Nivolumab monotherapy or combination with ipilimumab with or without cobimetinib in previously treated patients with pancreatic adenocarcinoma (CheckMate 032).

Background: Pancreatic cancer is one of the deadliest cancer types and represents a major unmet medical need. CheckMate 032 investigated safety and efficacy of nivolumab monotherapy and nivolumab plus ipilimumab with/without cobimetinib in advanced/metastatic solid tumors, including pancreatic cancer.

Methods: In the original pancreatic cancer cohort, previously treated patients (≥1 prior regimen) with advanced/metastatic pancreatic adenocarcinoma were assigned to nivolumab 3 mg/kg every 2 weeks (monotherapy arm) or nivolumab 1 mg/kg and ipilimumab 1 mg/kg or 3 mg/kg every 3 weeks for four doses, followed by nivolumab 3 mg/kg every 2 weeks (combination arm).

A Randomized Trial of Autologous Chondrocyte Implantation Versus Alternative Forms of Surgical Cartilage Management in Patients With a Failed Primary Treatment for Chondral or Osteochondral Defects in the Knee.

Background: There are limited randomized controlled trials with long-term outcomes comparing autologous chondrocyte implantation (ACI) versus alternative forms of surgical cartilage management within the knee.

Purpose: To determine at 5 years after surgery whether ACI was superior to alternative forms of cartilage management in patients after a failed previous treatment for chondral or osteochondral defects in the knee.

Study Design: Randomized controlled trial; Level of evidence, 1.

Broken guidewire retrieval from the hip joint: A case report.

Hardware breakage during orthopaedic surgery especially closed intramedullary nailing is a nightmare for orthopaedic surgeons. During hip fracture surgery a mechanical failure of the guidewire or the reamer poses an additional risk of intrapelvic migration and neurovascular or visceral injury which can lead to devastating complications and litigation. We report a case of removal of the broken guidewire using a cannulated reamer & discectomy forceps and recommend some suggestions for prevention of this catastrophe.

A human CD137×PD-L1 bispecific antibody promotes anti-tumor immunity via context-dependent T cell costimulation and checkpoint blockade.

Immune checkpoint inhibitors demonstrate clinical activity in many tumor types, however, only a fraction of patients benefit. Combining CD137 agonists with these inhibitors increases anti-tumor activity preclinically, but attempts to translate these observations to the clinic have been hampered by systemic toxicity. Here we describe a human CD137xPD-L1 bispecific antibody, MCLA-145, identified through functional screening of agonist- and immune checkpoint inhibitor arm combinations.

Addition of anti-TIM3 or anti-TIGIT Antibodies to anti-PD1 Blockade Augments Human T cell Adoptive Cell Transfer.

PD1 blockade to reinvigorate T cells has become part of standard of care for patients with NSCLC across disease stages. However, the majority of patients still do not respond. One potential mechanism of resistance is increased expression of other checkpoint inhibitory molecules on T cells leading to their suppression; however, this phenomenon has not been well studied in T cells.

Neoadjuvant Gene-Mediated Cytotoxic Immunotherapy for Non-Small-Cell Lung Cancer: Safety and Immunologic Activity.

Gene-mediated cytotoxic immunotherapy (GMCI) is an immuno-oncology approach involving local delivery of a replication-deficient adenovirus expressing herpes simplex thymidine kinase (AdV-tk) followed by anti-herpetic prodrug activation that promotes immunogenic tumor cell death, antigen-presenting cell activation, and T cell stimulation. This phase I dose-escalation pilot trial assessed bronchoscopic delivery of AdV-tk in patients with suspected lung cancer who were candidates for surgery. A single intra-tumoral AdV-tk injection in three dose cohorts (maximum 10 viral particles) was performed during diagnostic staging, followed by a 14-day course of the prodrug valacyclovir, and subsequent surgery 1 week later.

Phenotypic and functional analysis of malignant mesothelioma tumor-infiltrating lymphocytes.

Given the growing interest and promising preliminary results of immunotherapy in malignant pleural mesothelioma (MPM), it has become important to more fully understand the immune landscape in this tumor. This may be especially relevant in deciding who might benefit most from checkpoint blockade or agonist antibody therapy. Since the phenotype of tumor infiltrating lymphocytes (TILs) in MPM has not been fully described and their function has not been carefully assessed, we collected fresh tumor and blood from 22 patients undergoing surgical resection and analysed single cell suspensions by flow cytometry.

Function of Human Tumor-Infiltrating Lymphocytes in Early-Stage Non-Small Cell Lung Cancer.

Cancer progression is marked by dysfunctional tumor-infiltrating lymphocytes (TIL) with high inhibitory receptor (IR) expression. Because IR blockade has led to clinical responses in some patients with non-small cell lung cancer (NSCLC), we investigated how IRs influenced CD8 TIL function from freshly digested early-stage NSCLC tissues using a killing assay and intracellular cytokine staining after T-cell restimulation. Early-stage lung cancer TIL function was heterogeneous with only about one third of patients showing decrements in cytokine production and lytic function.

Human tumor-associated monocytes/macrophages and their regulation of T cell responses in early-stage lung cancer.

Data from mouse tumor models suggest that tumor-associated monocyte/macrophage lineage cells (MMLCs) dampen antitumor immune responses. However, given the fundamental differences between mice and humans in tumor evolution, genetic heterogeneity, and immunity, the function of MMLCs might be different in human tumors, especially during early stages of disease. Here, we studied MMLCs in early-stage human lung tumors and found that they consist of a mixture of classical tissue monocytes and tumor-associated macrophages (TAMs).

Epigenomic-Guided Mass Cytometry Profiling Reveals Disease-Specific Features of Exhausted CD8 T Cells.

Exhausted CD8 T (Tex) cells are immunotherapy targets in chronic infection and cancer, but a comprehensive assessment of Tex cell diversity in human disease is lacking. Here, we developed a transcriptomic- and epigenetic-guided mass cytometry approach to define core exhaustion-specific genes and disease-induced changes in Tex cells in HIV and human cancer. Single-cell proteomic profiling identified 9 distinct Tex cell clusters using phenotypic, functional, transcription factor, and inhibitory receptor co-expression patterns.

CAR T Cell Therapy for Solid Tumors.

The field of cancer immunotherapy has been re-energized by the application of chimeric antigen receptor (CAR) T cell therapy in cancers. These CAR T cells are engineered to express synthetic receptors that redirect polyclonal T cells to surface antigens for subsequent tumor elimination. Many CARs are designed with elements that augment T cell persistence and activity.

Origin and Role of a Subset of Tumor-Associated Neutrophils with Antigen-Presenting Cell Features in Early-Stage Human Lung Cancer.

Based on studies in mouse tumor models, granulocytes appear to play a tumor-promoting role. However, there are limited data about the phenotype and function of tumor-associated neutrophils (TANs) in humans. Here, we identify a subset of TANs that exhibited characteristics of both neutrophils and antigen-presenting cells (APCs) in early-stage human lung cancer.

Augmentation of CAR T-cell Trafficking and Antitumor Efficacy by Blocking Protein Kinase A Localization.

Antitumor treatments based on the infusion of T cells expressing chimeric antigen receptors (CAR T cells) are still relatively ineffective for solid tumors, due to the presence of immunosuppressive mediators [such as prostaglandin E2 (PGE2) and adenosine] and poor T-cell trafficking. PGE2 and adenosine activate protein kinase A (PKA), which then inhibits T-cell receptor (TCR) activation. This inhibition process requires PKA to localize to the immune synapse via binding to the membrane protein ezrin.

Provision of total hip replacement for displaced intracapsular hip fracture and the outcomes: audit of local practice based on NICE guidelines.

Introduction: Hip fractures are becoming an increasing public health issue due to an ageing population (1). Total hip replacements (THR) produce better outcomes in certain patients who were functioning independently before the injury (2). We aimed to assess whether the management of intracapsular hip fracture is carried out in accordance with the National Institute for Health and Care Excellence (NICE) hip fracture guidance (1) and the outcomes with regards to performing THRs on those patients who fulfil the described criteria.

HDAC5 controls the functions of Foxp3(+) T-regulatory and CD8(+) T cells.

Histone/protein deacetylases (HDACs) are frequently upregulated in human malignancies and have therefore become therapeutic targets in cancer therapy. However, inhibiting certain HDAC isoforms can have protolerogenic effects on the immune system, which could make it easier for tumor cells to evade the host immune system. Therefore, a better understanding of how each HDAC isoform affects immune biology is needed to develop targeted cancer therapy.

Blockade of Programmed Death 1 Augments the Ability of Human T Cells Engineered to Target NY-ESO-1 to Control Tumor Growth after Adoptive Transfer.

Purpose: Tumor-infiltrating lymphocytes (TILs) become hypofunctional, although the mechanisms are not clear. Our goal was to generate a model of human tumor-induced TIL hypofunction to study mechanisms and to test anti-human therapeutics.

Experimental Design: We transduced human T cells with a published, optimized T-cell receptor (TCR) that is directed to a peptide within the cancer testis antigen, NY-ESO-1.

CD38-Expressing Myeloid-Derived Suppressor Cells Promote Tumor Growth in a Murine Model of Esophageal Cancer.

Myeloid-derived suppressor cells (MDSC) are an immunosuppressive population of immature myeloid cells found in advanced-stage cancer patients and mouse tumor models. Production of inducible nitric oxide synthase (iNOS) and arginase, as well as other suppressive mechanisms, allows MDSCs to suppress T-cell-mediated tumor clearance and foster tumor progression. Using an unbiased global gene expression approach in conditional p120-catenin knockout mice (L2-cre;p120ctn(f/f)), a model of oral-esophageal cancer, we have identified CD38 as playing a vital role in MDSC biology, previously unknown.

Tumor-Promoting Desmoplasia Is Disrupted by Depleting FAP-Expressing Stromal Cells.

Malignant cells drive the generation of a desmoplastic and immunosuppressive tumor microenvironment. Cancer-associated stromal cells (CASC) are a heterogeneous population that provides both negative and positive signals for tumor cell growth and metastasis. Fibroblast activation protein (FAP) is a marker of a major subset of CASCs in virtually all carcinomas.

Increased systolic blood pressure reactivity to acute stress is related with better self-reported health.

The stress reactivity hypothesis posits that the magnitude of cardiovascular reactions to acute stress tasks is related with future blood pressure status, heart hypertrophy, and atherosclerosis. We assessed the stress reactivity hypothesis and aimed to identify which physiological indices (blood pressure, heart-rate, cortisol, salivary immunoglobulin A (sIgA)) related to self-reported mental and physical health. We also assessed if physiological reactions elicited by an acute stressor were more related than basal assessments.

Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production.

Naive CD4(+) T cells require signals from the TCR and CD28 to produce IL-2, expand, and differentiate. However, these same signals are not sufficient to induce autocrine IL-2 production by naive CD8(+) T cells, which require cytokines provided by other cell types to drive their differentiation. The basis for failed autocrine IL-2 production by activated CD8(+) cells is unclear.

Antibiotic prophylaxis for hip fracture surgery: three-dose cefuroxime versus single-dose gentamicin and amoxicillin.

Purpose: To compare a 3-dose cefuroxime regimen with a single-dose gentamicin and amoxicillin regimen as antibiotic prophylaxis for hip hemiarthroplasty in terms of microbiological outcome.

Methods: Records of 2 matched groups of patients who underwent hip hemiarthroplasty for femoral neck fractures were reviewed. 29 men and 84 women (mean age, 82 years) who received a 3-dose cefuroxime regimen in 2006 were compared with 23 men and 84 women (mean age, 83 years) who received a single-dose gentamicin and amoxicillin regimen in 2008.

Management of significant and widespread, acute subcutaneous emphysema: should we manage surgically or conservatively?

Background: Subcutaneous emphysema of a limb after acute injury is classically associated with gas gangrene. Delayed management can result in amputation and death. Typically caused by a clostridial infection, patients are unwell, with rapidly spreading clinical signs, abnormal laboratory results, and cultures positive.

The use of a revision femoral stem to manage a distal femoral periprosthetic fracture in a well-fixed total knee arthroplasty.

Managing very distal femoral periprosthetic fracture above a total knee arthroplasty (TKA) is a difficult problem. When a cruciate sacrificing TKA is used, bone stock around the implant is compromised and, therefore, can limit fixation options. We present technique using the revision system femoral stem for the PFC Sigma TKA (Depuy; Leeds, England) to stabilize this particular type of fracture.

Pericyte requirement for anti-leak action of angiopoietin-1 and vascular remodeling in sustained inflammation.

Blood vessel leakiness is an early, transient event in acute inflammation but can also persist as vessels undergo remodeling in sustained inflammation. Angiopoietin/Tie2 signaling can reduce the leakiness through changes in endothelial cells. The role of pericytes in this action has been unknown.

Angiopoietin/Tie2 signaling transforms capillaries into venules primed for leukocyte trafficking in airway inflammation.

Vascular endothelial growth factor (VEGF) is a key angiogenic factor in tumors, but less is known about what drives vascular remodeling in inflammation, where plasma leakage and leukocyte influx are prominent features. In chronic airway inflammation in mice infected by the bacterium Mycoplasma pulmonis (M. pulmonis), the segment of the microvasculature that supports leukocyte adhesion and migration expands through remodeling of capillaries into vessels with features of venules.