Lymphocytic Infiltration and Immune Escape Mechanisms in Human Chordoma

Recent advances in immunotherapy for cancer have led to increasing interest in the role of the immune system in the pathogenesis and treatment of various tumors. Tumor-infiltrating lymphocytes have been associated with more favorable prognoses in a number of malignancies, though the mechanism of such outcomes remains unclear. This study, to our knowledge, is the first to describe lymphocytic infiltration in chordoma. Slides from 62 patients with chordoma were evaluated for lymphocyte infiltrates. Lymphocytic infiltration was found in 84% of tumors. Twenty-four tumors were selected for immunohistochemical (IHC) analysis. All of the tumors with lymphocytic infiltration that underwent IHC staining had CD4-positive lymphocytes present. CD8-positive lymphocytes were noted in 52% of tumors. HLA class I antigen defects were noted in 79% of chordoma tumors. These included negative membranous and/or cytoplasmic staining patterns, weakly positive staining, and heterogeneous combinations of these defects. Both heavy chain isoforms and beta-2-microglobulin components were affected. Our novel finding of intratumoral lymphocytes in chordoma tumors suggests that a patient’s immune system mounts a response against their tumor. The absence of HLA class I antigen components is compatible with the possibility that a patient’s immune response imposes selective pressure that facilitates the outgrowth of chordoma cell subpopulations that have developed escape mechanisms from host immune recognition. While the clinical significance requires further evaluation, these data have implications in optimally selecting patients for appropriate treatment regimens. We believe these data will spark further inquiry into the role of immunotherapy in the treatment of chordoma and other bone tumors

Blocking the formation of radiation–induced breast cancer stem cells

The goal of adjuvant (post-surgery) radiation therapy (RT) for breast cancer (BC) is to eliminate residual cancer cells, leading to better local tumor control and thus improving patient survival. However, radioresistance increases the risk of tumor recurrence and negatively affects survival. Recent evidence shows that breast cancer stem cells (BCSCs) are radiation-resistant and that relatively differentiated BC cells can be reprogrammed into induced BCSCs (iBCSCs) via radiation-induced re-expression of the stemness genes. Here we show that in irradiation (IR)-treated mice bearing syngeneic mammary tumors, IR-induced stemness correlated with increased spontaneous lung metastasis (51.7%). However, IR-induced stemness was blocked by targeting the NF-κB- stemness gene pathway with disulfiram (DSF)and Copper (Cu2+). DSF is an inhibitor of aldehyde dehydrogenase (ALDH) and an FDA-approved drug for treating alcoholism. DSF binds to Cu2+ to form DSF-Cu complexes (DSF/Cu), which act as a potent apoptosis inducer and an effective proteasome inhibitor, which, in turn, inhibits NF-κB activation. Treatment of mice with RT and DSF significantly inhibited mammary primary tumor growth (79.4%) and spontaneous lung metastasis (89.6%) compared to vehicle treated mice. This anti-tumor efficacy was associated with decreased stem cell properties (or stemness) in tumors. We expect that these results will spark clinical investigation of RT and DSF as a novel combinatorial treatment for breast cancer

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p<0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p<0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p<0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP >5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Carbon Fiber Implants in Orthopaedic Oncology

Carbon fiber offers numerous material benefits including reduced wear, high strength-to-weight ratio, a similar elastic modulus to that of bone, and high biocompatibility. Carbon fiber implants are increasingly used in multiple arenas within orthopaedic surgery, including spine, trauma, arthroplasty, and oncology. In the orthopaedic oncologic population, the radiolucency of carbon fiber facilitates post-operative imaging for tumor surveillance or recurrence, the monitoring of bony healing and union, and radiation mapping and delivery

The Use of the Lateral Tibial Line to Assess Ankle Alignment: A Preliminary Investigation

BACKGROUND: Although the medial clear space (MCS) is commonly used to assess talar alignment and ankle stability, its measurement is variable with multiple reported normal values. We have observed that the lateral tibial shaft is a reliable landmark to assess talar alignment. The objective of the current investigation was to determine the normal relationship of the lateral tibia to the superolateral talus using a tangent drawn inferiorly from the lateral tibial shaft, which we refer to as the lateral tibial line (LTL). METHODS: The relationship of the LTL to the superolateral talus was assessed by three reviewers on 99 standing ankle mortise radiographs in uninjured patients. This relationship was quantified by measuring the distance (in millimeters) between the LTL and the superolateral talus. In addition, the interobserver reliability of the LTL measurement was recorded and compared with that of the MCS. RESULTS: The median value for the distance between the superolateral talus and LTL was -0.50 mm with an interquartile range of -1.4 to 0.0 mm. The LTL was within 1 mm of the lateral talus in 176 of 297 reviewer measurements (59.3%). Moreover, it was either lateral to or at most 1 mm medial to the lateral talus in 90.9% of cases. The LTL measurement also demonstrated good interobserver reliability (0.764, 95% confidence interval, 0.670 to 0.834), similar to the measurement of MCS (0.742, 95% confidence interval, 0.539 to 0.846). CONCLUSIONS: The relationship between the LTL and superolateral talus is easily measured with good reliability for assessing the anatomic relationship of the tibia and talus. The LTL uncommonly fell more than 1 mm medial to the superolateral talus, as might be seen with displaced ankle fractures. These findings will hopefully serve as a basis for future studies evaluating its role in assessing lateral displacement and stability of isolated fibula fractures. LEVEL OF EVIDENCE: Level III, retrospective review

Rare Incidence of Congestive Heart Failure in Gastrointestinal Stromal Tumor and Other Sarcoma Patients Receiving Imatinib Mesylate

BACKGROUND: We sought to determine the incidence and severity of cardiovascular toxicity due to imatinib mesylate(IM) in GIST and other sarcoma patients, and to explore cardiotoxicity due to IM using cell culture and in vitro models. METHODS: To determine the incidence and significance of serious cardiac adverse events in GIST and other sarcoma patients receiving IM, we performed a retrospective analysis of 219 consecutive patients treated with IM. In vitro studies of IM on cultured cardiomyocytes and biochemical studies of cardiac lysates from mice treated with IM were performed to define the potential cardiotoxic effects of IM. RESULTS: Grade III or IV potentially cardiotoxic adverse events (mostly edema or effusions) occurred in 8.2% of patients, were manageable with medical therapy, and infrequently required dose reduction or discontinuation of IM. Arrhythmias, acute coronary syndromes, or heart failure were uncommon, occurring in less than 1% of treated patients. However, administration of imatinib in a mouse model system resulted in inhibition of activation of protein kinases that are known to be important in the cardiac stress response. CONCLUSION: We conclude that imatinib is an uncommon cause of cardiotoxicity and that the cardiovascular adverse events that occur are manageable when recognized and treated. Nevertheless, our pre-clinical findings suggest that imatinib remains a potential cardiotoxin. Furthermore the cardiac consequences of long-term imatinib therapy remain unknown. We therefore recommend treatment of risk factors for cardiovascular disease in imatinib treated patients in accord with the American Heart Association guidelines for the prevention and treatment of heart failure

The Use of the Lateral Tibial Line to Assess Ankle Alignment: A Preliminary Investigation

Category: Ankle; Trauma Introduction/Purpose: Although the medial clear space (MCS) is commonly used to assess talar alignment and ankle stability, its measurement is variable with multiple reported “normal” values. We have observed that the lateral tibial shaft is a reliable landmark to assess talar alignment. The objective of the current investigation was to determine the normal relationship of the lateral tibia to the superolateral talus using a tangent drawn inferiorly from the lateral tibial shaft, which we refer to as the “lateral tibial line” (LTL). Methods: The relationship of the LTL to the superolateral talus was assessed and characterized on ninety-nine standing ankle mortise radiographs in uninjured patients. This relationship was quantified by measuring the distance (in millimeters) between the LTL and the superolateral talus. Additionally, the inter-observer reliability of the LTL measurement, determined by three reviewers, was recorded and compared to medial clear space measurements. Results: The median value for the lateral tibial line was -0.50 mm with an interquartile range of -1.4mm - 0.0mm. The LTL was within 1mm of the lateral talus in 176 of 297 reviewer measurements (59.3%). Moreover, it was either lateral to or was at most 1mm medial to the lateral talus in 90.9% of cases. The LTL measurement also demonstrated good inter-observer reliability (0.764, 95% CI: 0.670-0.834), similar to the measurement of MCS (0.742, 95% CI: 0.539-0.846). Conclusion: The LTL is easily measured with good reliability for assessing the anatomic relationship of the tibia and talus. It uncommonly fell more than 1 mm medial to the superolateral talus. In other words, it was uncommon for the talus to shift lateral to this line, as might be seen with displaced ankle fractures. These findings will hopefully serve as a standard for future studies evaluating the role of the LTL in assessing lateral displacement and stability of isolated fibula fractures

Cardiomyocyte PDGFR-β signaling is an essential component of the mouse cardiac response to load-induced stress

PDGFR is an important target for novel anticancer therapeutics because it is overexpressed in a wide variety of malignancies. Recently, however, several anticancer drugs that inhibit PDGFR signaling have been associated with clinical heart failure. Understanding this effect of PDGFR inhibitors has been difficult because the role of PDGFR signaling in the heart remains largely unexplored. As described herein, we have found that PDGFR-β expression and activation increase dramatically in the hearts of mice exposed to load-induced cardiac stress. In mice in which Pdgfrb was knocked out in the heart in development or in adulthood, exposure to load-induced stress resulted in cardiac dysfunction and heart failure. Mechanistically, we showed that cardiomyocyte PDGFR-β signaling plays a vital role in stress-induced cardiac angiogenesis. Specifically, we demonstrated that cardiomyocyte PDGFR-β was an essential upstream regulator of the stress-induced paracrine angiogenic capacity (the angiogenic potential) of cardiomyocytes. These results demonstrate that cardiomyocyte PDGFR-β is a regulator of the compensatory cardiac response to pressure overload–induced stress. Furthermore, our findings may provide insights into the mechanism of cardiotoxicity due to anticancer PDGFR inhibitors