ABSTRACT
OBJECTIVES: Inactivating GNAS mutations result in varied phenotypes depending on parental origin. Maternally inherited mutations typically lead to hormone resistance and Albright's hereditary osteodystrophy (AHO), characterised by short stature, round facies, brachydactyly and subcutaneous ossifications. Paternal inheritance presents with features of AHO or ectopic ossification without hormone resistance. This report describes the case of a child with osteoma cutis and medulloblastoma. The objective of this report is to highlight the emerging association between inactivating germline GNAS mutations and medulloblastoma, aiming to shed light on its implications for tumor biology and promote future development of targeted surveillance strategies to improve outcomes in paediatric patients with these mutations. CASE PRESENTATION: A 12-month-old boy presented with multiple plaque-like skin lesions. Biopsy confirmed osteoma cutis, prompting genetic testing which confirmed a heterozygous inactivating GNAS mutation. At 2.5 years of age, he developed neurological symptoms and was diagnosed with a desmoplastic nodular medulloblastoma, SHH molecular group, confirmed by MRI and histology. Further analysis indicated a biallelic loss of GNAS in the tumor. CONCLUSIONS: This case provides important insights into the role of GNAS as a tumor suppressor and the emerging association between inactivating GNAS variants and the development of medulloblastoma. The case underscores the importance of careful neurological assessment and ongoing vigilance in children with known inactivating GNAS variants or associated phenotypes. Further work to establish genotype-phenotype correlations is needed to inform optimal management of these patients.
Subject(s)
Cerebellar Neoplasms , Chromogranins , GTP-Binding Protein alpha Subunits, Gs , Medulloblastoma , Ossification, Heterotopic , Skin Diseases, Genetic , Humans , GTP-Binding Protein alpha Subunits, Gs/genetics , Male , Chromogranins/genetics , Medulloblastoma/genetics , Medulloblastoma/pathology , Ossification, Heterotopic/genetics , Ossification, Heterotopic/pathology , Skin Diseases, Genetic/genetics , Skin Diseases, Genetic/pathology , Skin Diseases, Genetic/complications , Infant , Cerebellar Neoplasms/genetics , Cerebellar Neoplasms/pathology , Cerebellar Neoplasms/complications , Prognosis , Bone Diseases, Metabolic/genetics , Bone Diseases, Metabolic/pathology , MutationABSTRACT
BACKGROUND: Opioid prescribing in the context of orthopaedic surgery has been recognized as having a critical role in the ongoing opioid epidemic. Given the negative consequences of chronic opioid use, great efforts have been made to reduce both preoperative and postoperative opioid prescribing and consumption in orthopaedic surgery. Musculoskeletal oncology patients represent a unique subset of patients, and there is a paucity of data evaluating perioperative opioid consumption and the risk for chronic use. The objective of the present study was to describe opioid consumption patterns and evaluate predictors of chronic opioid use in musculoskeletal oncology patients undergoing limb-salvage surgery and endoprosthetic reconstruction. METHODS: The present study was a secondary analysis of the recently completed PARITY (Prophylactic Antibiotic Regimens in Tumor Surgery) trial and included musculoskeletal oncology patients undergoing lower-extremity endoprosthetic reconstruction. The primary outcome was the incidence of opioid consumption over the study period. A multivariate binomial logistic regression model was created to explore predictors of chronic opioid consumption at 1 year postoperatively. RESULTS: Overall, 193 (33.6%) of 575 patients were consuming opioids preoperatively. Postoperatively, the number of patients consuming opioids was 82 (16.7%) of 492 at 3 months, 37 (8%) of 460 patients at 6 months, and 28 (6.6%) of 425 patients at 1 year. Of patients consuming opioids preoperatively, 12 (10.2%) of 118 had continued to consume opioids at 1 year postoperatively. The adjusted regression model found that only surgery for metastatic bone disease was predictive of chronic opioid use (odds ratio, 4.90; 95% confidence interval, 1.54 to 15.40; p = 0.007). Preoperative opioid consumption, older age, sex, longer surgical times, reoperation rates, and country of origin were not predictive of chronic use. CONCLUSIONS: Despite a high prevalence of preoperative opioid use, an invasive surgical procedure, and a high rate of reoperation, few patients had continued to consume opioids at 1 year postoperatively. The presence of metastases was associated with chronic opioid use. These results are a substantial departure from the existing orthopaedic literature evaluating other patient populations, and they suggest that specific prescribing guidelines are warranted for musculoskeletal oncology patients. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.
Subject(s)
Neoplasms , Opioid-Related Disorders , Humans , Analgesics, Opioid/therapeutic use , Opioid-Related Disorders/prevention & control , Pain, Postoperative/etiology , Practice Patterns, Physicians' , Retrospective StudiesABSTRACT
BACKGROUND: Although the treatment of lower-extremity bone tumors is similar between adult and pediatric patients, differences in outcomes are unknown. Outcomes for lower-extremity oncologic reconstruction have been challenging to study because of the low incidence and heterogeneity in disease and patient characteristics. The PARITY (Prophylactic Antibiotic Regimens in Tumor Surgery) trial is the largest prospective data set assembled to date for patients with lower-extremity bone tumors and presents an opportunity to investigate differences in outcomes between these groups. METHODS: Patient details were acquired from the prospectively collected PARITY trial database. The 1993 Musculoskeletal Tumor Society (MSTS-93) and Toronto Extremity Salvage Score (TESS) questionnaires were administered preoperatively and at 3, 6, and 12 months postoperatively. Continuous outcomes were compared between groups with use of the Student t test, and dichotomous outcomes were compared with use of the Pearson chi-square test. RESULTS: A total of 150 pediatric and 447 adult patients were included. Pediatric patients were more likely than adult patients to have a primary bone tumor (146 of 150 compared with 287 of 447, respectively; p < 0.001) and to have received adjuvant chemotherapy (140 of 149 compared with 195 of 441, respectively; p < 0.001). Reoperation rates were not significantly different between age groups (45 of 105 pediatric patients compared with 106 of 341 adult patients; p ≤ 0.13). Pediatric patients had higher mean MSTS-93 scores (64.7 compared with 53.8 among adult patients; p < 0.001) and TESS (73.4 compared with 60.4 among adult patients; p < 0.001) at baseline, which continued to 1 year postoperatively (mean MSTS-93 score, 82.0 compared with 76.8 among adult patients; p = 0.02; mean TESS, 87.7 compared with 78.6 among adult patients; p < 0.001). Despite the differences in outcomes between cohorts, pediatric and adult patients demonstrated similar improvement in MSTS-93 scores (mean difference, 17.4 and 20.0, respectively; p = 0.48) and TESS (mean difference, 14.1 and 14.7, respectively; p = 0.83) from baseline to 1 year postoperatively. CONCLUSIONS: Pediatric patients had significantly better functional outcomes than adult patients at nearly all of the included postoperative time points; however, pediatric and adult patients showed similar mean improvement in these outcomes at 1 year postoperatively. These findings may be utilized to help guide the postoperative expectations of patients undergoing oncologic reconstruction. LEVEL OF EVIDENCE: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence.
Subject(s)
Bone Neoplasms , Plastic Surgery Procedures , Adult , Child , Humans , Bone Neoplasms/surgery , Bone Neoplasms/pathology , Limb Salvage , Lower Extremity/surgery , Prospective Studies , Treatment OutcomeABSTRACT
Cancer metastasis to the brain is a significant clinical problem. Metastasis is the consequence of favorable interactions between invaded cancer cells and the microenvironment. Here, we demonstrate that cancer-activated astrocytes create a sustained low-level activated type I interferon (IFN) microenvironment in brain metastatic lesions. We further confirm that the IFN response in astrocytes facilitates brain metastasis. Mechanistically, IFN signaling in astrocytes activates C-C Motif Chemokine Ligand 2 (CCL2) production, which further increases the recruitment of monocytic myeloid cells. The correlation between CCL2 and monocytic myeloid cells is confirmed in clinical brain metastasis samples. Lastly, genetically or pharmacologically inhibiting C-C Motif Chemokine Receptor 2 (CCR2) reduces brain metastases. Our study clarifies a pro-metastatic effect of type I IFN in the brain even though IFN response has been considered to have anti-tumor effects. Moreover, this work expands our understandings on the interactions between cancer-activated astrocytes and immune cells in brain metastasis.
Subject(s)
Brain Neoplasms , Interferon Type I , Humans , Interferon Type I/metabolism , Astrocytes/metabolism , Chemokine CCL2/metabolism , Myeloid Cells/metabolism , Brain Neoplasms/pathology , Receptors, CCR2/metabolism , Tumor MicroenvironmentABSTRACT
In this study the aim was to resolve the taxonomy of several species of Argyria Hübner (Pyraloidea, Crambinae) with previously unrecognised morphological variation. By analysing the DNA barcode (COI-5P) in numerous specimens, the aim was to reconstruct phylogenetic relationships between species, to provide better evidence for synonymies, and to circumscribe their geographical distribution. Using an innovative DNA hybridisation capture protocol, the DNA barcode of the lectotype of Argyrialacteella (Fabricius, 1794) was partially recovered for comparison with the 229 DNA barcode sequences of Argyria specimens available in the Barcode of Life Datasystems, and this firmly establishes the identity of the species. The same protocol was used for the following type specimens: the Argyriaabronalis (Walker, 1859) holotype, thus confirming the synonymy of this name with A.lacteella, the holotype of A.lusella (Zeller, 1863), syn. rev., the holotype of A.multifacta Dyar, 1914, syn. nov. newly synonymised with A.lacteella, and a specimen of Argyriadiplomochalis Dyar, 1913, collected in 1992. In addition, nine specimens of A.lacteella, A.diplomochalis, A.centrifugens Dyar, 1914 and A.gonogramma Dyar, 1915, from North to South America were sampled using classical COI amplification and Sanger sequencing. Argyriagonogramma Dyar, described from Bermuda, is the name to be applied to the more widespread North American species formerly identified as A.lacteella. Following morphological study of its holotype, Argyriavestalis Butler, 1878, syn. nov. is also synonymised with A.lacteella. The name A.pusillalis Hübner, 1818, is considered a nomen dubium associated with A.gonogramma. The adult morphology is diagnosed and illustrated, and distributions are plotted for A.lacteella, A.diplomochalis, A.centrifugens, and A.gonogramma based on slightly more than 800 specimens. For the first time, DNA barcode sequences are provided for the Antillean A.diplomochalis. This work provides a modified, improved protocol for the efficient hybrid capture enrichment of DNA barcodes from 18th and 19th century type specimens in order to solve taxonomic issues in Lepidoptera.
ABSTRACT
Pediatric central nervous system (CNS) tumors represent the most common cause of cancer-related death in children aged 0-14 years. They differ from their adult counterparts, showing extensive clinical and molecular heterogeneity as well as a challenging histopathological spectrum that often impairs accurate diagnosis. Here, we use DNA methylation-based CNS tumor classification in combination with copy number, RNA-seq, and ChIP-seq analysis to characterize a newly identified CNS tumor type. In addition, we report histology, patient characteristics, and survival data in this tumor type. We describe a biologically distinct pediatric CNS tumor type (n = 31 cases) that is characterized by focal high-level amplification and resultant overexpression of either PLAGL1 or PLAGL2, and an absence of recurrent genetic alterations characteristic of other pediatric CNS tumor types. Both genes act as transcription factors for a regulatory subset of imprinted genes (IGs), components of the Wnt/ß-Catenin pathway, and the potential drug targets RET and CYP2W1, which are also specifically overexpressed in this tumor type. A derived PLAGL-specific gene expression signature indicates dysregulation of imprinting control and differentiation/development. These tumors occurred throughout the neuroaxis including the cerebral hemispheres, cerebellum, and brainstem, and were predominantly composed of primitive embryonal-like cells lacking robust expression of markers of glial or neuronal differentiation (e.g., GFAP, OLIG2, and synaptophysin). Tumors with PLAGL1 amplification were typically diagnosed during adolescence (median age 10.5 years), whereas those with PLAGL2 amplification were diagnosed during early childhood (median age 2 years). The 10-year overall survival was 66% for PLAGL1-amplified tumors, 25% for PLAGL2-amplified tumors, 18% for male patients, and 82% for female patients. In summary, we describe a new type of biologically distinct CNS tumor characterized by PLAGL1/2 amplification that occurs predominantly in infants and toddlers (PLAGL2) or adolescents (PLAGL1) which we consider best classified as a CNS embryonal tumor and which is associated with intermediate survival. The cell of origin and optimal treatment strategies remain to be defined.
Subject(s)
Central Nervous System Neoplasms , Neuroectodermal Tumors, Primitive , Child , Child, Preschool , Female , Humans , Infant , Male , Cell Cycle Proteins/genetics , Central Nervous System Neoplasms/genetics , DNA Methylation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Neuroectodermal Tumors, Primitive/genetics , RNA-Binding Proteins/genetics , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Suppressor Proteins/genetics , Wnt Signaling Pathway/geneticsABSTRACT
BACKGROUND: Expandable endoprostheses can be used to equalize limb length for pediatric patients requiring reconstruction following large bony oncologic resections. Outcomes of the Compress® Compliant Pre-Stress (CPS) spindle paired with an Orthopedic Salvage System expandable distal femur endoprosthesis have not been reported. METHODS: We conducted a multi-institutional retrospective study of pediatric patients with distal femoral bone sarcomas reconstructed with the above endoprostheses. Statistical analysis utilized Kaplan-Meier survival technique and competing risk analysis. RESULTS: Thirty-six patients were included from five institutions. Spindle survivorship was 86.3% (95% confidence interval [CI], 67.7-93.5) at 10 years. Two patients had a failure of osseointegration (5.7%), both within 12 months. Twenty-two (59%) patients had 70 lengthening procedures, with mean expansions of 3.2 cm (range: 1-9) over 3.4 surgeries. The expandable mechanism failed in eight patients with a cumulative incidence of 16.1% (95% CI, 5.6-31.5) at 5 years. Twenty-nine patients sustained International Society of Limb Salvage failures requiring 63 unplanned surgeries. Periprosthetic joint infection occurred in six patients (16.7%). Limb preservation rate was 91% at 10 years. CONCLUSIONS: There is a high rate of osseointegration of the Compress® spindle among pediatric patients when coupled with an expandable implant. However, there is a high rate of expansion mechanism failure and prosthetic joint infections requiring revision surgery. LEVEL OF EVIDENCE: Level IV, therapeutic study.
Subject(s)
Bone Neoplasms , Femoral Neoplasms , Child , Humans , Femoral Neoplasms/surgery , Prosthesis Design , Retrospective Studies , Prosthesis Implantation/methods , Prosthesis Failure , Osteotomy , Treatment Outcome , Risk Factors , Femur/surgery , Reoperation , Bone Neoplasms/surgeryABSTRACT
Most children with high-risk Langerhans cell histiocytosis (LCH) have BRAFV600E mutation. BRAFV600E alleles are detectable in myeloid mononuclear cells at diagnosis but it is not known if the cellular distribution of mutation evolves over time. Here, the profiles of 16 patients with high-risk disease were analyzed. Two received conventional salvage chemotherapy, 4 patients on inhibitors were tracked at intervals of 3 to 6 years, and 10 patients, also given inhibitors, were analyzed more than 2 years after diagnosis. In contrast to the patients responding to salvage chemotherapy who completely cleared BRAFV600E within 6 months, children who received inhibitors maintained high BRAFV600E alleles in their blood. At diagnosis, mutation was detected predominantly in monocytes and myeloid dendritic cells. With time, mutation switched to the T-cell compartment, which accounted for most of the mutational burden in peripheral blood mononuclear cells, more than 2 years from diagnosis (median, 85.4%; range, 44.5%-100%). The highest level of mutation occurred in naïve CD4+ T cells (median, 51.2%; range, 3.8%-93.5%). This study reveals an unexpected lineage switch of BRAFV600E mutation in high-risk LCH, which may influence monitoring strategies for the potential withdrawal of inhibitor treatment and has new implications for the pathogenesis of neurodegeneration, which occurred in 4 patients.
Subject(s)
Dendritic Cells , Histiocytosis, Langerhans-Cell , Monocytes , T-Lymphocytes , Humans , Dendritic Cells/pathology , Histiocytosis, Langerhans-Cell/genetics , Histiocytosis, Langerhans-Cell/pathology , Leukocytes, Mononuclear , Monocytes/pathology , Mutation , Male , Female , Infant , Child, Preschool , T-Lymphocytes/pathology , Cell Lineage/geneticsABSTRACT
The identity of Syllepte Hbner, 181921 is revised by designating a neotype from Neomabra Dognin, 1905, rev. syn., for the type species S. incomptalis Hbner, 181921 because the original type material is lost, and we consider it to be congeneric with Syllepte. We redescribe Syllepte based on S. incomptalis and S. nitidalis (Dognin, 1905), rev. comb., and place Syllepte in Agroterini Acloque, 1897, and consequently synonymize Syleptinae [sic] Swinhoe, 1900, syn. rev., with Agroterini. Pantographa Lederer, 1863 and Micromartinia Amsel, 1957 are redescribed, diagnosed, and restored to their status as valid genera, rev. stat., also in the tribe Agroterini. We designate lectotypes for Neomabra nitidalis Dognin, 1905, new lectotype, rev. comb., and Pantographa scripturalis (Guene, 1854), new lectotype, rev. stat., to stabilize the names of these species. Pantographa is compared to Haritalodes Warren, 1890. We newly combine Pantographa gorgonalis Druce, 1895, n. comb., rev. stat., and Pilocrocis cyrisalis (Druce, 1895), n. comb., with Micromartinia. One hundred and ninety-six species are listed that remain misplaced in the polyphyletic Syllepte and need further revision to determine their identity and proper generic placement.
Subject(s)
Lepidoptera , Moths , Songbirds , AnimalsABSTRACT
We identify ADIRF-AS1 circadian long non-coding RNA (lncRNA). Deletion of ADIRF-AS1 in U2OS cells alters rhythmicity of clock-controlled genes and expression of extracellular matrix genes. ADIRF-AS1 interacts with all components of the PBAF (PBRM1/BRG1) complex in U2OS cells. Because PBRM1 is a tumor suppressor mutated in over 40% of clear cell renal carcinoma (ccRCC) cases, we evaluate ADIRF-AS1 in ccRCC cells. Reducing ADIRF-AS1 expression in ccRCC cells decreases expression of some PBAF-suppressed genes. Expression of these genes is partially rescued by PBRM1 loss, consistent with ADIRF-AS1 acting in part to modulate PBAF. ADIRF-AS1 expression correlates with survival in human ccRCC, particularly in PBRM1 wild-type, but not mutant, tumors. Loss of ADIRF-AS1 eliminates in vivo tumorigenesis, partially rescued by concurrent loss of PBRM1 only when co-injected with Matrigel, suggesting a PBRM1-independent function of ADIRF-AS1. Our findings suggest that ADIRF-AS1 functions partly through PBAF to regulate specific genes as a BMAL1-CLOCK-regulated, oncogenic lncRNA.
Subject(s)
Carcinoma, Renal Cell , Kidney Neoplasms , RNA, Long Noncoding , Humans , ARNTL Transcription Factors , Carcinogenesis/genetics , Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , RNA, Long Noncoding/geneticsABSTRACT
BACKGROUND: Wound complications are common after resection of soft tissue sarcomas, with published infection rates ranging from 10% to 35%. Multiple studies have reported on the atypical flora comprising these infections, which are often polymicrobial and contain anaerobic bacteria, and recent studies have noted the high prevalence of anaerobic bacterial infections after soft tissue sarcoma resection [ 26, 35 ]. Based on this, our institution changed clinical practice to include an antibiotic with anaerobic coverage in addition to the standard first-generation cephalosporin for prophylaxis during soft tissue sarcoma resections. The current study was undertaken to evaluate whether this change was associated with a change in major wound complications, and if the change should therefore be adopted for future patients. QUESTIONS/PURPOSES: (1) After controlling for potentially confounding variables, was the broadening of the prophylactic antibiotic spectrum to cover anaerobic bacteria associated with a lower odds of major wound complications after soft tissue sarcoma resection? (2) Was the broadening of the prophylactic antibiotic spectrum to cover anaerobic bacteria associated with a lower odds of surgical site infections with polymicrobial or anaerobic infections after soft tissue sarcoma resection? (3) What are the factors associated with major wound complications after soft tissue sarcoma resection? METHODS: We retrospectively identified 623 patients who underwent soft tissue sarcoma resection at a single center between January 2008 and January 2021 using procedural terminology codes. Of these, four (0.6%) pediatric patients were excluded, as were five (0.8%) patients with atypical lipomatous tumors and two (0.3%) patients with primary bone tumors; 5% (33 of 623) who were lost to follow-up, leaving 579 for final analysis. The prophylactic antibiotic regimen given at the resection and whether a wound complication occurred were recorded. Patients received the augmented regimen based on whether they underwent resection after the change in practice in July 2018. A total of 497 patients received a standard antibiotic regimen (usually a first-generation cephalosporin), and 82 patients received an augmented regimen with anaerobic coverage (most often metronidazole). Of the 579 patients, 53% (307) were male (53% [264 of 497] in the standard regimen and 52% [43 of 82] in the augmented regimen), and the mean age was 59 ± 17 years (59 ± 17 and 60 ±17 years in the standard and augmented groups, respectively). Wound complications were defined as any of the following within 120 days of the initial resection: formal wound debridement in the operating room, other interventions such as percutaneous drain placement, readmission for intravenous antibiotics, or deep wound packing for more than 120 days from the resection. Patients were considered to have a surgical site infection if positive cultures resulted from deep tissue cultures taken intraoperatively at the time of debridement. The proportion of patients with major wound complications was 26% (150 of 579); it was 27% (136 of 497) and 17% (14 of 82) in the standard and augmented antibiotic cohorts, respectively (p = 0.049). With the numbers we had, we could not document that the addition of antibiotics with anaerobic coverage was associated with lower odds of anaerobic (4% versus 6%; p = 0.51) or polymicrobial infections (9% versus 14%; p = 0.25). Patient, tumor, and treatment (surgical, radiotherapy, and chemotherapy) variables were collected to evaluate factors associated with overall infection and anaerobic or polymicrobial infection. Patient follow-up was 120 days to capture early wound complications. A multivariable analysis was performed for all variables found to be significant in the univariate analysis. A p value < 0.05 was used as the threshold for statistical significance for all analyses. No patients were found to have an adverse reaction to the augmented regimen, including allergic reactions or Clostridioides (formerly Clostridium) difficile infection. RESULTS: After controlling for other potentially confounding factors such as neoadjuvant radiation, tumor size and anatomic location, as well as patient BMI, anaerobic coverage was associated with smaller odds of wound complications (OR 0.36 [95% confidence interval (CI) 0.18 to 0.68]; p = 0.003). Other factors associated with major wound complications were preoperative radiation (versus no preoperative radiation) (OR 2.66 [95% CI 1.72 to 4.15]; p < 0.001), increasing tumor size (OR 1.04 [95% CI 1.00 to 1.07]; p = 0.03), patient BMI (OR 1.07 [95% CI 1.04 to 1.11]; p < 0.001), and tumor in the distal upper extremity (versus proximal upper extremity, pelvis/groin/hip, and lower extremity) (OR 0.18 [95% CI 0.04 to 0.62]; p = 0.01). CONCLUSION: The addition of anaerobic coverage to the standard prophylactic regimen during soft tissue sarcoma resection demonstrated an association with smaller odds of major wound complications and no documented adverse reactions. Treating physicians should consider these findings but note that they are preliminary, and that further work is needed to replicate them in a more controlled study design such as a prospective trial. LEVEL OF EVIDENCE: Level III, therapeutic study.
Subject(s)
Antibiotic Prophylaxis , Sarcoma , Surgical Wound Infection , Adult , Aged , Female , Humans , Male , Middle Aged , Anaerobiosis , Anti-Bacterial Agents/therapeutic use , Cephalosporins , Prospective Studies , Retrospective Studies , Sarcoma/pathology , Sarcoma/surgery , Surgical Wound Infection/prevention & controlABSTRACT
IMPORTANCE: The use of perioperative, prophylactic, intravenous antibiotics is standard practice to reduce the risk of surgical site infection after oncologic resection and complex endoprosthetic reconstruction for lower extremity bone tumors. However, evidence guiding the duration of prophylactic treatment remains limited. OBJECTIVE: To assess the effect of a 5-day regimen of postoperative, prophylactic, intravenous antibiotics compared with a 1-day regimen on the rate of surgical site infections within 1 year after surgery. DESIGN, SETTING, AND PARTICIPANTS: This randomized clinical superiority trial was performed at 48 clinical sites in 12 countries from January 1, 2013, to October 29, 2019. The trial included patients with a primary bone tumor or a soft tissue sarcoma that had invaded the femur or tibia or oligometastatic bone disease of the femur or tibia with expected survival of at least 1 year who required surgical management by excision and endoprosthetic reconstruction. A total of 611 patients were enrolled, and 7 were excluded for ineligibility. INTERVENTIONS: A 1- or 5-day regimen of postoperative prophylactic intravenous cephalosporin (cefazolin or cefuroxime) that began within 8 hours after skin closure and was administered every 8 hours thereafter. Those randomized to the 1-day regimen received identical saline doses every 8 hours for the remaining 4 days; patients, care providers, and outcomes assessors were blinded to treatment regimen. MAIN OUTCOMES AND MEASURES: The primary outcome in this superiority trial was a surgical site infection (superficial incisional, deep incisional, or organ space) classified according to the criteria established by the Centers for Disease Control and Prevention within 1 year after surgery. Secondary outcomes included antibiotic-related complications, unplanned additional operations, oncologic and functional outcomes, and mortality. RESULTS: Of the 604 patients included in the final analysis (mean [SD] age, 41.2 [21.9] years; 361 [59.8%] male; 114 [18.9%] Asian, 43 [7.1%] Black, 34 [5.6%] Hispanic, 15 [2.5%] Indigenous, 384 [63.8%] White, and 12 [2.0%] other), 293 were randomized to a 5-day regimen and 311 to a 1-day regimen. A surgical site infection occurred in 44 patients (15.0%) allocated to the 5-day regimen and in 52 patients (16.7%) allocated to the 1-day regimen (hazard ratio, 0.93; 95% CI, 0.62-1.40; P = .73). Antibiotic-related complications occurred in 15 patients (5.1%) in the 5-day regimen and in 5 patients (1.6%) allocated to the 1-day regimen (hazard ratio, 3.24; 95% CI, 1.17-8.98; P = .02). Other secondary outcomes did not differ significantly between treatment groups. CONCLUSIONS AND RELEVANCE: This randomized clinical trial did not confirm the superiority of a 5-day regimen of postoperative intravenous antibiotics over a 1-day regimen in preventing surgical site infections after surgery for lower extremity bone tumors that required an endoprosthesis. The 5-day regimen group had significantly more antibiotic-related complications. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01479283.
Subject(s)
Antibiotic Prophylaxis , Bone Neoplasms , Adult , Anti-Bacterial Agents , Bone Neoplasms/drug therapy , Bone Neoplasms/surgery , Humans , Lower Extremity , Male , Surgical Wound Infection/drug therapy , Surgical Wound Infection/prevention & control , United StatesABSTRACT
A method is presented for correlating phylogenetic characters through cladistic analysis. It extends the use of phylogenetic datasets for diagnostic purposes. It improves matrix-based identification tools by predicting novel character-state combinations that were not observed when the key was constructed. By interpreting homoplasy as analytical error, hypothetical character-state combinations are tested for the homoplasy that they would add to the shortest tree(s). The correlation is equal to the homoplasy summed across all state combinations, divided by a maximum possible value. The results depend on uncertainty about the sequence of state transitions and their overlap among characters. A correlation index r is proposed for sets of non-additive characters; it is a kind of multiple-regression value, and its ensemble value R is a statistic of a whole matrix. This approach can be used to select sets of the best "proxy" characters to substitute for unobservable characters of interest. The concept can be extended to continuous characters. Worked examples are given with datasets of various insect orders.
Subject(s)
Phylogeny , AnimalsABSTRACT
OBJECTIVES: To determine the proportion of patients with extremity sarcoma who would be willing to participate in a clinical trial in which they would be randomised to one of four different postoperative sarcoma surveillance regimens. Additionally, we assessed patients' perspectives on the burden of cancer care, factors that influence comfort with randomisation and the importance of cancer research. DESIGN: Prospective, cross-sectional patient survey. SETTING: Outpatient sarcoma clinics in Canada, the USA and Spain between May 2017 and April 2020. Survey data were entered into a study-specific database. PARTICIPANTS: Patients with extremity sarcoma who had completed definitive treatment from seven clinics across Canada, the USA and Spain. MAIN OUTCOME MEASURES: The proportion of patients with extremity sarcoma who would be willing to participate in a randomised controlled trial (RCT) that evaluates varying postoperative cancer surveillance regimens. RESULTS: One hundred thirty complete surveys were obtained. Respondents reported a wide range of burdens related to clinical care and surveillance. The majority of patients (85.5%) responded that they would agree to participate in a cancer surveillance RCT if eligible. The most common reason to participate was that they wanted to help future patients. Those that would decline to participate most commonly reported that participating in research would be too much of a burden for them at a time when they are already feeling overwhelmed. However, most patients agreed that cancer research will help doctors better understand and treat cancer. CONCLUSIONS: These results demonstrate that most participants would be willing to participate in an RCT that evaluates varying postoperative cancer surveillance regimens. Participants' motivation for trial participation included altruistic reasons to help future patients and deterrents to trial participation included the overwhelming burden of a cancer diagnosis. These results will help inform the development of patient-centred RCT protocols in sarcoma surveillance research. LEVEL OF EVIDENCE: V.
Subject(s)
Motivation , Sarcoma , Canada , Cross-Sectional Studies , Humans , Randomized Controlled Trials as Topic , Sarcoma/therapy , SpainABSTRACT
Anti-PD-1 therapy is used as a front-line treatment for many cancers, but mechanistic insight into this therapy resistance is still lacking. Here we generate a humanized (Hu)-mouse melanoma model by injecting fetal liver-derived CD34+ cells and implanting autologous thymus in immune-deficient NOD-scid IL2Rγnull (NSG) mice. Reconstituted Hu-mice are challenged with HLA-matched melanomas and treated with anti-PD-1, which results in restricted tumor growth but not complete regression. Tumor RNA-seq, multiplexed imaging and immunohistology staining show high expression of chemokines, as well as recruitment of FOXP3+ Treg and mast cells, in selective tumor regions. Reduced HLA-class I expression and CD8+/Granz B+ T cells homeostasis are observed in tumor regions where FOXP3+ Treg and mast cells co-localize, with such features associated with resistance to anti-PD-1 treatment. Combining anti-PD-1 with sunitinib or imatinib results in the depletion of mast cells and complete regression of tumors. Our results thus implicate mast cell depletion for improving the efficacy of anti-PD-1 therapy.
Subject(s)
Drug Resistance, Neoplasm , Lymphocytes, Tumor-Infiltrating/immunology , Mast Cells/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Animals , B-Lymphocytes/drug effects , B-Lymphocytes/immunology , Drug Resistance, Neoplasm/drug effects , Humans , Immune Checkpoint Inhibitors/pharmacology , Lymphocytes, Tumor-Infiltrating/drug effects , Mast Cells/drug effects , Melanoma/immunology , Melanoma/pathology , Melanoma/therapy , Mice, Transgenic , Programmed Cell Death 1 Receptor/metabolism , Sunitinib/pharmacology , Sunitinib/therapeutic use , T-Lymphocytes/drug effects , T-Lymphocytes/immunologyABSTRACT
Liquid-liquid phase separation (LLPS) can drive formation of diverse and essential macromolecular structures, including those specified by viruses. Kaposi's Sarcoma-Associated Herpesvirus (KSHV) genomes associate with the viral encoded Latency-Associated Nuclear Antigen (LANA) to form stable nuclear bodies (NBs) during latent infection. Here, we show that LANA-NB formation and KSHV genome conformation involves LLPS. Using LLPS disrupting solvents, we show that LANA-NBs are partially disrupted, while DAXX and PML foci are highly resistant. LLPS disruption altered the LANA-dependent KSHV chromosome conformation but did not stimulate lytic reactivation. We found that LANA-NBs undergo major morphological transformation during KSHV lytic reactivation to form LANA-associated replication compartments encompassing KSHV DNA. DAXX colocalizes with the LANA-NBs during latency but is evicted from the LANA-associated lytic replication compartments. These findings indicate the LANA-NBs are dynamic super-molecular nuclear structures that partly depend on LLPS and undergo morphological transitions corresponding to the different modes of viral replication.
Subject(s)
Antigens, Viral/chemistry , Co-Repressor Proteins/metabolism , Genome, Viral/genetics , Herpesvirus 8, Human/genetics , Intranuclear Inclusion Bodies/metabolism , Molecular Chaperones/metabolism , Nuclear Proteins/chemistry , Sarcoma, Kaposi/virology , Antigens, Viral/genetics , Cell Line, Tumor , Herpesvirus 8, Human/physiology , Histones/metabolism , Humans , Inclusion Bodies, Viral/chemistry , Inclusion Bodies, Viral/metabolism , Intranuclear Inclusion Bodies/chemistry , Latent Infection , Liquid-Liquid Extraction , Nuclear Proteins/genetics , Plasmids/genetics , Virus Latency , Virus ReplicationABSTRACT
This review summarizes the biomechanical concepts, clinical outcomes and limitations of compressive osseointegration fixation for endoprosthetic reconstruction. Compressive osseointe - gration establishes stable fixation and integration through a novel mechanism; a Belleville washer system within the spindle applies 400-800 PSI force at the boneimplant interface. Compressive osseointegration can be used whenever standard endoprosthetic reconstruction is indicated. However, its mode of fixation allows for a shorter spindle that is less limited by the length of remaining cortical bone. Most often compressive osseointegration is used in the distal femur, proximal femur, proximal tibia, and humerus but these devices have been customized for use in less traditional locations. Aseptic mechanical failure occurs earlier than with standard endoprosthetic reconstruction, most often within the first two years. Compressive osseointegration has repeatedly been proven to be non-inferior to standard endoprosthetic reconstruction in terms of aseptic mechanical failure. No demographic, device specific, oncologic variables have been found to be associated with increased risk of aseptic mechanical failure. While multiple radiographic parameters are used to assess for aseptic mechanical failure, no suitable method of evaluation exists. The underlying pathology associated with aseptic mechanical failure demonstrates avascular bone necrosis. This is in comparison to the bone hypertrophy and ingrowth at the boneprosthetic interface that seals the endosteal canal, preventing aseptic loosening.
ABSTRACT
INTRODUCTION: A retrospective review was performed for patients in the Veterans Administration Healthcare System who underwent prophylactic stabilization of the femur for metastatic disease. The goal was to evaluate indications for prophylactic stabilization through Mirels criteria. METHODS: All veterans who underwent inpatient prophylactic femoral stabilization between October 2010 and September 2015 were identified. Procedure and demographic variables were collected by using chart review. Provider notes and radiographs were reviewed to calculate Mirels scores. RESULTS: Ninety-two patients underwent confirmed prophylactic stabilization for metastatic bone disease. Lung cancer and multiple myeloma accounted for most lesions. The mean Mirels score was 10.3 (range 7 to 12). 3.2% of patients had a score of 7, and 6.5% had a score of 8. Most lesions were peritrochanteric (66%) and lytic (85%). There was more variability in size (mean 2.3), with 15% being under one third of bony width and 38% between one and two-thirds. The mean pain score was 2.5; 73% reported functional pain. Of lytic and peritrochanteric lesions (53% of all cases), 55% were less than two-thirds the cortical width and 31% lacked functional pain. CONCLUSION: This retrospective study of prophylactically stabilized metastatic lesions revealed that more than 90% of patients had Mirels scores greater than 8, suggesting a substantial risk of pathologic fracture. Over half of all stabilized lesions were peritrochanteric and lytic. These criteria alone achieve a minimum Mirels score of 8; however, one-third of these lacked functional pain. Notably, Mirels' original paper found location and type criteria to be the least predictive of impending fracture. Contrariwise, functional pain was the most accurate predictor. Multiple studies have found poor specificity of the Mirels criteria. The high scores achievable by the location and type criteria may represent an overrepresentation of their contribution to fracture risk. Reconsideration of the relative weights of each criterion warrants further examination.
Subject(s)
Bone Neoplasms , United States Department of Veterans Affairs , Delivery of Health Care , Femur/diagnostic imaging , Humans , Retrospective Studies , United States/epidemiologyABSTRACT
Bottom Line Up Front: Prison, for most incarcerated persons, can be a harsh and oftentimes dehumanizing environment. The U.S. criminal justice system has become more punitive than rehabilitative since the 1970s. In a reversal of this trend, newly passed legislation has charged prisons with preparing incarcerated persons for reentry into society, reducing recidivism, and providing rehabilitation programs targeting individual needs and risk. At the same time, prison staff delivering these services are faced with the challenge of burn-out, fatigue, depression, PTSD, suicide, and substance abuse at higher rates than individuals in other professions. To sustainably deliver the newly mandated prison-based services with an emphasis on the health and wellbeing of both the staff and the incarcerated population, prisons and the criminal justice system must change dramatically. The key to accomplishing this change is a foundational shift in mindset, from a self-focused "inward mindset" to an in impact-focused "outward mindset." The purpose of this article is to hypothesize the potential for increased safety, security, and human wellbeing when a prison culture adopts an outward mindset.