitats is imperative for the timely detection of population trends, especially in response to management interventions. Here we use eDNA metabarcoding to identify the Critically Endangered Crocodylus rhombifer and the Vulnerable C. acutus, as well as vertebrate community diversity, in Cuba's Zapata Swamp. We tested four different primer sets, including those used previously in Crocodylus population genetic and phylogenetic research, for their efficiency at detecting crocodylian eDNA. We detected C. rhombifer eDNA in 11 out of 15 sampled locations within its historical geographic distribution. We found that data analyses using the VertCOI primers and the mBRAVE bioinformatics pipeline were the most effective molecular marker and pipeline combination for identifying this species from environmental samples. We also identified 55 vertebrate species in environmental samples across the four bioinformatics pipelines- ~ 85% known to be present in the Zapata ecosystem. Among them were eight species previously undetected in the area and eight alien species, including known predators of hatchling crocodiles (e.g., Clarias sp.) and egg predators (e.g., Mus musculus). This study highlights eDNA metabarcoding as a powerful tool for crocodylian biomonitoring within fragile and diverse ecosystems, particularly where fast, non-invasive methods permit detection in economically important areas and will lead to a better understanding of complex human-crocodile interactions and evaluate habitat suitability for potential reintroductions or recovery programs for threatened crocodylian species.

Intussusception Allograft Prosthetic Composites in Total Hip Arthroplasty: A Salvage Operation for Extensive Femoral Bone Loss.

BACKGROUND: Allograft prosthetic composites (APCs) have been used to perform revision total hip arthroplasty (THA) for massive femoral bone loss or deformity. Intussusception, or "telescoping", APC techniques have been proposed to enhance the contact area of this interface and provide superior mechanical fixation over conventional methods. The purpose of this study is to present to our knowledge, the largest series of telescoping APC THAs, along with surgical technique details and midterm (average 5-10 years) clinical results. METHODS: Between 1994 and 2015, 46 revision THAs performed with proximal femoral telescoping APCs were retrospectively reviewed at a single institution. Overall survival, reoperation-free survival, and construct survival rates were calculated via Kaplan-Meier methods. In addition, radiographic analyses were performed to evaluate for component loosening, union at the APC-host interface, and resorption of the allograft. RESULTS: At 10 years, the overall patient survival was 58%, reoperation-free survival was 76%, and construct survival was 95%. Reoperation was performed in 20% (n = 9) and only 2 constructs required resection. Radiographic analyses performed at latest follow-up revealed no instances of radiographic femoral stem loosening, an 86% union rate at the APC-host site, 23% with signs of some allograft resorption, and a 54% trochanteric union. The mean postoperative Harris hip score was 71 points (range, 46-100). CONCLUSION: Telescoping APCs are technically demanding, but provide reliable mechanical fixation for the reconstructing of large proximal femoral bone deficits in revision THA with excellent construct survivorship, acceptable reoperation rates, and good clinical outcomes. LEVEL OF EVIDENCE: IV.

Risk Factors for Allograft Subsidence Following Anterior Cervical Discectomy and Fusion.

OBJECTIVE: The purpose this study was to precisely characterize patterns of allograft subsidence following anterior cervical discectomy and fusion (ACDF) utilizing computed tomography scans, determine risk factors for cervical allograft subsidence, and investigate the impact of subsidence on pseudarthrosis rates. METHODS: We performed a retrospective review of patients undergoing 1-to 3-level ACDF utilizing allograft interbodies with anterior plating between 2011 and 2019. Subsidence measurements were performed by 2 independent reviewers on computed tomography scans obtained 6 months postoperatively. Subsidence was then classified as mild if subsidence into the inferior and superior endplates were both ≤2 mm, moderate if the worst subsidence into the inferior- or superior endplate was between 2 and 4 mm, or severe if the worst subsidence into the inferior- or superior endplate was ≥4 mm. Multivariate analysis was performed to identify risk factors for the development of subsidence. RESULTS: We identified 98 patients (152 levels) for inclusion. A total of 73 levels demonstrated mild subsidence (≤2 mm), 61 demonstrated moderate subsidence (2-4 mm), and 18 demonstrated severe subsidence (≥4 mm). On multivariate analysis, risk factors for severe subsidence included excessive vertebral endplate resection and lower screw tip to vertebral body height ratio. Severe subsidence was associated with an increased rate of pseudarthrosis (94.1% vs. 13.6%) without an associated increase in reoperation rate. CONCLUSIONS: Following ACDF with allograft interbodies, 50% of interbodies will subside >2 mm and 10% of interbodies will subside >4 mm. Risk factors for severe subsidence should be mitigated to decrease the risk of pseudarthrosis.

Gastrointestinal symbiont diversity in wild gorilla: A comparison of bacterial and strongylid communities across multiple localities.

Western lowland gorillas (Gorilla gorilla gorilla) are Critically Endangered and show continued population decline. Consequently, pressure is mounting to better understand their conservation threats and ecology. Gastrointestinal symbionts, such as bacterial and eukaryotic communities, are believed to play vital roles in the physiological landscape of the host. Gorillas host a broad spectrum of eucaryotes, so called parasites, with strongylid nematodes being particularly prevalent. While these communities are partially consistent, they are also shaped by various ecological factors, such as diet or habitat type. To investigate gastrointestinal symbionts of wild western lowland gorillas, we analysed 215 faecal samples from individuals in five distinct localities across the Congo Basin, using high-throughput sequencing techniques. We describe the gut bacterial microbiome and genetic diversity of strongylid communities, including strain-level identification of amplicon sequence variants (ASVs). We identified strongylid ASVs from eight genera and bacterial ASVs from 20 phyla. We compared these communities across localities, with reference to varying environmental factors among populations, finding differences in alpha diversity and community compositions of both gastrointestinal components. Moreover, we also investigated covariation between strongylid nematodes and the bacterial microbiome, finding correlations between strongylid taxa and Prevotellaceae and Rikenellaceae ASVs that were consistent across multiple localities. Our research highlights the complexity of the bacterial microbiome and strongylid communities in several gorilla populations and emphasizes potential interactions between these two symbiont communities. This study provides a framework for ongoing research into strongylid nematode diversity, and their interactions with the bacterial microbiome, among great apes.

Contemporary Outcomes of Transfemoral Amputation After Total Knee Arthroplasty.

BACKGROUND: Transfemoral amputation (TFA) is a salvage procedure for unreconstructable failed total knee arthroplasty (TKA). Prior studies have reported poor outcomes, patient survival, and prosthetic use. The purpose of this study was to analyze patient outcomes and prosthetic utilization in a contemporary group of patients undergoing TFA in the setting of a TKA. METHODS: We reviewed 112 patients undergoing TFA with a prior TKA. Indications for amputation and postoperative functional measures were captured through chart review. Patients were contacted by survey to assess the quality of life. The mean follow-up after TFA was 4 years. RESULTS: Amputations were performed for a chronically infected TKA (n = 87, 78%) and an ischemic limb without signs of an infected TKA (n = 22, 20%). The 10-year survival after TFA was 21%. Of the patients not lost to follow-up, 53 (47%) patients were fitted for a prosthesis. Patients who underwent a TFA after the year 2000 were more likely to be fit for a prosthesis (odds ratio 7.27, P < .01); however, patients were likely to be ambulatory before TFA than after TFA (odds ratio 3.68, P < .01). After TFA, the mean 12-Item Short Form Survey scores for the mental and physical components were 54 ± 13 and 34 ± 7, with no difference in scores between patients fitted for a prosthesis and those who were not (P > .05). CONCLUSION: Patients undergoing a TFA after TKA due to failure of the TKA are more likely to be fit for a prosthesis; however, they reported no better quality of life and satisfaction compared with patients not fit for a prosthesis. LEVELS OF EVIDENCE: Level III, Therapeutic.

Allograft Subsidence Decreases Postoperative Segmental Lordosis With Minimal Effect on Global Alignment Following ACDF.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: Studies investigating the impact of interbody subsidence in ACDF suggest a correlation between subsidence and worse radiographic and patient-reported outcomes. The purpose of this study was to assess whether allograft subsidence assessed on CT is associated with worse cervical alignment. METHODS: We performed a retrospective review of a prospective cohort of patients undergoing 1 to 3 level ACDF. Cervical alignment was assessed on standing radiographs performed preoperatively, less than 2 months postoperatively, and greater than 6 months postoperatively. Allograft subsidence was assessed on CT scan performed at least 6 months postoperatively. Patients with at least 1 level demonstrating greater than 4mm of cage subsidence were classified as severe subsidence. Student's t-test was used to compare all means between groups. RESULTS: We identified 66 patients for inclusion, including 56 patients with non-severe subsidence and 10 patients with severe subsidence. For the entire cohort, there was a significant increase in C2-7 Lordosis (p = 0.005) and Segmental Lordosis (p < 0.00 001) from preoperative to early postoperative. On comparison of severely and non-severely subsided levels, severely subsided levels demonstrated a significantly greater loss of segmental lordosis from early to mid-term follow-up than non-severely subsided levels (-4.89 versus -2.59 degrees, p < 0.0001), manifesting as a significantly lower segmental lordosis at >6 months postoperative (0.54 versus 3.82 degrees, p < 0.00 001). There were no significant differences in global cervical alignment parameters between patients with severe and non-severe subsidence. CONCLUSIONS: Severe subsidence is associated with a significant increase in loss of segmental lordosis, but has minimal effect on global cervical alignment parameters.

Anterior Shoulder Instability in Throwers and Overhead Athletes: Long-term Outcomes in a Geographic Cohort.

BACKGROUND: Athletes of all sports often have shoulder instability, most commonly as anterior shoulder instability (ASI). For overhead athletes (OHAs) and those participating in throwing sports, clinical and surgical decision making can be difficult owing to a lack of long-term outcome studies in this population of athletes. PURPOSE/HYPOTHESIS: To report presentation characteristics, pathology, treatment strategies, and outcomes of ASI in OHAs and throwers in a geographic cohort. We hypothesized that OHAs and throwers would have similar presenting characteristics, management strategies, and clinical outcomes but lower rates of return to play (RTP) when compared with non-OHAs (NOHAs) and nonthrowers, respectively. STUDY DESIGN: Cohort study; Level of evidence, 3. METHODS: An established geographic medical record system was used to identify OHAs diagnosed with ASI in the dominant shoulder. An overall 57 OHAs with ASI were matched 1:2 with 114 NOHAs with ASI. Of the OHAs, 40 were throwers. Sports considered overhead were volleyball, swimming, racquet sports, baseball, and softball, while baseball and softball composed the thrower subgroup. Records were reviewed for patient characteristics, type of sport, imaging findings, treatment strategies, and surgical details. Patients were contacted to collect Western Ontario Shoulder Instability index (WOSI) scores and RTP data. Statistical analysis compared throwers with nonthrowers and OHAs with NOHAs. RESULTS: Four patients, 3 NOHAs and 1 thrower, were lost to follow-up at 6 months. Clinical follow-up for the remaining 167 patients (98%) was 11.9 ± 7.2 years (mean ± SD). Of the 171 patients included, an overall 41 (36%) NOHAs, 29 (51%) OHAs, and 22 (55%) throwers were able to be contacted for WOSI scores and RTP data. OHAs were more likely to initially present with subluxations (56%; P = .030). NOHAs were more likely to have dislocations (80%; P = .018). The number of instability events at presentation was similar. OHAs were more likely to undergo initial operative management. Differences in rates of recurrent instability were not significant after initial nonoperative management (NOHAs, 37.1% vs OHAs, 28.6% [P = .331] and throwers, 21.2% [P = .094]) and surgery (NOHAs, 20.5% vs OHAs, 13.0% [P = .516] and throwers, 9.1% [P = .662]). Rates of revision surgery were similar (NOHAs, 18.0% vs OHAs, 8.7% [P = .464] and throwers, 18.2% [P > .999]). RTP rates were 80.5% in NOHAs, as compared with 71.4% in OHAs (P = .381) and 63.6% in throwers (P = .143). Median WOSI scores were 40 for NOHAs, as compared with 28 in OHAs (P = .425) and 28 in throwers (P = .615). CONCLUSION: In a 1:2 matched comparison of general population athletes, throwers and OHAs were more likely to have more subtle instability, as evidenced by higher rates of subluxations rather than frank dislocations, when compared with NOHAs. Despite differences in presentation and the unique sport demands of OHAs, rates of recurrent instability and revision surgery were similar across groups. Similar outcomes in terms of RTP, level of RTP, and WOSI scores were achieved for OHAs and NOHAs, but these results must be interpreted with caution given the limited sample size.

Detectability and impact of repetitive surveys on threatened West African crocodylians.

West African crocodylians are among the most threatened and least studied crocodylian species globally. Assessing population status and establishing a basis for population monitoring is the highest priority action for this region. Monitoring of crocodiles is influenced by many factors that affect detectability, including environmental variables and individual- or population-level wariness. We investigated how these factors affect detectability and counts of the critically endangered Mecistops cataphractus and the newly recognized Crocodylus suchus. We implemented 195 repetitive surveys at 38 sites across Côte d'Ivoire between 2014 and 2019. We used an occupancy-based approach and a count-based GLMM analysis to determine the effect of environmental and anthropogenic variables on detection and modeled crocodile wariness over repetitive surveys. Despite their rarity and level of threat, detection probability of both species was relatively high (0.75 for M. cataphractus and 0.81 for C. suchus), but a minimum of two surveys were required to infer absence of either species with 90% confidence. We found that detection of M. cataphractus was significantly negatively influenced by fishing net encounter rate, while high temperature for the previous 48 h of the day of the survey increased C. suchus detection. Precipitation and aquatic vegetation had significant negative and positive influence, respectively, on M. cataphractus counts and showed the opposite effect for C. suchus counts. We also found that fishing encounter rate had a significant negative effect on C. suchus counts. Interestingly, survey repetition did not generally affect wariness for either species, though there was some indication that at least M. cataphractus was more wary by the fourth replicate. These results are informative for designing future survey and monitoring protocols for these threatened crocodylians in West Africa and for other endangered crocodylians globally.

The Open Triradiate Cartilage: How Young Is Too Young for Total Hip Arthroplasty?

BACKGROUND: There is, to our knowledge, no published literature regarding primary total hip arthroplasty (THA) in pediatric patients with an open triradiate cartilage. The purpose of this study was to report the outcomes following primary THA in pediatric patients with open triradiate cartilage at a single intuition. METHODS: Using a single institution's Total Joint Registry, 12 patients (13 hips) were identified as having undergone primary THA with open triradiate cartilage between the years of 2000 and 2019. The mean age and body mass index of this group were 13.1 years and 25.5 kg/m2, respectively. The cohort was composed of 10 males, and the mean follow up was 5.5 years. Indications for surgery, functional outcomes, and radiographic signs of stable fixation were analyzed. RESULTS: The most common indication for surgery was avascular necrosis secondary to corticosteroid use (31%), followed by avascular necrosis after operative management of slipped capital femoral epiphysis (23%). The proportion of patients able to achieve independent, gait-aid free, ambulation improved from 23% to 100%. Mean postoperative Harris Hip Score was 92.3. All constructs were cementless, and bearing surfaces included ceramic-on-ceramic in 62% and ceramic on highly crosslinked polyethylene bearings in the remainder. Radiographic review at final follow up demonstrated osseointegration in 12 of 13 (92%) acetabular components. Although 1 patient experienced both acetabular component loosening and instability, on separate occasions, there were no incidences of infection, wound dehiscence, thromboembolic events, or failure secondary to wear. CONCLUSIONS: In this study, THA in patients with an open triradiate cartilage yielded significant clinical improvement, low complication rates and good initial implant survivorship at early follow up. Awaiting closure of the triradiate cartilage for concerns of decreased fixation and implant survivorship may be unnecessary. LEVEL OF EVIDENCE: Level IV-case series.

Increased risk of periprosthetic joint infection after acute, traumatic wound dehiscence following primary total knee arthroplasty.

AIMS: To describe the risk of periprosthetic joint infection (PJI) and reoperation in patients who have an acute, traumatic wound dehiscence following total knee arthroplasty (TKA). METHODS: From January 2002 to December 2018, 16,134 primary TKAs were performed at a single institution. A total of 26 patients (0.1%) had a traumatic wound dehiscence within the first 30 days. Mean age was 68 years (44 to 87), 38% (n = 10) were female, and mean BMI was 34 kg/m2 (23 to 48). Median time to dehiscence was 13 days (interquartile range (IQR) 4 to 15). The dehiscence resulted from a fall in 22 patients and sudden flexion after staple removal in four. The arthrotomy was also disrupted in 58% (n = 15), including a complete extensor mechanism disruption in four knees. An irrigation and debridement with component retention (IDCR) was performed within 48 hours in 19 of 26 knees and two-thirds were discharged on antibiotic therapy. The mean follow-up was six years (2 to 15). The association of wound dehiscence and the risk of developing a PJI was analyzed. RESULTS: Patients who sustained a traumatic wound dehiscence had a 6.5-fold increase in the risk of PJI (95% confidence interval (CI) 1.6 to 26.2; p = 0.008). With the small number of PJIs, no variables were found to be significant risk factors. However, there were no PJIs in any of the patients who were treated with IDCR and a course of antibiotics. Three knees required reoperation including one two-stage exchange for PJI, one repeat IDCR for PJI, and one revision for aseptic loosening of the tibial component. CONCLUSION: Despite having a traumatic wound dehiscence, the risk of PJI was low, but much higher than experienced in all other TKAs during the same period. We recommend urgent IDCR and a course of postoperative antibiotics to decrease the risk of PJI. A traumatic wound dehiscence increases risk of PJI by 6.5-fold. Cite this article: Bone Joint J 2021;103-B(6 Supple A):191-195.

Use of continuous cranial shape variation in the identification of divergent crocodile species of the genus Mecistops.

The discovery of cryptic biodiversity has blossomed under the advancements of genetic techniques, but species identification via morphology remains crucial to effective conservation efforts. In this study, we tested the use of continuous cranial shape variation in distinguishing the two living species of Mecistops: the West African slender-snouted crocodile (M. cataphractus) and the Central African slender-snouted crocodile (M. leptorhynchus). Using a combination of geometric morphometric characters and ratios of linear measurements, we identified statistically significant variation in cranial bone and overall skull shape of mature individuals that corroborates existing molecular and discrete morphological evidence for two distinct, extant species within Mecistops. Specifically, variation in the shape of the nasal appears particularly diagnostic, while ratios involving metrics of snout length to snout width at the premaxillary notch offer distinguishing features easily measured in the field. Because of the complementary results and applications of the morphometric and cranial ratio analyses, we argue that both methodologies remain relevant to species identification. Moreover, we recommend continued cooperation between geneticists and morphologists in diagnosing species of conservation concern.

RAF-Mutant Melanomas Differentially Depend on ERK2 Over ERK1 to Support Aberrant MAPK Pathway Activation and Cell Proliferation.

Half of advanced human melanomas are driven by mutant BRAF and dependent on MAPK signaling. Interestingly, the results of three independent genetic screens highlight a dependency of BRAF-mutant melanoma cell lines on BRAF and ERK2, but not ERK1. ERK2 is expressed higher in melanoma compared with other cancer types and higher than ERK1 within melanoma. However, ERK1 and ERK2 are similarly required in primary human melanocytes transformed with mutant BRAF and are expressed at a similar, lower amount compared with established cancer cell lines. ERK1 can compensate for ERK2 loss as seen by expression of ERK1 rescuing the proliferation arrest mediated by ERK2 loss (both by shRNA or inhibition by an ERK inhibitor). ERK2 knockdown, as opposed to ERK1 knockdown, led to more robust suppression of MAPK signaling as seen by RNA-sequencing, qRT-PCR, and Western blot analysis. In addition, treatment with MAPK pathway inhibitors led to gene expression changes that closely resembled those seen upon knockdown of ERK2 but not ERK1. Together, these data demonstrate that ERK2 drives BRAF-mutant melanoma gene expression and proliferation as a function of its higher expression compared with ERK1. Selective inhibition of ERK2 for the treatment of melanomas may spare the toxicity associated with pan-ERK inhibition in normal tissues. IMPLICATIONS: BRAF-mutant melanomas overexpress and depend on ERK2 but not ERK1, suggesting that ERK2-selective inhibition may be toxicity sparing.

Inhibition of MDM2 Promotes Antitumor Responses in p53 Wild-Type Cancer Cells through Their Interaction with the Immune and Stromal Microenvironment.

p53 is a transcription factor that plays a central role in guarding the genomic stability of cells through cell-cycle arrest or induction of apoptosis. However, the effects of p53 in antitumor immunity are poorly understood. To investigate the role of p53 in controlling tumor-immune cell cross-talk, we studied murine syngeneic models treated with HDM201, a potent and selective second-generation MDM2 inhibitor. In response to HDM201 treatment, the percentage of dendritic cells increased, including the CD103+ antigen cross-presenting subset. Furthermore, HDM201 increased the percentage of Tbet+Eomes+ CD8+ T cells and the CD8+/Treg ratio within the tumor. These immunophenotypic changes were eliminated with the knockout of p53 in tumor cells. Enhanced expression of CD80 on tumor cells was observed in vitro and in vivo, which coincided with T-cell-mediated tumor cell killing. Combining HDM201 with PD-1 or PD-L1 blockade increased the number of complete tumor regressions. Responding mice developed durable, antigen-specific memory T cells and rejected subsequent tumor implantation. Importantly, antitumor activity of HDM201 in combination with PD-1/PD-L1 blockade was abrogated in p53-mutated and knockout syngeneic tumor models, indicating the effect of HDM201 on the tumor is required for triggering antitumor immunity. Taken together, these results demonstrate that MDM2 inhibition triggers adaptive immunity, which is further enhanced by blockade of PD-1/PD-L1 pathway, thereby providing a rationale for combining MDM2 inhibitors and checkpoint blocking antibodies in patients with wild-type p53 tumors. SIGNIFICANCE: This study provides a mechanistic rationale for combining checkpoint blockade immunotherapy with MDM2 inhibitors in patients with wild-type p53 tumors.

Humeral amputation following total elbow arthroplasty.

PURPOSE: Total elbow arthroplasty (TEA) is associated with a relatively high complication rate, and exceptionally catastrophic complications might lead to amputation. The purpose of this study was to determine the incidence and aetiology of amputation performed at our institution in upper extremity limbs with a prior TEA. METHODS: Between 1973 and 2018, 1906 consecutive TEAs were performed at our institution. Upper extremity amputation was performed in seven (0.36%) elbows with five transhumeral amputations and two shoulder disarticulations. The group consisted of five females and two males with a mean age of 64 years (range, 37-80). The index TEA had been performed for rheumatoid arthritis (n = 2), rheumatoid arthritis with acute fracture (n = 2), radiation associated nonunion (n = 2), and metastatic cancer (n = 1). Mean follow-up after amputation was three years (range, 3 months-5 years). RESULTS: Mean time between amputation and TEA was 5 years (range, 2 months-13 years). The indications for amputation included uncontrolled deep infection in six (86%) elbows and tumor recurrence in one (14%) elbow. Only one elbow (14%) was fitted with a prosthesis. Six (86%) patients died at a mean of three years (range, 3 months-5 years) after amputation. CONCLUSION: The results of this study highlight a low incidence of amputation after TEA. Most amputations were the direct result of TEA complications, with infection being the most common cause of amputation. Outcomes after amputation are concerning, with poor overall survival and few patients being fit for a prosthesis.

Hip Arthroplasty Following Subtotal Sacrectomy for Chordoma.

BACKGROUND/AIM: Chordomas often affect the sacrum with a high predilection for local-regional recurrence. Patients typically retain their ability to ambulate, and the development of metastatic disease in the periacetabular region can have significant morbidity and pain with ambulation. The purpose of the study was to describe the outcome of patients undergoing a hip arthroplasty following resection of a sacral chordoma. PATIENTS AND METHODS: From 1990 to 2015, 84 patients underwent sacrectomy for chordoma, while four of these (5%) patients underwent hip arthroplasty. The most common level of nerve root sacrifice was S2-5 (n=2). The mean time between sacrectomy and hip arthroplasty was 7 years. Indications for arthroplasty included metastatic disease (n=3) and coxarthrosis (n=1). RESULTS: Postoperatively two patients ambulated with a gait aid, and no patient had a Trendelenburg gait. The mean Harris Hip Score significantly improved from 49 to 80 postoperatively (p=0.02). CONCLUSION: The results of this study indicate that hip arthroplasty is a durable treatment option for patients with metastatic disease or coxarthrosis following subtotal sacrectomy for chordoma.

Opportunistic Computed Tomography and Spine Surgery: A Narrative Review.

STUDY DESIGN: Narrative review. OBJECTIVE: This article seeks to provide a narrative review regarding the ability of opportunistic information available from computed tomography (CT) scans to guide decisions in spine surgery related to patient bone quality. METHODS: A review of the literature (limited to human and English language) was performed via PubMed and Google Scholar using the search terms; "osteoporosis" AND "opportunistic" AND "computed tomography" AND "spine surgery." The titles and then abstracts of all identified citations were reviewed for inclusion by 2 of the authors (MS, BAF). Relevant articles were then studied in full text. RESULTS: A review of the literature found 25 articles that were selected for inclusion in this narrative review. These articles were broadly divided into 4 subcategories: (1) opportunistic CT (oCT) and osteoporosis detection, (2) oCT data and the quality of screw fixation, (3) utilization of Hounsfield units to assess clinical and/or radiographic outcomes following spine fusion, and (4) virtual stress testing in spine surgery. CONCLUSION: The literature on oCT, as well as associated virtual stress-testing techniques, demonstrate the potential to enhance spine surgery outcomes by preoperatively identifying at-risk patients in need of bone health optimization and informing best techniques for performing spinal fusion surgery on patients with diminished bone quality. While our narrative summary of the limited literature to date suggests a promising future for oCT data, significant additional research and/or radiographic workflow standardization is needed to validate these methods for clinical use.

The Discovery of SWI/SNF Chromatin Remodeling Activity as a Novel and Targetable Dependency in Uveal Melanoma.

Uveal melanoma is a rare and aggressive cancer that originates in the eye. Currently, there are no approved targeted therapies and very few effective treatments for this cancer. Although activating mutations in the G protein alpha subunits, GNAQ and GNA11, are key genetic drivers of the disease, few additional drug targets have been identified. Recently, studies have identified context-specific roles for the mammalian SWI/SNF chromatin remodeling complexes (also known as BAF/PBAF) in various cancer lineages. Here, we find evidence that the SWI/SNF complex is essential through analysis of functional genomics screens and further validation in a panel of uveal melanoma cell lines using both genetic tools and small-molecule inhibitors of SWI/SNF. In addition, we describe a functional relationship between the SWI/SNF complex and the melanocyte lineage-specific transcription factor Microphthalmia-associated Transcription Factor, suggesting that these two factors cooperate to drive a transcriptional program essential for uveal melanoma cell survival. These studies highlight a critical role for SWI/SNF in uveal melanoma, and demonstrate a novel path toward the treatment of this cancer.