Challenges and Opportunities in the Clinical Development of Immune Checkpoint Inhibitors for Hepatocellular Carcinoma.

After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPIs) has been shown to be effective in advanced hepatocellular carcinoma (HCC). The clinical development of novel ICPIs continues at a rapid pace, with more than 50 clinical trials of immunotherapeutic agents registered as of May 2018 for this indication. The development of ICPI is particularly challenging in patients with HCC, a population with unique features which impact on safety and efficacy of immune-modulating therapies. In this review, we discuss the biological foundations supporting the development of ICPIs across the advancing stages of HCC, focusing on the rational positioning of ICPIs across the various Barcelona-Clinic Liver Cancer (BCLC) stages of the disease. Translational studies should guide adequate prioritization of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.

Clinical implications of heterogeneity in PD-L1 immunohistochemical detection in hepatocellular carcinoma: the Blueprint-HCC study.

Programmed cell death ligand-1 immunohistochemical detection (PD-L1 IHC) is a putative predictor of response to PD-1/PD-L1-targeted checkpoint inhibitors. However, there is no gold standard assay in hepatocellular carcinoma (HCC). We evaluated 5 PD-L1 IHC assay platforms (E1LN3, 28-8, 22c3, SP263 and SP142) in 100 HCCs reporting PD-L1 expression in malignant (M) and tumour-infiltrating immune cells (TICs) and non-tumorous cirrhotic tissues (NTICs). We found substantial inter-assay heterogeneity in detecting PD-L1 expression in M (R2 = 0.080-0.921), TICs (Cohen's κ = 0.175-0.396) and NTICs (κ = 0.004-0.505). Such diversity may impact on the reliability and reproducibility of PD-L1 IHC assays as a predictor of response to immune checkpoint inhibitors.

Role of Vitamin D Supplementation in Improving Cytokine Profile in Patients of Non-ST-Elevation Acute Coronary Syndrome.

Sub endothelial infarcts leads to non-ST-elevation acute coronary syndrome. Proinflammatory cytokines are raised in serum, the severity of which is a poor prognostic sign. Vitamin D deficiency is prevalent among patients of ACS. Vitamin D has immunomodulatory roles having effects on various aspects of inflammation. A total of 40 patients were divided into experimental (n=20) and control (n=20) groups. Experimental group was given single dose of vitamin D 200,000 IU. They were assessed for baseline C-reactive protein, interleukin-6, tumor necrosis factor-α levels by using sandwich ELISA technique. Four months after intervention resampling was done for the same parameters. Findings were expressed as mean±SD. Independent sample t-test was used to compare effect of vitamin D intervention between control group and intervention group. p-value of ≤0.05 was considered to be significant. The serum C-reactive protein showed significant reduction (p=0.028*) after intervention with vitamin D. Serum interleukin-6 (p=0.848), tumor necrosis factor-α (p=0.20) were decreased non-significantly in experimental as compared to the control group. It was concluded that a single large dose of vitamin D was able to reduce the C-reactive protein in non-ST-elevation acute coronary syndrome patients while non-significant reductions in interleukin-6 and tumor necrosis factor-α were observed.

The environmental consequences of foreign aid and key economic indicators: the Sino-Africa perspective.

The study differs substantially from earlier studies, by probing the environmental consequences of foreign aid and selected key economic indicators with a special focus on Sino-Africa. The study focused on China and its top foreign aid recipients in Africa in the last decade. This paper utilizes the Dynamic Augmented Mean Group Estimator (AMG), a robust and recent econometric approach to provide better statistical inferences; crucial for policy formulation and future reforms on foreign aid, trade, energy, pollutions, and economic growth of economies. The findings of the study revealed the China's Foreign aid oriented towards infrastructure has varying impacts on the economic growth and the environment of most recipient African Countries. The findings revealed the incidence of foreign aid ameliorating pollution of the countries: Nigeria and Morocco under strong domestic institutions. The study is of key relevance for policymakers and stakeholders as it explicates the key pillars, policies, and guidelines needed for foreign aid, trade, economic growth, and related internal reforms for mitigating resulting environmental pollution across a wider international context.

Phenotypic Characteristics of the Tumour Microenvironment in Primary and Secondary Hepatocellular Carcinoma.

(1) Background: The intra-tumoural heterogeneity (ITH) of hepatocellular carcinoma (HCC) and its microenvironment (TME) across primary and secondary disease is poorly characterised. (2) Methods: Intra-tumoural (IT) and peri-tumoural (PT) staining of matched primary and secondary samples was conducted to evaluate the distribution of CD4+/FOXP3+ and CD8+/PD1+ T-cells. Samples underwent PD-L1/2 immunostaining, tumour mutational burden (TMB) evaluation, and high-resolution T-cell receptor (TCR) sequencing to derive T-cell clonality and targeted transcriptomics. (3) Results: We analysed 24 samples from matched primary (n = 11) and secondary (n = 13; 5 synchronous, 6 metachronous) deposits, 11 being extrahepatic (84.6%). IT CD8+ density was lower than PT in both primary (p = 0.005) and secondary deposits (p = 0.01), consistent with immune exclusion. PD-L1+ tumours displayed higher IT and PT CD8+/PD1+ cell density compared to PD-L1- (p < 0.05), and primary IT infiltrate was enriched in CD4+/FOXP3+ cells, compared to PT regions (p = 0.004). TCR-sequencing demonstrated enrichment of the top T-cell clonotype in secondary versus primary HCC (p = 0.02), without differences in overall productive clonality (p = 0.35). TMB was similar across primary versus secondary HCC (p = 0.95). While directed gene set analysis demonstrated the uniformity of transcriptional signatures of individual immune cell types, secondary deposits demonstrated higher COLEC12 (p = 0.004), CCL26 (p = 0.02), CD1E (p = 0.02) and CD36 (p = 0.03) expression with downregulation of CXCL1 (p = 0.03), suggesting differential regulation of innate immunity. (4) Conclusion: Immune exclusion is a defining feature of the HCC TME. Despite evidence of homogeneity in somatic TMB, secondary HCC is characterised by the expansion of a distinct T-cell clonotype and differential regulation of innate immune pathways.

Objective Analysis of Neck Muscle Boundaries for Cervical Dystonia Using Ultrasound Imaging and Deep Learning.

OBJECTIVE: To provide objective visualization and pattern analysis of neck muscle boundaries to inform and monitor treatment of cervical dystonia. METHODS: We recorded transverse cervical ultrasound (US) images and whole-body motion analysis of sixty-one standing participants (35 cervical dystonia, 26 age matched controls). We manually annotated 3,272 US images sampling posture and the functional range of pitch, yaw, and roll head movements. Using previously validated methods, we used 60-fold cross validation to train, validate and test a deep neural network (U-net) to classify pixels to 13 categories (five paired neck muscles, skin, ligamentum nuchae, vertebra). For all participants for their normal standing posture, we segmented US images and classified condition (Dystonia/Control), sex and age (higher/lower) from segment boundaries. We performed an explanatory, visualization analysis of dystonia muscle-boundaries. RESULTS: For all segments, agreement with manual labels was Dice Coefficient (64 ± 21%) and Hausdorff Distance (5.7 ± 4 mm). For deep muscle layers, boundaries predicted central injection sites with average precision 94 ± 3%. Using leave-one-out cross-validation, a support-vector-machine classified condition, sex, and age from predicted muscle boundaries at accuracy 70.5%, 67.2%, 52.4% respectively, exceeding classification by manual labels. From muscle boundaries, Dystonia clustered optimally into three sub-groups. These sub-groups are visualized and explained by three eigen-patterns which correlate significantly with truncal and head posture. CONCLUSION: Using US, neck muscle shape alone discriminates dystonia from healthy controls. SIGNIFICANCE: Using deep learning, US imaging allows online, automated visualization, and diagnostic analysis of cervical dystonia and segmentation of individual muscles for targeted injection.

Yunis-Varon Syndrome.

Yunis-Varon syndrome is a rare autosomal recessive disorder with characteristic facial features and limb anomalies. We report a neonate born to consanguineously married normal parents with typical clinical and radiologic features of Yunis-Varon syndrome along with complete cleft lip and palate: an infrequent association. The family had two previous babies with similar features who died in infancy. This is a first reported case of Yunis-Varon syndrome in Pakistan.

PD-L1.

Programmed death ligand 1 (PD-L1) is the principal ligand of programmed death 1 (PD-1), a coinhibitory receptor that can be constitutively expressed or induced in myeloid, lymphoid, normal epithelial cells and in cancer. Under physiological conditions, the PD-1/PD-L1 interaction is essential in the development of immune tolerance preventing excessive immune cell activity that can lead to tissue destruction and autoimmunity. PD-L1 expression is an immune evasion mechanism exploited by various malignancies and is generally associated with poorer prognosis. PD-L1 expression is also suggested as a predictive biomarker of response to anti-PD-1/PD-L1 therapies; however, contradictory evidence exists as to its role across histotypes. Over the years, anti-PD-1/PD-L1 agents have gained momentum as novel anticancer therapeutics, by inducing durable tumour regression in numerous malignancies including metastatic lung cancer, melanoma and many others. In this review, we discuss the immunobiology of PD-L1, with a particular focus on its clinical significance in malignancy.