Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis

ObjectivePancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood.DesignThe impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment.ResultsWe show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants.ConclusionCombining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.

Spatiotemporal Quantification of Metastatic Tumour Cell Growth and Distribution in Lymph Nodes by Whole-Mount Tissue 3D Imaging

Lymph nodes (LNs) are a common site of metastasis in many solid cancers. Tumour cells can migrate to LNs for further metastatic colonization of distant organs, indicating poor prognosis and requiring different clinical interventions. The current histopathological diagnostic methods used for the detection of clinical lymph node metastasis (LNM) still have some limitations, such as incomplete observation. To obtain a complete picture of tumour-metastasized LNs at spatial and temporal scales, we used 3D imaging of solvent-cleared organs (uDISCO) and 3D rapid immunostaining. MC38 cells tagged with EGFP were injected into the left footpad of C57BL/6 mice. Draining lymph nodes (DLNs) obtained from these mice were cleared using uDISCO. Metastatic colorectal cancer (CRC) cells in various regions of DLNs from mice at different time points were quantified using whole-mount tissue 3D imaging. The results revealed several stages of tumour cell growth and distribution in LNs: 1) invasion of lymphatic vessels (LVs) and blood vessels (BVs); 2) dispersion outside LVs and BVs for proliferation and expansion; and 3) re-entry into BVs and efferent lymphatic vessels (ELVs) for further distant metastasis. Moreover, these data demonstrated that mouse fibroblast cells (MFCs) could not only promote the LNM of tumour cells but could also metastasize to LNs together with tumour cells, thus providing a “soil” for tumour cell colonization. In conclusion, whole-mount tissue 3D imaging and spatiotemporal analysis of LNM may together constitute an auxiliary method to improve the accuracy of clinical LNM detection in the future.

The role of thoracoscopic lung biopsy in the management of children with solid organ malignancies and suspected lung metastases in a developing country

Background Accurate diagnosis of lung lesions appearing on computed tomographic (CT) imaging in children with solid organ malignancies can be difficult. Therefore, this study aimed to determine, in a developing country setting, (1) the utility of thoracoscopic lung biopsy for assessment of suspected lung metastases in solid organ malignancies, and (2) the pathology of biopsied lesions suspected to be malignancies. The electronic records of all patients with solid organ malignancies who underwent thoracoscopic lung biopsies for suspected metastases at a tertiary hospital in South Africa between January 2012 and December 2017 were analysed retrospectively. Results A total of 29 thoracoscopic biopsies were taken from 25 patients. In eight biopsies (27.6%), viable metastatic tumour was identified; in one, a completely necrotic tumour was found. Seven patients (28.0%) were found to have infective aetiologies which required alternative therapies: of these, three patients had tuberculosis; three had bronchopneumonia and one had a fungal lung infection. Other findings included haemorrhagic infarction (n = 1); non-specific fibrosis (n = 1) and reactive lymph node (n = 1). In ten biopsies (34.5%), no lesion was found on thoracoscopy. Conclusions Thoracoscopy was found to improve the management of children with solid organ malignancies and suspected metastases. Thoracoscopy enabled many patients to avoid additional chemotherapy and radiotherapy and its negative consequences and enabled therapy for specific benign pathologies including infections.

Acetabular complications are the most common cause for revision surgery following proximal femoral endoprosthetic replacement

Aims Proximal femoral endoprosthetic replacements (PFEPRs) are the most common reconstruction option for osseous defects following primary and metastatic tumour resection. This study aimed to compare the rate of implant failure between PFEPRs with monopolar and bipolar hemiarthroplasties and acetabular arthroplasties, and determine the optimum articulation for revision PFEPRs. Methods This is a retrospective review of 233 patients who underwent PFEPR. The mean age was 54.7 years (SD 18.2), and 99 (42.5%) were male. There were 90 patients with primary bone tumours (38.6%), 122 with metastatic bone disease (52.4%), and 21 with haematological malignancy (9.0%). A total of 128 patients had monopolar (54.9%), 74 had bipolar hemiarthroplasty heads (31.8%), and 31 underwent acetabular arthroplasty (13.3%). Results At a mean 74.4 months follow-up, the overall revision rate was 15.0%. Primary malignancy (p < 0.001) and age < 50 years (p < 0.001) were risk factors for revision. The risks of death and implant failure were similar in patients with primary disease (p = 0.872), but the risk of death was significantly greater for patients who had metastatic bone disease (p < 0.001). Acetabular-related implant failures comprised 74.3% of revisions; however, no difference between hemiarthroplasty or arthroplasty groups (p = 0.209), or between monopolar or bipolar hemiarthroplasties (p = 0.307), was observed. There was greater radiological wear in patients with longer follow-up and primary bone malignancy. Re-revision rates following a revision PFEPR was 34.3%, with dual-mobility bearings having the lowest rate of instability and re-revision (15.4%). Conclusion Hemiarthroplasty and arthroplasty PFEPRs carry the same risk of revision in the medium term, and is primarily due to acetabular complications. There is no difference in revision rates or erosion between monopolar and bipolar hemiarthroplasties. The main causes of failure were acetabular wear in the hemiarthroplasty group and instability in the arthroplasty group. These risks should be balanced and patient prognosis considered when contemplating the bearing choice. Dual-mobility, constrained bearings, or large diameter heads (> 32 mm) are recommended in all revision PFEPRs. Cite this article: Bone Joint J 2021;103-B(10):1633–1640.

Single-cell exome sequencing reveals multiple subclones in metastatic colorectal carcinoma

Background Colorectal cancer (CRC) is a major cancer type whose mechanism of metastasis remains elusive. Methods In this study, we characterised the evolutionary pattern of metastatic CRC (mCRC) by analysing bulk and single-cell exome sequencing data of primary and metastatic tumours from 7 CRC patients with liver metastases. Here, 7 CRC patients were analysed by bulk whole-exome sequencing (WES); 4 of these were also analysed using single-cell sequencing. Results Despite low genomic divergence between paired primary and metastatic cancers in the bulk data, single-cell WES (scWES) data revealed rare mutations and defined two separate cell populations, indicative of the diverse evolutionary trajectories between primary and metastatic tumour cells. We further identified 24 metastatic cell-specific-mutated genes and validated their functions in cell migration capacity. Conclusions In summary, scWES revealed rare mutations that failed to be detected by bulk WES. These rare mutations better define the distinct genomic profiles of primary and metastatic tumour cell clones.

Responsive and Minimalist App Based on Explainable AI to Assess Palliative Care Needs during Bedside Consultations on Older Patients

Palliative care is an alternative to standard care for gravely ill patients that has demonstrated many clinical benefits in cost-effective interventions. It is expected to grow in demand soon, so it is necessary to detect those patients who may benefit from these programs using a personalised objective criterion at the correct time. Our goal was to develop a responsive and minimalist web application embedding a 1-year mortality explainable predictive model to assess palliative care at bedside consultation. A 1-year mortality predictive model has been trained. We ranked the input variables and evaluated models with an increasing number of variables. We selected the model with the seven most relevant variables. Finally, we created a responsive, minimalist and explainable app to support bedside decision making for older palliative care. The selected variables are age, medication, Charlson, Barthel, urea, RDW-SD and metastatic tumour. The predictive model achieved an AUC ROC of 0.83 [CI: 0.82, 0.84]. A Shapley value graph was used for explainability. The app allows identifying patients in need of palliative care using the bad prognosis criterion, which can be a useful, easy and quick tool to support healthcare professionals in obtaining a fast recommendation in order to allocate health resources efficiently.

Expression of TXNIP is associated with angiogenesis and postoperative relapse of conventional renal cell carcinoma

One of the common mediator of tumour progression is the oxidative stress induced by inflammatory tumour microenvironment (TME). Activated fibroblasts, local and immune cells produce reactive oxygen species (ROS) supporting tumour cell proliferation and pave the way for metastatic tumour growth. TXNIP regulates ROS generation by inhibiting the antioxidative function of thioredoxin (TXN). The shift of TXNIP/TXN balance towards overexpression of TXNIP is associated with proliferation of endothelial cells during tumor angiogenesis. The oxidative stress activates the hypoxia inducible factor-1 (HIF-1), which plays an important role in the biology of conventional RCC (cRCC). Under oxydative stress TXNIP interacts with NLRP3 inflammasome leading to maturation and secretion of inflammatory cytokine IL1β. To establish the role of TXNIP and downstream genes HIF1α and IL1β in the biology of cRCC, we have applied immunohistochemistry to multi-tissue arrays containing tumours of 691 patients without detectable metastases at the time of operation. We found that cRCC displaying a fine organised capillary network with nuclear translocation of TXNIP and expressing IL1β have a good prognosis. In contrary, we showed a significant correlation between cytoplasmic TXNIP expression, inefficient vascularisation by unorganized and tortuous vessels causing tumour cell necrosis and postoperative tumour relapse of cRCC.

The role of radiotherapy in locally advanced pancreatic cancer

At diagnosis, about 15% of patients with pancreatic cancer present with a resectable tumour, 50% have a metastatic tumour, and 35% a locally advanced tumour, non-metastatic but unresectable due to vascular invasion, or borderline resectable. Despite the technical progress made in the field of radiation therapy and the improvement of the efficacy of chemotherapy, the prognosis of these patients remains very poor. Recently, the role of radiation therapy in the management of pancreatic cancer has been much debated. This review aims to evaluate the role of radiation therapy for patients with locally advanced tumours.

BILATERAL PROPTOSIS - INITIAL AND RARE PRESENTATION: AML

We report bilateral proptosis as the initial presentation of Acute Myeloid Leukemia (AML) in a child. An Eight year child presented with a history of painless proptosis in the both eyes within 10 days. Radiological investigation (CT scan) showed inltration of orbit with the metastatic tumour cell. AML was diagnosed with complete blood count, General Blood Picture (GBP) and bone marrow biopsy. The presumptive diagnosis of leukemic inltration of the orbit is made. We report this case as AML can rarely present in child as a bilateral proptosis due to leukemic inltration. Urgent treatment modality for this rare condition is radiation.