Severe acute myositis and myocarditis on initiation of 6-weekly pembrolizumab post-COVID-19 mRNA vaccination.

We describe three cases of critical acute myositis with myocarditis occurring within 22 days of each other at a single institution, all within 1 month of receiving the initial cycle of the anti-PD-1 drug pembrolizumab. Analysis of T cell receptor repertoires from peripheral blood and tissues revealed a high degree of clonal expansion and public clones between cases, with several T cell clones expanded within the skeletal muscle putatively recognizing viral epitopes. All patients had recently received a COVID-19 mRNA booster vaccine prior to treatment and were positive for SARS-CoV2 Spike antibody. In conclusion, we report a series of unusually severe myositis and myocarditis following PD-1 blockade and the COVID-19 mRNA vaccination.

IFNγ signaling in cytotoxic T cells restricts anti-tumor responses by inhibiting the maintenance and diversity of intra-tumoral stem-like T cells.

IFNγ is an immune mediator with concomitant pro- and anti-tumor functions. Here, we provide evidence that IFNγ directly acts on intra-tumoral CD8 T cells to restrict anti-tumor responses. We report that expression of the IFNγ receptor ß chain (IFNγR2) in CD8 T cells negatively correlates with clinical responsiveness to checkpoint blockade in metastatic melanoma patients, suggesting that the loss of sensitivity to IFNγ contributes to successful antitumor immunity. Indeed, specific deletion of IFNγR in CD8 T cells promotes tumor control in a mouse model of melanoma. Chronic IFNγ inhibits the maintenance, clonal diversity and proliferation of stem-like T cells. This leads to decreased generation of T cells with intermediate expression of exhaustion markers, previously associated with beneficial anti-tumor responses. This study provides evidence of a negative feedback loop whereby IFNγ depletes stem-like T cells to restrict anti-tumor immunity. Targeting this pathway might represent an alternative strategy to enhance T cell-based therapies.

IL7 genetic variation and toxicity to immune checkpoint blockade in patients with melanoma.

Treatment with immune checkpoint blockade (ICB) frequently triggers immune-related adverse events (irAEs), causing considerable morbidity. In 214 patients receiving ICB for melanoma, we observed increased severe irAE risk in minor allele carriers of rs16906115, intronic to IL7. We found that rs16906115 forms a B cell-specific expression quantitative trait locus (eQTL) to IL7 in patients. Patients carrying the risk allele demonstrate increased pre-treatment B cell IL7 expression, which independently associates with irAE risk, divergent immunoglobulin expression and more B cell receptor mutations. Consistent with the role of IL-7 in T cell development, risk allele carriers have distinct ICB-induced CD8+ T cell subset responses, skewing of T cell clonality and greater proportional repertoire occupancy by large clones. Finally, analysis of TCGA data suggests that risk allele carriers independently have improved melanoma survival. These observations highlight key roles for B cells and IL-7 in both ICB response and toxicity and clinical outcomes in melanoma.

Immune checkpoint blockade sensitivity and progression-free survival associates with baseline CD8+ T cell clone size and cytotoxicity.

The antitumor action of immune checkpoint blockade (ICB) is primarily mediated by CD8+ T cells. How sensitivity to ICB varies across CD8+ T cell subsets and clonotypes and the relationship of these with clinical outcome is unclear. To explore this, we used single-cell V(D)J and RNA-sequencing to track gene expression changes elicited by ICB across individual peripheral CD8+ T cell clones, identify baseline markers of CD8+ T cell clonal sensitivity, and chart how CD8+ T cell transcriptional changes vary according to phenotypic subset and clonal size. We identified seven subsets of CD8+ T cells with divergent reactivity to ICB and found that the cytotoxic effector subset showed the greatest number of differentially expressed genes while remaining stable in clonal size after ICB. At the level of CD8+ T cell clonotypes, we found a relationship between transcriptional changes and clone size, with large clones showing a greater number of differentially regulated genes enriched for pathways including T cell receptor (TCR) signaling. Cytotoxic CD8+ effector clones were more likely to persist following ICB and were more likely to correspond with public tumor-infiltrating lymphocyte clonotypes. Last, we demonstrated that individuals whose CD8+ T cell pretreatment showed low cytotoxicity and had fewer expanded clones typically had worse outcomes after ICB treatment. This work further advances understanding of the molecular determinants of ICB response, assisting in the search for peripheral prognostic biomarkers and highlighting the importance of the baseline CD8+ immune landscape in determining ICB response in metastatic melanoma.

Checkpoint-blocker-induced autoimmunity is associated with favourable outcome in metastatic melanoma and distinct T-cell expression profiles.

BACKGROUND: Immune checkpoint blockers (ICBs) activate CD8+ T cells, eliciting both anti-cancer activity and immune-related adverse events (irAEs). The relationship of irAEs with baseline parameters and clinical outcome is unclear. METHODS: Retrospective evaluation of irAEs on survival was performed across primary (N = 144) and secondary (N = 211) independent cohorts of patients with metastatic melanoma receiving single agent (pembrolizumab/nivolumab-sICB) or combination (nivolumab and ipilimumab-cICB) checkpoint blockade. RNA from pre-treatment and post-treatment CD8+ T cells was sequenced and differential gene expression according to irAE development assessed. RESULTS: 58.3% of patients developed early irAEs and this was associated with longer progression-free (PFS) and overall survival (OS) across both cohorts (log-rank test, OS: P < 0.0001). Median survival for patients without irAEs was 16.6 months (95% CI: 10.9-33.4) versus not-reached (P = 2.8 × 10-6). Pre-treatment monocyte and neutrophil counts, but not BMI, were additional predictors of clinical outcome. Differential expression of numerous gene pathway members was observed in CD8+ T cells according to irAE development, and patients not developing irAEs demonstrating upregulated CXCR1 pre- and post-treatment. CONCLUSIONS: Early irAE development post-ICB is associated with favourable survival in MM. Development of irAEs is coupled to expression of numerous gene pathways, suggesting irAE development in-part reflects baseline immune activation.

Cardiopulmonary resuscitation discussions with patients admitted to acute oncology wards: A national audit of current practice.

OBJECTIVES: To map current practice regarding discussions around resuscitation across England and Scotland in patients with cancer admitted acutely to hospital and to demonstrate the value of medical students in rapidly collecting national audit data. METHODS: Collaborators from the Macmillan medical student network collected data from 251 patient encounters across eight hospitals in England and Scotland. Data were collected to identify whether discussion regarding resuscitation was documented as having taken place during inpatient admission to acute oncology. As an audit standard, it was expected that all patients should be invited to discuss resuscitation within 24 hr of admission. RESULTS: Resuscitation discussions were had in 43.1% of admissions and of these 64.0% were within 24 hr; 27.6% of all admissions. 6.5% of patients had a "do not attempt resuscitation" order prior to admission with a difference noted between patients receiving palliative and curative treatment (8.5% and 0.39%, respectively, p < .05). Discussions regarding escalation of care took place in only 29.3% of admissions. CONCLUSIONS: These data highlight deficiencies in the number of discussions regarding resuscitation that are being conducted with cancer patients that become acutely unwell. It also demonstrates the value of medical student collaboration in rapidly collecting national audit data.

Peripheral CD8+ T cell characteristics associated with durable responses to immune checkpoint blockade in patients with metastatic melanoma.

Immune checkpoint blockade (ICB) of PD-1 and CTLA-4 to treat metastatic melanoma (MM) has variable therapeutic benefit. To explore this in peripheral samples, we characterized CD8+ T cell gene expression across a cohort of patients with MM receiving anti-PD-1 alone (sICB) or in combination with anti-CTLA-4 (cICB). Whereas CD8+ transcriptional responses to sICB and cICB involve a shared gene set, the magnitude of cICB response is over fourfold greater, with preferential induction of mitosis- and interferon-related genes. Early samples from patients with durable clinical benefit demonstrated overexpression of T cell receptor-encoding genes. By mapping T cell receptor clonality, we find that responding patients have more large clones (those occupying >0.5% of repertoire) post-treatment than non-responding patients or controls, and this correlates with effector memory T cell percentage. Single-cell RNA-sequencing of eight post-treatment samples demonstrates that large clones overexpress genes implicated in cytotoxicity and characteristic of effector memory T cells, including CCL4, GNLY and NKG7. The 6-month clinical response to ICB in patients with MM is associated with the large CD8+ T cell clone count 21 d after treatment and agnostic to clonal specificity, suggesting that post-ICB peripheral CD8+ clonality can provide information regarding long-term treatment response and, potentially, facilitate treatment stratification.

Tumor heterogeneity: does it matter?

Introduction: It has long been recognized that tumors are composed of a mosaic of cells and numerous methods have been developed to detect tumor heterogeneity, including in situ hybridization, multi-regional sampling, cytological assays, and whole genome and single cell sequencing. Using these methods, heterogeneity has been observed at the genetic, epigenetic, and phenotypic level in numerous cancers. With the advent of deep sequencing technology, we now appreciate a greater complexity of distinct genotypes and phenotypes that drive the biological behavior of cancer. Despite decades of progress in detecting tumor heterogeneity, the question remains: to what extent does it matter? Areas covered: This review explores the evidence for and against the importance of tumor heterogeneity in three main areas: prognostication, development of targeted therapeutics and tumor resistance; summarizing current understanding before evaluating ongoing experimental and clinical developments. Expert opinion: Theoretical understanding and in vitro detection of intratumour heterogeneity promises much but is yet to translate into meaningful clinical benefit. However, the recent emergence of a host of technological innovations and upcoming clinical trials may soon change the landscape of this field.

Is microwave ablation an alternative to stereotactic ablative body radiotherapy in patients with inoperable early-stage primary lung cancer?

A best evidence topic was written according to a structured protocol. The question addressed was: in patients with inoperable early-stage primary lung cancer does microwave ablation (MWA) or stereotactic ablative body radiotherapy (SBRT) achieve improved outcomes in terms of local control, recurrence, survival and complications? Altogether, more than 550 papers were found using the reported search, of which 12 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. No single study directly compared the effects of MWA with SBRT. However, the best available evidence for MWA (7 studies) was compared to that for SBRT (5 studies). The range of 3-year survival reported for MWA was 29.2-84.7%, compared with 42.7-63.5% for SBRT. The range of median survival was 35-60 months for MWA and 32.6-48 months for SBRT. This suggests similar outcomes between these two 2 techniques. Different side-effect profiles were observed between techniques with MWA associated with pneumothorax and fever and SBRT most commonly causing radiation pneumonitis and rib fractures. The evidence base for MWA is less than that for SBRT and is heterogenous in terms of participants and technical design. However, within these limitations, we conclude that MWA appears comparable with SBRT in terms of local control and survival rates.

Development of a best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours in the UK.

Bleomycin, a cytotoxic chemotherapy agent, forms a key component of curative regimens for lymphoma and germ cell tumours. It can be associated with severe toxicity, long-term complications and even death in extreme cases. There is a lack of evidence or consensus on how to prevent and monitor bleomycin toxicity. We surveyed 63 germ cell cancer physicians from 32 cancer centres across the UK to understand their approach to using bleomycin. Subsequent guideline development was based upon current practice, best available published evidence and expert consensus. We observed heterogeneity in practice in the following areas: monitoring; route of administration; contraindications to use; baseline and follow-up investigations performed, and advice given to patients. A best-practice clinical guideline for the use of bleomycin in the treatment of germ cell tumours has been developed and includes recommendations regarding baseline investigations, the use of pulmonary function tests, route of administration, monitoring and patient advice. It is likely that existing heterogeneity in clinical practice of bleomycin prescribing has significant economic, safety and patient experience implications. The development of an evidence-based consensus guideline was supported by 93% of survey participants and aims to address these issues and homogenise practice across the UK.

Value of Supraregional Multidisciplinary Review for the Contemporary Management of Testicular Tumors.

PURPOSE: Testicular cancers are an uncommon and highly curable group of tumors that are typically managed by specialist multidisciplinary teams (MDTs). Although recent guidelines have emphasized the importance of tumor prognostic factors in predicting recurrence and personalizing therapy in early-stage disease, the role of central pathology review in determining these factors is unclear. PATIENTS AND METHODS: We compared the referral histopathology reports with those obtained after expert central review for all cases reviewed by the UK Thames Valley Cancer Network testicular tumor MDT from August 2004 to September 2012. For cases in which the findings differed, we recorded the effect of the alteration on the estimates of patient prognosis and predicted clinical management using international (European Society of Medical Oncology [ESMO]) and local guidelines. RESULTS: The histopathology reports were altered after central review in 129 of 465 cases (27.7%) referred to the testicular tumor MDT during the study period. These resulted in changes in the estimation of prognosis for 42 patients (9.0% total), with a predicted affect on management according to the ESMO guidelines in 30 cases (6.5%). These proportions were broadly similar for both seminoma and nonseminoma, although the reasons for the discrepancies differed between the 2 (principally errors in categorization of rete testis invasion in seminoma and of lymphovascular invasion in nonseminoma). Changes to the tumor type were uncommon (2 cases). CONCLUSION: Central MDT review results in frequent, clinically relevant alterations to testicular tumor histopathology reports for testicular tumors. The results of our study demonstrate the importance of specialist MDTs to inform patient-centered care and ensure best practice in the management of these uncommon cancers.

Unemployment, public-sector healthcare expenditure and colorectal cancer mortality in the European Union: 1990-2009.

OBJECTIVES: We examined the association between unemployment and government spending on healthcare with colorectal cancer mortality. METHODS: Retrospective observational study using data from the World Bank and WHO. Multivariate regression analysis was used, controlling for country-specific differences in infrastructure and demographics. RESULTS: A 1 % increase in unemployment was associated with a significant increase in colorectal cancer mortality in both men and women [men: coefficient (R) = 0.0995, 95 % confidence interval (CI) 0.0132-0.1858, P = 0.024; women: R = 0.0742, 95 % CI 0.0160-0.1324, P = 0.013]. A 1 % increase in government spending on healthcare was associated with a statistically significant decrease in colorectal cancer mortality across both sexes (men: R = -0.4307, 95 % CI -0.6057 to -0.2557, P < 0.001; women: R = -0.2162, 95 % CI -0.3407 to -0.0917, P = 0.001). The largest changes in mortality occurred 3-4 years following changes in either economic variable. CONCLUSIONS: Unemployment rises are associated with a significant increase in colorectal cancer mortality, whilst government healthcare spending rises are associated with falling mortality. This is likely due, in part, to reduced access to healthcare services and has major implications for clinicians and policy makers alike.

A low-cost surgical application of additive fabrication.

OBJECTIVE: This study was used to test the feasibility of using additive fabrication techniques 3-dimensional (3D) printing to create personalized/patient-specific hepatic 3D physical models from clinical radiology studies for surgical resident education. DESIGN: Patient-specific imaging data from either computed tomography or magnetic resonance imaging scans, in Digital Imaging and Communications in Medicine format, were rendered and manipulated with computer software, translating the medical imaging data sets into useful 3D geometry files in stereo lithography format for 3D printing. A commercial third party was used to print the 3D models in laser sintered nylon, which provided access to expensive, industrial-grade, high-resolution 3-D printers at a low cost. RESULTS: Multiple patient-specific preoperative 3D physical models were printed of portal and hepatic venous anatomy at a cost of less than $100 per model. CONCLUSION: Current 3D printing techniques can be used to create low-cost personalized/patient-specific hepatic 3D models from clinical radiology studies for surgical resident education.

Hand motion patterns of Fundamentals of Laparoscopic Surgery certified and noncertified surgeons.

BACKGROUND: With the increasing use of simulation in surgical training there is an increasing need for low cost methods of objective assessment. METHODS: Hand-motion data (3 degrees of freedom) were acquired using microelectromechanical gyroscope tracking devices worn on both hands during an intracorporeal suture/knot-tying laparoscopic task performed by FLS-certified and non-FLS-certified surgeons. Each data sample was processed into a symbolic time series, and the Lempel-Ziv complexity metric was calculated for each hand for the whole task and the first 60 seconds of the task from the dominant hand. RESULTS: FLS-certified surgeons had more complex hand-motion patterns. This was statistically significant only for the dominant hand (P = .02) but was still statistically significant when calculated from the first 60 seconds of the task (P = .04) and therefore independent of the total time taken to complete the task. CONCLUSIONS: Hand-motion patterns were quantified and shown to be different between FLS-certified and non-FLS-certified surgeons using low-cost microelectromechanical technology and the Lempel-Ziv complexity metric.

Radial artery for coronary artery bypass grafting: does proximal anastomosis to the aorta or left internal mammary artery achieve better patency?

A best evidence topic in cardiac surgery was written according to a structured protocol. The question addressed was 'in coronary artery bypass grafting using radial artery grafts, does proximal anastomosis to the aorta or left internal mammary artery achieve better patency'. Altogether >183 papers were found using the reported search, of which 9 represented the best evidence to answer the clinical question. The authors, journal, date and country of publication, patient group studied, study type, relevant outcomes and results of these papers are tabulated. Radial artery grafts typically have a narrower lumen than vein grafts, and as such there is some concern that anastomosing them directly to the aorta during coronary artery bypass grafting (CABG) may impair graft patency. As such, some surgeons prefer to anastomose radial artery grafts to a second-order vessel such as the left internal mammary artery (LIMA). We sought to assess the evidence for this. A handful of papers directly addressing the issue of the effect of the site of proximal anastomosis on graft patency were found, with three showing no significant difference. One such study reported an insignificant difference in angiographic patency at 32 months postoperatively, with 94.1% of off-aorta grafts remaining patent vs 87.2% of off-LIMA grafts (p = 0.123). However, a large-scale well-designed study was able to demonstrate a statistically significant difference at five years postoperatively, with 74.3% of off-aorta grafts patent, compared with 65.2% of off-LIMA (p = 0.004). Nonetheless, a number of papers that report patency for either off-aorta or off-LIMA grafts give comparable figures for each technique. Additionally, different centres and investigators report very different patency results for grafts that have the same site of proximal anastomosis. One centre was able to achieve patency rates for off-LIMA grafts of 88% up to a mean of 7.7 years postoperatively while another centre reported a patency rate of only 78.6% at three years. Given this, and the plethora of other factors influencing graft patency, we conclude that the best evidence suggests that the site of proximal anastomosis has little or no effect on radial artery graft patency following CABG.

What is the potential of oligodendrocyte progenitor cells to successfully treat human spinal cord injury?

BACKGROUND: Spinal cord injury is a serious and debilitating condition, affecting millions of people worldwide. Long seen as a permanent injury, recent advances in stem cell research have brought closer the possibility of repairing the spinal cord. One such approach involves injecting oligodendrocyte progenitor cells, derived from human embryonic stem cells, into the injured spinal cord in the hope that they will initiate repair. A phase I clinical trial of this therapy was started in mid 2010 and is currently underway. DISCUSSION: The theory underlying this approach is that these myelinating progenitors will phenotypically replace myelin lost during injury whilst helping to promote a repair environment in the lesion. However, the importance of demyelination in the pathogenesis of human spinal cord injury is a contentious issue and a body of literature suggests that it is only a minor factor in the overall injury process. SUMMARY: This review examines the validity of the theory underpinning the on-going clinical trial as well as analysing published data from animal models and finally discussing issues surrounding safety and purity in order to assess the potential of this approach to successfully treat acute human spinal cord injury.