Long Cephalomedullary Nails Can Be a Cheap and Effective Interval Revision Prosthesis in Infected Hip Replacements That Require Proximal Femoral Replacement: A Small Case Series.

Hip prosthetic joint infection management is complex and expensive, especially in severe bone loss. Reducing the price of interval prosthesis when performing staged revision could minimize costs without compromising outcomes. We present 2 similar techniques developed independently that use an antibiotic-coated cephalomedullary nail with a total hip arthroplasty bearing (head and cemented acetabular component) attached to it as an interval proximal femoral replacement prosthesis. Using this technique, the femoral implant cost was reduced up to 10-fold. All patients have recovered well with resolution of infection and functional recovery similar to patients undergoing proximal femoral replacement. In one case, the lag screw (femoral neck) fractured at 5 months prompting the second-stage revision. This complication should be considered when deciding the timing of second-stage revisions in these cases.

Efficacy of immune checkpoint inhibitors in non-small cell lung cancer: A systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have demonstrated remarkable efficacy in non-small cell lung cancer (NSCLC). However, only a minority of NSCLC patients benefit from ICIs, and whether the magnitude of benefit is specific factor-dependent remains unclear. We performed a systematic review to improve our understanding of clinicopathologic and biomolecular features associated with improved survival upon treatment with ICIs for NSCLC. Methods: We searched PubMed, Web of Science, Embase, and Scopus from database inception to August 31, 2021, for randomized controlled trials (RCTs) comparing overall survival (OS) in NSCLC treated with ICIs vs control therapies. We calculated the pooled OS hazard ratio (HR) and 95% CI in subgroups using a random-effects model, and assessed the heterogeneity between the paired estimates using an interaction test. Results: A total of 23 RCTs involving 15,829 patients were included. We found that wild-type EGFR, high PD-L1 expression, and high bTMB were associated with a significant OS benefit from ICIs, but not mutant EGFR, low PD-L1 expression, and low bTMB. The differences of OS benefit between wild-type and mutant EGFR (HR=1.53, 95%CI 1.13-2.08), high and low PD-L1 (HR=1.35; 95%CI 1.14-1.61), high and low bTMB (HR=1.71; 95%CI 1.17-2.52) were statistically significant. OS benefit was found in all subgroups regardless of sex, age, ECOG PS, histology, smoking history, baseline brain metastasis, race, and region, and the interaction test demonstrated no significant difference of the OS benefit between these opposed subgroups (e.g. male vs female). Conclusions: Wild-type EGFR, high PD-L1 expression, and high bTMB are associated with a greater magnitude of efficacy from ICIs vs control therapies in NSCLC. However, the administration of ICIs should not be restricted to other clinicopathological factors (sex, smoking history, race, etc.).

Vitamin D Status: A U-shaped relationship for SARS-CoV-2 seropositivity in UK healthcare workers

BackgroundVitamin D has numerous mechanistic roles within the immune system. There is increasing evidence to suggest Vitamin D deficiency may increase individuals risk of COVID-19 infection and susceptibility. We aimed to determine the relationship between severity of vitamin D deficiency and sufficiency and COVID-19 infection within healthcare workers. MethodsThe study included an observational cohort of healthcare workers who isolated due to COVID-19 symptoms from 12th to 22nd May 2020, from the University Hospitals Birmingham NHS Foundation Trust (UHBFT). This was part of the COVID-19 convalescent immunity study (COCO). Data collected included SARS-CoV-2 seroconversion status, serum 25(OH)D3 levels as well as age, body mass index (BMI), sex, ethnicity, job role, and co-morbidities. Participants were grouped into four vitamin D (VD) categories. 1) Severe VD deficiency (VD <30 nmol/L); 2) VD deficiency (30 nmol/L [≤] VD <50 nmol/L); 3) VD insufficiency (50 nmol/L [≤] VD <75 nmol/L); 4) VD sufficiency (VD [≥]75 nmol/L). ResultsWhen VD levels were compared against COVID-19 seropositivity rate, a U-shaped curve was identified in the total population. This trend repeated when split into subgroups of age, sex, ethnicity, BMI, and co-morbidity status. Significant difference was identified in the COVID-19 seropositivity rate between VD groups between multiple VD groups in the total population, males, females, BAME, BMI<30 (kg/m2), 0 and +1 comorbidities; the majority of which were differences when the severely VD deficient category were compared to the other group. A significantly larger proportion of those within the Black, Asian, minority ethnic (BAME) group (vs. white ethnicity) were severely vitamin D deficient (P <0.00001). A significantly higher proportion of the 0-comorbidity subgroup were vitamin D deficient in comparison to the 1+ comorbidity subgroup (P = 0.046). ConclusionsFurther investigation of the U-shaped curves is required to determine whether high VD levels can have a detrimental effect on susceptibility to COVID-19 infection. Future randomised clinical trials of VD supplementation could potentially identify optimal VD levels. This would allow for targeted therapeutic treatment for those at-risk such as in the BAME group.

Altered neutrophil phenotype and function in non-ICU COVID-19 patients correlated with disease severity

RationalInfection with the SARS-CoV2 virus is associated with elevated neutrophil counts. Evidence of neutrophil dysfunction in COVID-19 is based predominantly on transcriptomics or single functional assays. Cell functions are interwoven pathways, and so understanding the effect of COVID-19 across the spectrum of neutrophil function may identify tractable therapeutic targets. ObjectivesExamine neutrophil phenotype and functional capacity in COVID-19 patients versus age-matched controls (AMC) MethodsIsolated neutrophils from 41 hospitalised, non-ICU COVID-19 patients and 23 AMC underwent ex vivo analyses for migration, bacterial phagocytosis, ROS generation, NET formation (NETosis) and cell surface receptor expression. DNAse 1 activity was measured, alongside circulating levels of cfDNA, MPO, VEGF, IL-6 and sTNFRI. All measurements were correlated to clinical outcome. Serial sampling on day 3-5 post hospitalisation were also measured. ResultsCompared to AMC, COVID-19 neutrophils demonstrated elevated transmigration (p=0.0397) and NETosis (p=0.0366), but impaired phagocytosis (p=0.0236) associated with impaired ROS generation (p<0.0001). Surface expression of CD54 (p<0.0001) and CD11c (p=0.0008) was significantly increased and CD11b significantly decreased (p=0.0229) on COVID-19 patient neutrophils. COVID-19 patients showed increased systemic markers of NETosis including increased cfDNA (p=0.0153) and impaired DNAse activity (p<0.0.001). MPO (p<0.0001), VEGF (p<0.0001), TNFRI (p<0.0001) and IL-6 (p=0.009) were elevated in COVID-19, which positively correlated with disease severity by 4C score. ConclusionCOVID-19 is associated with neutrophil dysfunction across all main effector functions, with altered phenotype, elevated migration, impaired antimicrobial responses and elevated NETosis. These changes represent a clear mechanism for tissue damage and highlight that targeting neutrophil function may help modulate COVID-19 severity.

Utilization Trends and Factors Associated With ROS1 Testing Among Patients With Advanced Non-small-cell Lung Cancer in US Community Practices.

BACKGROUND: Targeted therapy for patients with non-small-cell lung cancer (NSCLC) harboring ROS proto-oncogene 1 (ROS1) rearrangements was approved in 2016. However, little is known about real-world ROS1 testing practices in United States community practice. We aimed to characterize ROS1 testing rates and identify potential barriers to ROS1 testing. PATIENTS AND METHODS: Flatiron Health's de-identified electronic health record-derived database was used to identify patients diagnosed with advanced NSCLC from July 2016 through December 2018 who received systemic treatment in a community practice setting. ROS1 and other biomarker testing was recorded. Regression analysis identified demographic and clinical characteristics associated with occurrence of ROS1 testing, longer time (≥ 25 days) from diagnosis to ROS1 result, and initiation of therapy prior to ROS1 result. RESULTS: Among 11,409 patients, documented ROS1 testing rates increased during the study period in squamous (from 30% to 48%) and nonsquamous (63% to 78%) histologies. Patients who were older, male, black, or with squamous histology, higher Eastern Cooperative Oncology Group score, recurrent disease, or history of smoking were significantly less likely to be tested. Among patients not tested for ROS1, 63% were tested for other biomarkers. Use of next-generation sequencing, older age, Hispanic/Latino ethnicity, squamous histology, de novo disease, and smoking history predicted longer time to test result post-diagnosis. Patients with delayed results were 9.7 times more likely to receive treatment prior to ROS1 test result. CONCLUSION: In real-world practice, some patient subgroups may be less likely to receive timely ROS1 testing and to be identified for potential targeted therapy.

Impact of delaying initiation of anaplastic lymphoma kinase inhibitor treatment on survival in patients with advanced non-small-cell lung cancer.

INTRODUCTION: Several obstacles may delay receipt of targeted treatment in patients with anaplastic lymphoma kinase positive (ALK+) non-small-cell lung cancer (NSCLC). This study examined the factors associated with delayed initiation of ALK inhibitor (ALKi) treatment and its impact on overall survival (OS) as well as the impact of initiating chemotherapy before biomarker test results. MATERIALS AND METHODS: Advanced NSCLC (aNSCLC) patients selected from the deidentified Flatiron Health electronic health record-derived database were stratified into early- and delayed-use cohorts based on initiation of ALKi treatment relative to time since receiving ALK+ biomarker test results; cohorts were further stratified by timing of chemotherapy initiation relative to availability of ALK+ test results. Prescription-time matching (PTM) was used to examine the effect of delayed ALKi treatment and chemotherapy on survival; Cox proportional hazards models adjusting for baseline characteristics before and after PTM were used to examine factors associated with delayed ALKi treatment and the effects of delayed ALKi treatment and chemotherapy on OS, respectively. RESULTS: Comparison of OS between early- and delayed-use cohorts (N = 442 ALK + aNSCLC patients) demonstrated that a >3-week delay in the initiation of ALKi treatment was associated with a >2-fold higher risk of death (adjusted hazard ratio [HR] [95 % CI] 2.05 [1.13, 3.71]. The number of office visits, age factors, and use of chemotherapy were associated with an increased risk of being untreated >3 weeks after ALK+ test results. There were no significant differences in survival outcomes regardless of whether patients received chemotherapy before the ALK+ test result or ALKi treatment (adjusted HR [95 % CI] 1.02 [0.64, 1.63]). Completing the chemotherapy regimen after receiving ALK+ test results did not appear to improve survival (adjusted HR [95 % CI] 0.84 [0.38, 1.9]). CONCLUSION: Initiating ALKi treatment for aNSCLC patients in a timely manner may have a positive impact on survival outcomes.

Chromosomal rearrangements and their neoantigenic potential in mesothelioma.

Chromosomal rearrangements are a defining molecular feature of mesothelioma that are not readily detected by standard DNA sequencing approaches but could be detected by whole genome sequencing methods such as mate-pair sequencing. These chromosomal rearrangements result in novel, unique gene junctions that can be expressed and potentially result in the presentation of several neoantigens. These predicted neoantigens can be presented by tumors on major histocompatibility complex (MHC) proteins and are correlated with clonal expansion of tumor infiltrating T cells. T cells responsive to these neoantigens have been identified in the circulation of a patient. The predictive values of next generation sequencing-based tumor mutation burden measurements may be significantly enhanced by the addition of techniques such as mate-pair sequencing that can detect chromosomal rearrangements. Furthermore, rearrangement associated neo-antigens may also represent valuable targets for future anti-tumor vaccine strategies. Finally, chromosomal rearrangements are now recognized as a mutation signature in cancer and these events are likely to be important in the oncogenesis and immune recognition of not only in mesothelioma but multiple malignancies including non-small cell lung cancer.

B7-H1 expression in malignant pleural mesothelioma is associated with sarcomatoid histology and poor prognosis.

INTRODUCTION: B7 homolog 1 (B7-H1; aka programmed cell death 1 ligand 1) is a negative costimulatory molecule that is associated with poor prognosis in many tumor types. Given the poor prognosis and the limited treatments available for mesothelioma, we decided to examine B7-H1 expression and its association with survival in patients with mesothelioma. METHODS: Expression of B7-H1 was determined in 106 patients using a mouse monoclonal antihuman B7-H1 (clone 5H1-A3) antibody with immunohistochemistry. Positive expression was defined as ≥5% positively stained cells. Clinicopathologic features and survival were compared between B7-H1-positive and B7-H1-negative groups. RESULTS: Malignant mesotheliomas of 42 patients (40%) expressed B7-H1. Patients with B7-H1-postive tumors were less likely to be offered or undergo therapeutic surgery (p = 0.03). All sarcomatoid mesotheliomas except one desmoplastic subtype expressed B7-H1. Survival was significantly decreased for patients whose tumors expressed B7-H1 (5 months median, 2-9.5 months interquartile range) compared with those whose tumors did not (14.5 months, 9.25-19 months; p < 0.0001). In a multivariate model, B7-H1 expression and sarcomatoid mesothelioma remained significantly associated with worse survival (risk ratio 1.71, 95% confidence interval 1.03-2.78 [p = 0.04] and risk ratio 2.18, 1.08-4.23 [p = 0.03], respectively). CONCLUSIONS: B7-H1 is expressed in a substantial proportion of malignant pleural mesotheliomas and is associated with poor survival. Almost all malignant pleural mesotheliomas with sarcomatoid differentiation expressed B7-H1. The expression of B7-H1 may have important therapeutic implications for the management of malignant pleural mesothelioma.

Metastasis to sentinel lymph nodes in breast cancer is associated with maturation arrest of dendritic cells and poor co-localization of dendritic cells and CD8+ T cells.

The regional immune systems of patients with breast cancer are immunosuppressed. Dendritic cells are professional antigen-presenting cells and present cancer-associated antigens to the adaptive immune system in sentinel lymph nodes. Dendritic cells may promote, or inhibit, an adaptive immune response to specific antigens. Our aim was to assess whether dendritic cells were associated with nodal metastasis in patients with breast cancer. Sentinel lymph nodes of 47 patients with breast cancer with varying degrees of nodal disease and ten controls were evaluated using immunohistochemistry for the accumulation of dendritic cells in general (CD1a(+)), mature dendritic cells (CD208(+)), and plasmacytoid dendritic cells (CD123(+)). Cytotoxic T cell and regulatory T cell accumulation were also evaluated. Sentinel lymph nodes with macrometastases demonstrated fewer mature dendritic cells than sentinel lymph nodes without metastasis (p = 0.028), but not controls. There were fewer mature dendritic cells to cytotoxic T cells in sentinel lymph nodes with metastasis than those without (p = 0.033). Also, there were more regulatory T cells to mature dendritic cells in sentinel lymph nodes with metastasis than those without (p = 0.02). In conclusion, our study suggests that sentinel lymph nodes with metastasis have arrest of maturation of dendritic cells, fewer mature dendritic cell interactions with cytotoxic T cells, and more regulatory T cells than sentinel lymph nodes without metastasis in patients with breast cancer. These findings extend our understanding of regional immunosuppression and suggest that most regional immunosuppressive changes are associated with nodal metastasis in breast cancer.

Brain metastases from hepatocellular carcinoma in US patients.

Hepatocellular carcinoma (HCC) is a disease on the rise in the United States, due to the epidemic of hepatitis C-induced liver disease. Better chemotherapy options, aggressive surgery, and liver transplantation have led to improved patient survival and an increase in late-appearing, distant metastases from HCC. Brain metastases, although formerly thought of as rare manifestations of HCC, may be more likely to come to clinical and pathological attention than extrahepatic metastases in other sites since they often produce clinical symptoms that necessitate neurosurgical intervention and metastasis removal. In addition, brain metastases from HCC are frequently associated with mass-producing hemorrhage, further requiring evacuation. Hence, pathologists are relatively more likely to encounter brain metastases from HCC as surgical specimens than metastases from HCC to some other common sites of spread, such as bone, lymph nodes, or adrenal. Brain metastases from HCC are being increasingly documented in areas of the world with high endemic rates such as Asia, but thus far have only very rarely been reported in patients native to the United States. We describe our institution's experience with three Caucasian US males, two with hepatitis C as risk factors, who developed metastatic HCC to the brain. We expect clinicians and pathologists will encounter more patients with HCC and extrahepatic metastases, particularly those to brain, in the near future.

Pediatric adrenal cortical carcinoma: brain metastases and relationship to NF-1, case reports and review of the literature.

Adrenal cortical carcinoma (ACC) is a rare childhood neoplasm that seldom manifests brain metastases; hence few papers in the literature focus on neurological manifestations associated with ACC. Although ACC is known to be a signature tumor type in several inherited cancer predisposition syndromes, particularly Li Fraumeni, ACC has not been previously associated with neurofibromatosis, type 1 (NF-1), an inherited disorder with frequent CNS lesions that might prompt concern for metastatic disease by neuroimaging studies. We present two pediatric patients with ACC and unusual CNS findings. The first child developed metastasis to the brain 4 years after resection of his adrenal primary and 2 and 1 years, respectively, after metastases to the liver and lungs. Soon after our experience with this patient, a girl with known NF-1 presented with virilization; adrenalectomy disclosed an ACC and systemic metastases were found within months. Disseminated disease prompted concern that her complex intracranial lesions identified by neuroimaging studies might represent brain metastases, but this proved to be NF1-related hamartomatous lesions. We review the literature on ACCs in pediatric patients regarding brain metastases and previous associations with NF-1.