Myositis/myasthenia after pembrolizumab in a bladder cancer patient with an autoimmunity-associated HLA: Immune\u2013biological evaluation and case report

Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe immune-related (ir) adverse events (AEs). Here, we report the clinical and immune\u2013biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting

Changes in gene expression in human skeletal stem cells transduced with constitutively active Gs\u3b1 correlates with hallmark histopathological changes seen in fibrous dysplastic bone

Fibrous dysplasia (FD) of bone is a complex disease of the skeleton caused by dominant activating mutations of the GNAS locus encoding for the \u3b1 subunit of the G protein-coupled receptor complex (Gs\u3b1). The mutation involves a substitution of arginine at position 201 by histidine or cysteine (Gs\u3b1R201H or R201C), which leads to overproduction of cAMP. Several signaling pathways are implicated downstream of excess cAMP in the manifestation of disease. However, the pathogenesis of FD remains largely unknown. The overall FD phenotype can be attributed to alterations of skeletal stem/progenitor cells which normally develop into osteogenic or adipogenic cells (in cis), and are also known to provide support to angiogenesis, hematopoiesis, and osteoclastogenesis (in trans). In order to dissect the molecular pathways rooted in skeletal stem/progenitor cells by FD mutations, we engineered human skeletal stem/progenitor cells with the Gs\u3b1R201C mutation and performed transcriptomic analysis. Our data suggest that this FD mutation profoundly alters the properties of skeletal stem/progenitor cells by pushing them towards formation of disorganized bone with a concomitant alteration of adipogenic differentiation. In addition, the mutation creates an altered in trans environment that induces neovascularization, cytokine/chemokine changes and osteoclastogenesis. In silico comparison of our data with the signature of FD craniofacial samples highlighted common traits, such as the upregulation of ADAM (A Disintegrin and Metalloprotease) proteins and other matrix-related factors, and of PDE7B (Phosphodiesterase 7B), which can be considered as a buffering process, activated to compensate for excess cAMP. We also observed high levels of CEBPs (CCAAT-Enhancer Binding Proteins) in both data sets, factors related to browning of white fat. This is the first analysis of the reaction of human skeletal stem/progenitor cells to the introduction of the FD mutation and we believe it provides a useful background for further studies on the molecular basis of the disease and for the identification of novel potential therapeutic targets

GOLFIG Chemo-Immunotherapy in Metastatic Colorectal Cancer Patients. A Critical Review on a Long-Lasting Follow-Up

Background: GOLFIG is a chemo-immunotherapy regimen established in preclinical models that combines gemcitabine + FOLFOX (fluoropyrimidine backbone coupled to oxaliplatin) poly-chemotherapy with low-dose s. c. recombinant interleukin-2 (rIL-2) and granulocyte-macrophage colony stimulating factor (GM-CSF). Promising antitumor effects in metastatic colorectal cancer (mCRC) patients were obtained in previous phase II and III trials. Here we report the results of 15 years of follow-up. Methods: This is a multi-institutional retrospective analysis including 179 mCRC patients receiving GOLFIG regimen between June 2002 and June 2018. Sixty-two of them received the treatment as frontline (enrolled in the GOLFIG-2 phase III trial) and 117 as second/third line (49 enrolled in the GOLFIG-1 phase II trial and 68 as compassionate use). One hundred twelve patients showed a primary left side and 67 a primary right side; K/N-ras mutational status was available in 74 cases, and an activating mutation was detected in 33. Kaplan–Meier and Cox regression analyses were carried out to relate PFS and OS with different parameters. Results: Overall, we recorded a mean PFS and OS of 15.28 (95% CI: 10.36–20.20) and 24.6 (95% CI: 19.07–30.14) months, respectively, with 14 patients surviving free of progression for 10 years. This regimen, in our updated survey of the GOLFIG-2 trial, confirmed superiority over FOLFOX in terms of PFS (hazard ratio (HR) = 0.58, p = 0.006) with a trend to a longer OS (HR = 0.69, P = 0.06) in the first line. Our analysis also confirmed significant antitumor activity in pre-treated patients, reporting a mean PFS and OS of 12.55 (95% CI: 7.19–17.9) and 20.28 (95% CI: 14.4–26.13) months, respectively. Immune-related adverse events (irAEs) were recorded in 24% of the cases and were related to a longer survival (HR = 0.36; P = 0.0001). Finally, patients' outcome was not correlated to sex, sidedness, and MT-K/N-ras. Conclusions: The GOLFIG regimen is a reliable underestimated therapeutic option in pre-treated mCRC patients and offers a strong rationale to design further trials

PRMT1-dependent regulation of RNA metabolism and DNA damage response sustains pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer that has remained clinically challenging to manage. Here we employ an RNAi-based in vivo functional genomics platform to determine epigenetic vulnerabilities across a panel of patient-derived PDAC models. Through this, we identify protein arginine methyltransferase 1 (PRMT1) as a critical dependency required for PDAC maintenance. Genetic and pharmacological studies validate the role of PRMT1 in maintaining PDAC growth. Mechanistically, using proteomic and transcriptomic analyses, we demonstrate that global inhibition of asymmetric arginine methylation impairs RNA metabolism, which includes RNA splicing, alternative polyadenylation, and transcription termination. This triggers a robust downregulation of multiple pathways involved in the DNA damage response, thereby promoting genomic instability and inhibiting tumor growth. Taken together, our data support PRMT1 as a compelling target in PDAC and informs a mechanism-based translational strategy for future therapeutic development. Statement of significance PDAC is a highly lethal cancer with limited therapeutic options. This study identified and characterized PRMT1-dependent regulation of RNA metabolism and coordination of key cellular processes required for PDAC tumor growth, defining a mechanism-based translational hypothesis for PRMT1 inhibitors

Modulation of the thalamus by microburst vagus nerve stimulation: a feasibility study protocol

Vagus nerve stimulation (VNS) was the first device-based therapy for epilepsy, having launched in 1994 in Europe and 1997 in the United States. Since then, significant advances in the understanding of the mechanism of action of VNS and the central neurocircuitry that VNS modulates have impacted how the therapy is practically implemented. However, there has been little change to VNS stimulation parameters since the late 1990s. Short bursts of high frequency stimulation have been of increasing interest to other neuromodulation targets e.g., the spine, and these high frequency bursts elicit unique effects in the central nervous system, especially when applied to the vagus nerve. In the current study, we describe a protocol design that is aimed to assess the impact of high frequency bursts of stimulation, called “Microburst VNS”, in subjects with refractory focal and generalized epilepsies treated with this novel stimulation pattern in addition to standard anti-seizure medications. This protocol also employed an investigational, fMRI-guided titration protocol that permits personalized dosing of Microburst VNS among the treated population depending on the thalamic blood-oxygen-level-dependent signal. The study was registered on clinicaltrials.gov (NCT03446664). The first subject was enrolled in 2018 and the final results are expected in 2023

Integrative Genomic Analysis of Cholangiocarcinoma Identifies Distinct IDH -Mutant Molecular Profiles

Cholangiocarcinoma (CCA) is an aggressive malignancy of the bile ducts, with poor prognosis and limited treatment options. Here, we describe the integrated analysis of somatic mutations, RNA expression, copy number, and DNA methylation by The Cancer Genome Atlas of a set of predominantly intrahepatic CCA cases and propose a molecular classification scheme. We identified an IDH mutant-enriched subtype with distinct molecular features including low expression of chromatin modifiers, elevated expression of mitochondrial genes, and increased mitochondrial DNA copy number. Leveraging the multi-platform data, we observed that ARID1A exhibited DNA hypermethylation and decreased expression in the IDH mutant subtype. More broadly, we found that IDH mutations are associated with an expanded histological spectrum of liver tumors with molecular features that stratify with CCA. Our studies reveal insights into the molecular pathogenesis and heterogeneity of cholangiocarcinoma and provide classification information of potential therapeutic significance

The somatic genomic landscape of glioblastoma

We describe the landscape of somatic genomic alterations based on multidimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors, including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

The Somatic Genomic Landscape of Glioblastoma

We describe the landscape of somatic genomic alterations based on multi-dimensional and comprehensive characterization of more than 500 glioblastoma tumors (GBMs). We identify several novel mutated genes as well as complex rearrangements of signature receptors including EGFR and PDGFRA. TERT promoter mutations are shown to correlate with elevated mRNA expression, supporting a role in telomerase reactivation. Correlative analyses confirm that the survival advantage of the proneural subtype is conferred by the G-CIMP phenotype, and MGMT DNA methylation may be a predictive biomarker for treatment response only in classical subtype GBM. Integrative analysis of genomic and proteomic profiles challenges the notion of therapeutic inhibition of a pathway as an alternative to inhibition of the target itself. These data will facilitate the discovery of therapeutic and diagnostic target candidates, the validation of research and clinical observations and the generation of unanticipated hypotheses that can advance our molecular understanding of this lethal cancer

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Elbow arthroplasty: current techniques and complications

This handbook provides detailed, state-of-the-art information on total elbow replacement, covering all relevant aspects, from basic science and pathogenesis to clinical and instrumental evaluation, and treatment techniques. Elbow arthroplasties have undergone a considerable evolution in recent decades due to better anatomical and biomechanical knowledge, continuous development of biomaterials, improvement of operative techniques and better definition of the surgical indications. This book enables readers to better understand the main indications, the outcomes and the complications following total elbow arthroplasty, radial head arthroplasty, radiocapitellar arthroplasty and distal humerus hemiarthroplasty. The closing section addressing the post-operative management of the patients who have undergone elbow replacement is provided in order to optimize the relationship between the orthopedic surgeon and the rehabilitation physician. Written by leading experts in the field, the book is an invaluable tool for experienced surgeons, orthopedic residents and shoulder fellows