Micronodular thymoma with lymphoid stroma: As benign as it sounds.

ABSTRACT: Micronodular thymoma (MNT) is a rare subtype of thymoma (reported incidence is approximately 1-5%). We report a case received as a core biopsy from the "right lung mass" of a 31-year-old female. CT scan showed an 8.1 cm large well-defined mass lesion in the right middle lobe, causing indentation and mild compression of the right atrium. Microscopically, the biopsy showed a thymic neoplasm comprised of multiple discrete and coalescing nodules of bland epithelioid tumor cells separated by an epithelial cell-free lymphocyte-rich stroma. On immunohistochemistry, cytokeratin highlighted the thymic epithelial cells. The lymphoid cells showed a naive T-cell phenotype (TdT+ CD 3+). It is worthwhile recognizing this rare variant of thymoma as almost all the patients present with localized low stage disease with rare/no reports of recurrences or distant metastases.

Synthetic Interbody Devices and Traditional Bone Graft Are Associated With a Similar Rate of Surgical Complications After 1-2 Level Anterior Cervical Discectomy and Fusions.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: To compare the rates of all-cause surgical complications of synthetic interbody devices versus allograft or autograft in patients undergoing 1-2 levels anterior cervical discectomy and fusion (ACDF) procedures. SUMMARY OF BACKGROUND DATA: Cervical degenerative disorders affect up to 60% of older adults in the United States. Both traditional allograft or autograft and synthetic interbody devices (polyetheretherketone or titanium) are used for decompression and arthrodesis, with increasing utilization of the latter. However, the differences in their postsurgical complication profiles are not well-characterized. PATIENTS AND METHODS: Patients who underwent 1-2 level ACDFs for cervical radiculopathy or myelopathy between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Patients undergoing surgery for nondegenerative pathologies, such as tumors, trauma, or infection, were excluded. 1:1 exact matching was performed based on factors that were significant predictors of all-cause surgical complications in a linear regression model. The primary outcome measure was the development of all-cause surgical complications after 1-2 level ACDFs. The secondary outcome was all-cause medical complications. RESULTS: 1:1 exact matching resulted in two equal groups of 11,430 patients who received treatment with synthetic interbody devices or allograft/autograft. No statistically significant difference in all-cause surgical complications was found between the synthetic cohort and the allograft or autograft cohort after 1-2 level ACDFs (Relative Risk: 0.86, 95% confidence interval: 0.730-1.014, P = 0.079). No significant differences were observed regarding any specific surgical complications except for pseudoarthrosis (Relative Risk: 0.73, 95% confidence interval: 0.554-0.974, P = 0.037), which was higher in the allograft/autograft cohort. CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that all-cause surgical complications are similar in patients undergoing ACDFs with synthetic interbody devices or allograft/autographs. However, the rate of pseudarthrosis appears to be higher in patients with allograft/autographs. Future prospective studies are needed to corroborate these findings.

Cannabis Use is Associated With Higher Rates of Pseudarthrosis Following TLIF: A Multi-Institutional Matched-Cohort Study.

STUDY DESIGN: This was a retrospective cohort study. OBJECTIVE: To compare the rates of pseudarthrosis in patients undergoing 1 to 3 level transforaminal lumbar interbody fusion (TLIF) procedures between cannabis users and noncannabis users. SUMMARY OF BACKGROUND DATA: Recreational use of cannabis is common, though it remains poorly studied and legally ambiguous in the United States. Patients with back pain may turn to adjunctive use of cannabis to manage their pain. However, the implications of cannabis use on the achievement of bony fusion are not well-characterized. METHODS: Patients who underwent 1 to 3 level TLIF for degenerative disc disease or degenerative spondylolisthesis between 2010 and 2022 were identified using the PearlDiver Mariner all-claims insurance database. Cannabis users were identified with ICD 10 code F12.90. Patients undergoing surgery for nondegenerative pathologies such as tumors, trauma, or infection were excluded. 1:1 exact matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with pseudarthrosis in a linear regression model. The primary outcome measure was development of pseudarthrosis within 24 months after 1 to 3 level TLIF. The secondary outcomes were the development of all-cause surgical complications as well as all-cause medical complications. RESULTS: A 1:1 exact matching resulted in two equal groups of 1593 patients who did or did not use cannabis and underwent 1 to 3 level TLIF. Patients who used cannabis were 80% more likely to experience pseudarthrosis compared with patients who do not [relative risk (RR): 1.816, 95% CI: 1.291-2.556, P <0.001]. Similarly, cannabis use was associated with significantly higher rates of all-cause surgical complications (RR: 2.350, 95% CI: 1.399-3.947, P =0.001) and all-cause medical complications (RR: 1.934, 95% CI: 1.516-2.467, P <0.001). CONCLUSION: After 1:1 exact matching to control for confounding variables, the findings of this study suggest that cannabis use is associated with higher rates of pseudarthrosis, as well as higher rates of all-cause surgical and all-cause medical complications. Further studies are needed to corroborate our findings.

Correlation Between Rod Fracture and Shear Stress: A Novel Parameter.

BACKGROUND: We sought to assess the accuracy of a novel parameter proportional to the rod shear stress (RSS) in identifying patients at risk of rod fracture (RF) after surgery for correction of adult spinal deformity. METHODS: We performed a retrospective medical record review of patients aged ≥18 years treated for adult spinal deformity between 2004 and 2014 with ≥24 months of follow-up. The primary outcome was RFs identified radiographically. Patient weight (w), number of instrumented levels (N), and minimum rod diameter (d) were recorded and used to calculate the RSS parameter (RSS=Nwd2). Receiver operating characteristic curves were produced and the area under the curve (AUC ± 95% confidence interval [CI]) was calculated to compare this parameter's discriminative accuracy to that of its constituent variables. The sensitivity, specificity, and likelihood ratios (LRs) were calculated. RESULTS: A total of 28 RF-positive and 154 RF-negative patients were included. The average age was 59.2 ± 9.6 years, and 93.4% were women. The RSS parameter produced the greatest AUC (0.73 ± 0.11). At an RSS cutoff of 30.1, it achieved a sensitivity of 71.4% and specificity of 71.4% (LR, 2.5; 95% CI, 1.8-3.5). The number of instrumented levels produced the next-greatest AUC (0.65 ± 0.12), with a sensitivity of 78.6% and specificity of 50.0% at a cutoff of 15 (LR, 1.6; 95% CI, 1.2-2.0). CONCLUSIONS: The RSS is calculated using easily obtainable information and shows potential as a tool for predicting patient-specific risk of RF after spinal fusion. The number of instrumented levels also correlates strongly with the occurrence of RFs and is not significantly less accurate than the RSS. A larger sample size and prospective validation would be useful in determining with greater confidence which parameter is superior for predicting RFs after spinal fusion.

Massive parallel sequencing unveils homologous recombination deficiency in follicular dendritic cell sarcoma.

Standardized treatment options are lacking for patients with unresectable or multifocal follicular dendritic cell sarcoma (FDCS) and disease-related mortality is as high as 20%. Applying whole genome sequencing (WGS) in one case and whole exome sequencing (WES) in additional twelve, this study adds information on the molecular landscape of FDCS, expanding knowledge on pathobiological mechanisms and identifying novel markers of potential theragnostic significance. Massive parallel sequencing showed high frequency of mutations on oncosuppressor genes, particularly in RB1, CARS and BRCA2 and unveiled alterations on homologous recombination DNA damage repair related genes in 70% (9/13) of cases. This indicates that patients with high stage FDCS may be eligible for poly ADP ribose polymerase inhibition protocols. Low tumor mutational burden was confirmed in this study despite common PDL1 expression in FDCS arguing on the efficacy of immune checkpoint inhibitors. CDKN2A deletion, detected by WGS and confirmed by FISH in 41% of cases (9/22) indicates that impairment of cell cycle regulation may sustain oncogenesis in FDCS. Absence of mutations in the RAS/RAF/MAPK pathway and lack of clonal hematopoiesis related mutations in FDCS sanction its differences from dendritic cell-derived neoplasms of haematopoietic derivation. WGS and WES in FDCS provides additional information on the molecular landscape of this rare tumor, proposing novel candidate genes for innovative therapeutical approaches to improve survival of patients with multifocal disease.

No Difference in Surgical Outcomes between Stand-Alone Devices and Anterior Plating for 1-2 level Anterior Cervical Discectomy and Fusion: A 1:1 Exact Matched Analysis.

STUDY DESIGN: Retrospective cohort. OBJECTIVE: Compare rates of all-cause surgical and medical complications between zero-profile (stand-alone) implants versus any graft type with anterior plate in patients undergoing 1-2 level anterior cervical discectomy and fusion (ACDF) for treatment of degenerative cervical myeloradiculopathy. SUMMARY OF BACKGROUND DATA: Degenerative cervical myeloradiculopathy is increasingly prevalent in older adults. ACDF is a common surgical procedure for decompression of neural structures and stabilization and has been shown to have excellent outcomes. While ACDFs performed with a graft and plate has been the gold standard, more recently, zero-profile implants were developed to decrease implant related complications, such as severe postoperative dysphagia. However, there is a paucity of papers comparing the surgical and medical complications profile of zero-profile (stand-alone) implants to grafts with plating systems. METHODS: Data was extracted from the PearlDiver Mariner Database using CPT codes to classify patients into 1-level, 2-levels, and total 1-2 level ACDFs. Patients undergoing surgery for non-degenerative pathologies such as tumors, trauma, or infection were excluded. RESULTS: 1:1 exact matching created two equal groups of 7,284 patients that underwent 1-2 level ACDF with either grafting with a plate or zero-profile (standalone) implant. There were no statistically significant difference in all-cause surgical complications, pseudarthrosis rate, dysphagia or need for revision surgery between both cohorts (RR 0.99, 95% CI 0.80-1.21, P = 0.95). Additionally, all-cause medical complications were similar between both cohorts (RR 1.07, 95% CI 0.862-1.330, P = 0.573) or any specific surgical or medical complication included in this study. CONCLUSION: After 1:1 exact matching, the results of this study suggest that zero-profile (stand-alone) implants have similar outcomes compared to grafts with plating systems, with no observed differences in all-cause surgical or medical complications profile.

Surgeon Experience Matters: An Exact Matched Analysis of TLIF Outcomes Demonstrates No Difference in Surgical Outcomes Between Experienced Neurosurgeons and Orthopedic Surgeons.

STUDY DESIGN: Retrospective cohort study. OBJECTIVE: To compare surgical and medical complications profile between neurosurgeons and orthopedic surgeons after transforaminal lumbar interbody fusion (TLIF) procedures. BACKGROUND: Studies comparing the impact of spine surgeon specialty (neurosurgery vs. orthopedic spine) on TLIF outcomes have been inconclusive and failed to control for operative learning curves and surgical maturity. Orthopedic spine surgeons perform fewer spine procedures in residency, although these differences may be attenuated by mandatory fellowship before starting practice. Any observed differences are likely attenuated with increasing surgeon experience. MATERIALS AND METHODS: Using an all-payer claims database, PearlDiver Mariner, 120 million patient records were analyzed between 2010 and 2022, to identify individuals with lumbar stenosis or spondylolisthesis who underwent index one- to three-level TLIF procedures. International Classification of Diseases-Ninth Edition (ICD-9), International Classification of Diseases-10th Edition (ICD-10) and Current Procedural Terminology (CPT) codes were used to query the database. Only Neurosurgeons and Orthopedic spine surgeons who had performed at least 250 procedures were included in the study. Patients undergoing surgery for tumor, trauma, or infection were excluded. 1:1 exact matching was performed using demographic factors, medical comorbidities, and surgical factors which were significantly associated with all-cause surgical or medical complications in a linear regression model. RESULTS: 1:1 exact matching created two equal groups of 18,195 patients without baseline differences who underwent TLIF procedures by neurosurgeons or orthopedic surgeons. There was no difference in all-cause surgical complications between neurosurgeons and orthopedic spine surgeons (relative risk=1.008, 95% CI: 0.850-1.195, P =0.965). All-cause medical complication rate was higher in the neurosurgery cohort (relative risk=1.144, 95% CI: 1.042-1.258, P =0.005). CONCLUSION: The results of this study suggest that after accounting for surgical maturity, neurosurgeons and orthopedic spine surgeons have similar surgical outcomes. However, neurosurgeons have higher all-cause medical complication rates compared with orthopedic spine surgeons. Further research is warranted to validate this relationship in other spine procedures and for other outcomes.

Metastatic sclerosing epithelioid fibrosarcoma in an adult male from a tertiary care centre in India: a case report.

Background: Sclerosing epithelioid fibrosarcoma (SEF) is an extremely rare subtype of soft tissue sarcoma and the data from India is sparse. It is an unusual variant of fibrosarcoma that commonly arises in the soft tissues of the limb, head and neck, trunk and occasionally in the visceral organs and bones. This entity is commonly reported in the middle age group, men and women alike. Pathological clinchers include MUC 4 (Mucin 4, cell surface associated) positivity by immunohistochemistry, FUS-CREB3L1 fusion and EWSR1 rearrangement. This disease is notoriously known for its local recurrence and metastatic spread. Response to systemic therapy is poor and relapses are frequent. The role of targeted and immunotherapy is not well defined. Case presentation: Here we report a 46-year-old gentleman who presented to the Sarcoma Medical Oncology Clinic in our centre. He had primary involvement of right pubic bone with metastasis to liver, lung and diffuse lytic bony lesions. His diagnosis was reviewed multiple times before coming to final diagnosis of SEF. His molecular test for EWSR1 rearrangement was positive by fluorescence in-situ hybridisation. He did not respond to palliative doxorubicin, pazopanib and gemcitabine and docetaxel. Conclusion: Through this case report, we would like to highlight the rarity of this sarcoma, its classical pathological features, its close relationship to low-grade fibromyxoid sarcoma and the limited therapeutic options available. Hence, there is a need for further research in this entity.

The immune landscape of undifferentiated pleomorphic sarcoma.

Introduction: Undifferentiated pleomorphic sarcoma (UPS) can be associated with a relatively dense immune infiltration. Immune checkpoint inhibitors (anti-PD1, anti-PDL1, and anti-CTLA4) are effective in 20% of UPS patients. We characterize the immune microenvironment of UPS and its association with oncologic outcomes. Material and methods: Surgically resected UPS samples were stained by immunohistochemistry (IHC) for the following: tumor-associated immune cells (CD3, CD8, CD163, CD20), immune checkpoints (stimulatory: OX40, ICOS; inhibitory: PD-L1, LAG3, IDO1, PD1), and the adenosine pathway (CD73, CD39). Sections were reviewed for the presence of lymphoid aggregates (LA). Clinical data were retrospectively obtained for all samples. The Wilcoxon rank-sum and Kruskal-Wallis tests were used to compare distributions. Correlations between biomarkers were measured by Spearman correlation. Univariate and multivariate Cox models were used to identify biomarkers associated with overall survival (OS) and disease-free survival (DFS). Unsupervised clustering was performed, and Kaplan-Meier curves and log-rank tests used for comparison of OS and DFS between immune clusters. Results: Samples analyzed (n=105) included 46 primary tumors, 34 local recurrences, and 25 metastases. LA were found in 23% (n=10/43), 17% (n=4/24), and 30% (n=7/23) of primary, recurrent, and metastatic samples, respectively. In primary UPS, CD73 expression was significantly higher after preoperative radiation therapy (p=0.009). CD39 expression was significantly correlated with PD1 expression (primary: p=0.002, recurrent: p=0.004, metastatic: p=0.001), PD-L1 expression (primary: p=0.009), and CD3+ cell densities (primary: p=0.016, recurrent: p=0.043, metastatic: p=0.028). In recurrent tumors, there was a strong correlation between CD39 and CD73 (p=0.015), and both were also correlated with CD163+ cell densities (CD39 p=0.013; CD73 p<0.001). In multivariate analyses, higher densities of CD3+ and CD8+ cells (Cox Hazard Ratio [HR]=0.33; p=0.010) were independently associated with OS (CD3+, HR=0.19, p<0.001; CD8+, HR= 0.33, p=0.010) and DFS (CD3+, HR=0.34, p=0.018; CD8+, HR=0.34, p= 0.014). Unsupervised clustering of IHC values revealed three immunologically distinct clusters: immune high, intermediate, and low. In primary tumors, these clusters were significantly associated with OS (log-rank p<0.0001) and DFS (p<0.001). Conclusion: We identified three immunologically distinct clusters of UPS Associated with OS and DFS. Our data support further investigations of combination anti-PD-1/PD-L1 and adenosine pathway inhibitors in UPS.

A 7-Year-Old With Persistent Fever and Cough.

A previously healthy, fully immunized 7-year-old girl presented with a 7-week history of daily fevers and a worsening cough with persistently elevated inflammatory markers. Before admission, she had an unrevealing outpatient workup by infectious disease, rheumatology, pulmonology, and otorhinolaryngology for her fever and other symptoms. Multiple courses of antibiotics had no effect, but brief courses of steroids seemed to modestly alleviate her symptoms. At an outside hospital, a computed tomography neck and chest scan revealed mediastinal lymphadenopathy. She was subsequently transferred to the authors' institution. Her examination was notable for a febrile, tired-appearing girl in respiratory distress with a muffled voice and inspiratory stridor. Her laboratory tests revealed leukocytosis with left shift, microcytic anemia, and hypoalbuminemia, as well as elevated inflammatory markers, ferritin, and fecal calprotectin. Her peripheral smear, uric acid, and lactate dehydrogenase were all within normal limits. Infectious study results, including blood and urine cultures, cytomegalovirus serologies, and Bartonella serologies were negative. On the second read of her outside computed tomography imaging, her lymphadenopathy was felt to be nonpathologic. Based on a recommendation by rheumatology, an ophthalmologic examination was obtained, which revealed bilateral anterior uveitis; however, rheumatologic laboratory test results returned negative. Her fevers continued, and inflammatory markers remained elevated despite antibiotics. On day 6 of hospitalization, she developed worsening respiratory distress, necessitating intubation and transfer to the ICU. Repeat laryngoscopy and bronchoscopy revealed severe purulent tracheitis; however, throat cultures remained sterile. Her clinical deterioration without identification of an offending organism prompted additional evaluation for a systemic etiology.

Challenges and Opportunities for Immunoprofiling Using a Spatial High-Plex Technology: The NanoString GeoMx® Digital Spatial Profiler.

Characterization of the tumor microenvironment through immunoprofiling has become an essential resource for the understanding of the complex immune cell interactions and the assessment of biomarkers for prognosis and prediction of immunotherapy response; however, these studies are often limited by tissue heterogeneity and sample size. The nanoString GeoMx® Digital Spatial Profiler (DSP) is a platform that allows high-plex profiling at the protein and RNA level, providing spatial and temporal assessment of tumors in frozen or formalin-fixed paraffin-embedded limited tissue sample. Recently, high-impact studies have shown the feasibility of using this technology to identify biomarkers in different settings, including predictive biomarkers for immunotherapy in different tumor types. These studies showed that compared to other multiplex and high-plex platforms, the DSP can interrogate a higher number of biomarkers with higher throughput; however, it does not provide single-cell resolution, including co-expression of biomarker or spatial information at the single-cell level. In this review, we will describe the technical overview of the platform, present current evidence of the advantages and limitations of the applications of this technology, and provide important considerations for the experimental design for translational immune-oncology research using this tissue-based high-plex profiling approach.

Role of SMARCA4 (BRG1) and SMARCB1 (INI1) in Dedifferentiated Endometrial Carcinoma With Paradoxical Aberrant Expression of MMR in the Well-Differentiated Component: A Case Report and Review of the Literature.

INTRODUCTION: Dedifferentiated endometrial carcinoma is an uncommon highly aggressive uterine tumor. It comprises 2 components: a well-differentiated, low-grade epithelial carcinoma and an undifferentiated carcinoma. The undifferentiated carcinoma frequently exhibits rhabdoid cytologic features. Many of these tumors are characterized by an aberrant switch/sucrose non-fermenting (SWI/SNF) complex. They may also exhibit aberrant expression of mismatch repair (MMR) proteins. Together, these play an important role in the pathogenesis and aggressive nature of the tumor. MATERIAL AND METHODS: We present a case of dedifferentiated endometrial carcinoma in a 63-year-old female showing loss of expression of SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4 (SMARCA4/BRG1), and aberrant expression of MMR proteins. We also review the literature starting from the earliest recognition of this entity and the various studies done to explain its molecular pathogenesis and prognostic importance. RESULTS AND CONCLUSIONS: Recognition of SWI/SNF complex-deficient dedifferentiated endometrial carcinoma is important as these tumors do not respond to platinum-based chemotherapy, and consideration of alternative therapies is often necessary. We also want to emphasize that though most of the studies have found MMR deficiency in the undifferentiated carcinoma component, it may be seen only in the low-grade, well-differentiated component, as observed in this case.

Extranodal Follicular Dendritic Cell Sarcoma-A Review: "What the Mind Does Not Know the Eye Does Not See".

Follicular dendritic cell sarcoma (FDCS) is an intermediate-grade malignancy of follicular dendritic cells, which are derived from mesenchymal stem cells. Nodal FDCS is well-recognized. However, when it occurs at an extranodal site, it may not be recognized and is often misdiagnosed. These tumors exhibit a variable spindle to epithelioid cell morphology with a lymphocytic infiltrate and a distinct immunophenotype. The World Health Organization has classified this entity under tumors of hematopoietic and lymphoid tissue, that is, histiocytic and dendritic cell neoplasms. However, its occurrence at extranodal sites and its behavior and management more closely resemble that of a soft tissue tumor. Increased awareness about the existence of FDCS at extranodal sites may aid in the reduction of diagnostic errors. We wish to draw attention to this entity by reporting our experience of 54 cases of extranodal FDCS encountered over a period of 14 years and present a review of the literature of this underrecognized entity. We also describe the ontogeny and molecular pathogenesis of this uncommon lesion.

Serum S100A8/A9 and S100A12 Levels in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis: Relationship to Maintenance of Clinically Inactive Disease During Anti-Tumor Necrosis Factor Therapy and Occurrence of Disease Flare After Discontinuation of Therapy.

OBJECTIVE: To determine the relationship between serum levels of S100A8/A9 and S100A12 and the maintenance of clinically inactive disease during anti-tumor necrosis factor (anti-TNF) therapy and the occurrence of disease flare following withdrawal of anti-TNF therapy in patients with polyarticular forms of juvenile idiopathic arthritis (JIA). METHODS: In this prospective, multicenter study, 137 patients with polyarticular-course JIA whose disease was clinically inactive while receiving anti-TNF therapy were enrolled. Patients were observed for an initial 6-month phase during which anti-TNF treatment was continued. For those patients who maintained clinically inactive disease over the 6 months, anti-TNF was withdrawn and they were followed up for 8 months to assess for the occurrence of flare. Serum S100 levels were measured at baseline and at the time of anti-TNF withdrawal. Spearman's rank correlation test, Mann-Whitney U test, Kruskal-Wallis test, receiver operating characteristic (ROC) curve, and Kaplan-Meier survival analyses were used to assess the relationship between serum S100 levels and maintenance of clinically inactive disease and occurrence of disease flare after anti-TNF withdrawal. RESULTS: Over the 6-month initial phase with anti-TNF therapy, the disease state reverted from clinically inactive to clinically active in 24 (18%) of the 130 evaluable patients with polyarticular-course JIA; following anti-TNF withdrawal, 39 (37%) of the 106 evaluable patients experienced a flare. Serum levels of S100A8/A9 and S100A12 were elevated in up to 45% of patients. Results of the ROC analysis revealed that serum S100 levels did not predict maintenance of clinically inactive disease during anti-TNF therapy nor did they predict disease flare after treatment withdrawal. Elevated levels of S100A8/A9 were not predictive of the occurrence of a disease flare within 30 days, 60 days, 90 days, or 8 months following anti-TNF withdrawal, and elevated S100A12 levels had a modest predictive ability for determining the risk of flare within 30, 60, and 90 days after treatment withdrawal. Serum S100A12 levels at the time of anti-TNF withdrawal were inversely correlated with the time to disease flare (r = -0.36). CONCLUSION: Serum S100 levels did not predict maintenance of clinically inactive disease or occurrence of disease flare in patients with polyarticular-course JIA, and S100A12 levels were only moderately, and inversely, correlated with the time to disease flare.

Pilot study comparing the childhood arthritis and rheumatology research alliance consensus treatment plans for induction therapy of juvenile proliferative lupus nephritis.

BACKGROUND: To reduce treatment variability and facilitate comparative effectiveness studies, the Childhood Arthritis and Rheumatology Research Alliance (CARRA) published consensus treatment plans (CTPs) including one for juvenile proliferative lupus nephritis (LN). Induction immunosuppression CTPs outline treatment with either monthly intravenous (IV) cyclophosphamide (CYC) or mycophenolate mofetil (MMF) in conjunction with one of three corticosteroid (steroid) CTPs: primarily oral, primarily IV or mixed oral/IV. The acceptability and in-practice use of these CTPs are unknown. Therefore, the primary aims of the pilot study were to demonstrate feasibility of adhering to the LN CTPs and delineate barriers to implementation in clinical care in the US. Further, we aimed to explore the safety and effectiveness of the treatments for induction therapy. METHODS: Forty-one patients were enrolled from 10 CARRA sites. Patients had new-onset biopsy proven ISN/RPS class III or IV proliferative LN, were starting induction therapy with MMF or IV CYC and high-dose steroids and were followed for up to 24 months. Routine clinical data were collected at each visit. Provider reasons for CTP selection were assessed at baseline. Adherence to the CTPs was evaluated by provider survey and medication logs. Complete and partial renal responses were reported at 6 months. RESULTS: The majority of patients were female (83%) with a mean age of 14.7 years, SD 2.8. CYC was used more commonly than MMF for patients with ISN/RPS class IV LN (vs. class III), those who had hematuria, and those with adherence concerns. Overall adherence to the immunosuppression induction CTPs was acceptable with a majority of patients receiving the target MMF (86%) or CYC (63%) dose. However, adherence to the steroid CTPs was poor (37%) with large variability in dosing. Renal response endpoints were exploratory and did not show a significant difference between CYC and MMF. CONCLUSIONS: Overall, the immunosuppression CTPs were followed as intended in the majority of patients however, adherence to the steroid CTPs was poor indicating revision is necessary. In addition, our pilot study revealed several sources of treatment selection bias that will need to be addressed in for future comparative effectiveness research.

Risk, Timing, and Predictors of Disease Flare After Discontinuation of Anti-Tumor Necrosis Factor Therapy in Children With Polyarticular Forms of Juvenile Idiopathic Arthritis With Clinically Inactive Disease.

OBJECTIVE: To determine the frequency, time to flare, and predictors of disease flare upon withdrawal of anti-tumor necrosis factor (anti-TNF) therapy in children with polyarticular forms of juvenile idiopathic arthritis (JIA) who demonstrated ≥6 months of continuous clinically inactive disease. METHODS: In 16 centers 137 patients with clinically inactive JIA who were receiving anti-TNF therapy (42% of whom were also receiving methotrexate [MTX]) were prospectively followed up. If the disease remained clinically inactive for the initial 6 months of the study, anti-TNF was stopped and patients were assessed for flare at 1, 2, 3, 4, 6, and 8 months. Life-table analysis, t-tests, chi-square test, and Cox regression analysis were used to identify independent variables that could significantly predict flare by 8 months or time to flare. RESULTS: Of 137 patients, 106 (77%) maintained clinically inactive disease while receiving anti-TNF therapy for the initial 6 months and were included in the phase of the study in which anti-TNF therapy was stopped. Stopping anti-TNF resulted in disease flare in 39 (37%) of 106 patients by 8 months. The mean/median ± SEM time to flare was 212/250 ± 9.77 days. Patients with shorter disease duration at enrollment, older age at onset and diagnosis, shorter disease duration prior to experiencing clinically inactive disease, and shorter time from onset of clinically inactive disease to enrollment were found to have significantly lower hazard ratios for likelihood of flare by 8 months (P < 0.05). CONCLUSION: Over one-third of patients with polyarticular JIA with sustained clinically inactive disease will experience a flare by 8 months after discontinuation of anti-TNF therapy. Several predictors of lower likelihood of flare were identified.

High Levels of DEK Autoantibodies in Sera of Patients With Polyarticular Juvenile Idiopathic Arthritis and With Early Disease Flares Following Cessation of Anti-Tumor Necrosis Factor Therapy.

OBJECTIVE: The nuclear oncoprotein DEK is an autoantigen associated with juvenile idiopathic arthritis (JIA), especially the oligoarticular subtype. DEK is a secreted chemotactic factor. Abundant levels of DEK and DEK autoantibodies are found in inflamed synovium in JIA. We undertook this study to further characterize the nature of DEK autoantibodies in screening serum samples from 2 different cohorts that consisted mostly of patients with JIA. METHODS: DEK autoantibody levels were analyzed in sera from 33 JIA patients, 13 patients with other inflammatory conditions, and 11 healthy controls, as well as in 89 serum samples from JIA patients receiving anti-tumor necrosis factor (anti-TNF) therapy. Recombinant His-tagged full-length DEK protein (1-375 amino acids [aa]) and the 187-375-aa and 1-350-aa His-tagged DEK fragments made in a baculovirus system were used for enzyme-linked immunosorbent assay (ELISA) and immunoblotting. The C-terminal 25-aa fragment of DEK was expressed in a glutathione S-transferase-tagged vector. ELISA results were calculated as area under the curve by the trapezoidal rule. RESULTS: DEK autoantibody levels were significantly higher in patients with polyarticular JIA than in those with oligoarticular JIA, and were higher in patients with polyarticular JIA who had more active disease after cessation of anti-TNF therapy. Immunoblotting against the C-terminal 25-aa fragment of DEK confirmed that this section of the DEK molecule is the most immunogenic domain. CONCLUSION: DEK autoantibody levels are higher in patients with polyarticular JIA than in those with oligoarticular JIA, and higher in patients who have disease flares after cessation of anti-TNF therapy. The C-terminal 25-aa fragment is the most immunogenic portion of DEK. These findings are significant with respect to the nature of DEK autoantibodies, their contribution to JIA pathogenesis, and their implications for JIA management.

Identification of novel follicular dendritic cell sarcoma markers, FDCSP and SRGN, by whole transcriptome sequencing.

Follicular dendritic cell (FDC)-sarcoma is a rare neoplasm with morphologic and phenotypic features of FDCs. It shows an extremely heterogeneous morphology, therefore, its diagnosis relys on the phenotype of tumor cells. Aim of the present study was the identification of new specific markers for FDC-sarcoma by whole transcriptome sequencing (WTS). Candidate markers were selected based on gene expression level and biological function. Immunohistochemistry was performed on reactive tonsils, on 22 cases of FDC-sarcomas and 214 control cases including 114 carcinomas, 87 soft tissue tumors, 5 melanomas, 5 thymomas and 3 interdigitating dendritic cell sarcomas. FDC secreted protein (FDCSP) and Serglycin (SRGN) proved to be specific markers of FDC and related tumor. They showed better specificity and sensitivity values than some well known markers used in FDC sarcoma diagnosis (specificity: 98.6%, and 100%, respectively; sensitivity: 72.73% and 68.18%, respectively). In our cohorts CXCL13, CD21, CD35, FDCSP and SRGN were the best markers for FDC-sarcoma diagnosis and could discriminate 21/22 FDC sarcomas from other mesenchymal tumors by linear discriminant analysis. In summary, by WTS we identified two novel FDC markers and by the analysis of a wide cohort of cases and controls we propose an efficient marker panel for the diagnosis of this rare and enigmatic tumor.

Askin (PNET) Tumor Unmasked by Trauma in a Young Male Patient.

A young male labourer developed pain at the site of blunt trauma over back of chest followed by fever, cough with expectoration, breathlessness and hemorrhagic pleural effusion in the side of injury. What could have been passed as a sequel of trauma turned out to be the consequences of an underlying rare and aggressive malignant tumor of the chest wall known as Askin tumor or Primitive Neuroectodermal Tumor (PNET). CT thorax with guided FNAC, debulking operation, histopathological examination followed by immunohistochemistry of the tumor tissue led to the final diagnosis. Chemotherapy was administered following surgical resection. The patient died within nine months after diagnosis.