Publications by authors named "Tony Ng"

175 Publications

Systemic immune reaction in axillary lymph nodes adds to tumor-infiltrating lymphocytes in triple-negative breast cancer prognostication.

NPJ Breast Cancer 2021 Jul 5;7(1):86. Epub 2021 Jul 5.

Cancer Bioinformatics, School of Cancer & Pharmaceutical Sciences, King's College London Faculty of Life Sciences and Medicine, London, UK.

The level of stromal tumor-infiltrating lymphocytes (sTILs) in triple-negative (TNBC) and HER2-positive breast cancers convey prognostic information. The importance of systemic immunity to local immunity is unknown in breast cancer. We previously demonstrated that histological alterations in axillary lymph nodes (LNs) carry clinical relevance. Here, we capture local immune responses by scoring TILs at the primary tumor and systemic immune responses by recording the formation of secondary follicles, also known as germinal centers, in 2,857 cancer-free and involved axillary LNs on haematoxylin and eosin (H&E) stained sections from a retrospective cohort of 161 LN-positive triple-negative and HER2-positive breast cancer patients. Our data demonstrate that the number of germinal center formations across all cancer-free LNs, similar to high levels of TILs, is associated with a good prognosis in low TILs TNBC. This highlights the importance of assessing both primary and LN immune responses for prognostication and for future breast cancer research.
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http://dx.doi.org/10.1038/s41523-021-00292-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8257702PMC
July 2021

Cobalt ions induce metabolic stress in synovial fibroblasts and secretion of cytokines/chemokines that may be diagnostic markers for adverse local tissue reactions to hip implants.

Acta Biomater 2021 Jun 27. Epub 2021 Jun 27.

Department of Urologic Sciences, University of British Columbia, Vancouver, Canada; Vancouver Prostate Centre, Cox: 2660 Oak Street, Vancouver, Canada. Electronic address:

Adverse local tissue reactions (ALTRs) are a prominent cause of hip implant failure. ALTRs are characterized by aseptic necrosis and leukocyte infiltration of synovial tissue. The prevalence of ALTRs in hips with failing metal implants, with highest rates occurring in patients with metal-on-metal articulations, suggests a role for CoCrMo corrosion in ALTR formation. Although hypersensitivity reactions are the most accepted etiology, the precise cellular mechanism driving ALTR pathogenesis remains enigmatic. Here we show that cobalt ions released by failing hip implants induce mitochondrial stress and cytokine secretion by synovial fibroblasts: the presumptive initiators of ALTR pathogenesis. We found that in-vitro treatment of synovial fibroblasts with cobalt, but not chromium, generated gene expression changes indicative of hypoxia and mitophagy responses also observed in ALTRs biopsies. Inflammatory factors secreted by cobalt-exposed synovial fibroblasts were among those most concentrated in ALTR synovial fluid. Furthermore, both conditioned media from cobalt-exposed synovial fibroblasts, and synovial fluid from ALTRs patients, elicit endothelial activation and monocyte migration. Finally, we identify the IL16/CTACK ratio in synovial fluid as a possible diagnostic marker of ALTRs. Our results provide evidence suggesting that metal ions induce cell stress in synovial fibroblasts that promote an inflammatory response consistent with initiating ALTR formation. STATEMENT OF SIGNIFICANCE: We demonstrate that the cytotoxic effects of cobalt ions on the synovial cells (fibroblast) is sufficient to trigger inflammation on hip joints with metal implants. Cobalt ions affect mitochondrial function, leading to the auto phagocytosis of mitochondria and trigger a hypoxic response. The cell's hypoxic response includes secretion of cytokines that are capable of trigger inflammation by activating blood vessels and enhancing leukocyte migration. Among the secreted cytokines is IL-16, which is highly concentrated in the synovial fluid of the patients with adverse local tissue reactions and could be use as diagnostic marker. In conclusion we define the cells of the hip joint as key players in triggering the adverse reactions to hip implants and providing biomarkers for early diagnosis of adverse reactions to hip implants.
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http://dx.doi.org/10.1016/j.actbio.2021.06.039DOI Listing
June 2021

Texture Analysis of Fractional Water Content Images Acquired during PET/MRI: Initial Evidence for an Association with Total Lesion Glycolysis, Survival and Gene Mutation Profile in Primary Colorectal Cancer.

Cancers (Basel) 2021 May 31;13(11). Epub 2021 May 31.

Research Department of Imaging, Division of Medicine, University College London (UCL), London WC1E 6BT, UK.

To assess the capability of fractional water content (FWC) texture analysis (TA) to generate biologically relevant information from routine PET/MRI acquisitions for colorectal cancer (CRC) patients. Thirty consecutive primary CRC patients (mean age 63.9, range 42-83 years) prospectively underwent FDG-PET/MRI. FWC tumor parametric images generated from Dixon MR sequences underwent TA using commercially available research software (TexRAD). Data analysis comprised (1) identification of functional imaging correlates for texture features (TF) with low inter-observer variability (intraclass correlation coefficient: ICC > 0.75), (2) evaluation of prognostic performance for FWC-TF, and (3) correlation of prognostic imaging signatures with gene mutation (GM) profile. Of 32 FWC-TF with ICC > 0.75, 18 correlated with total lesion glycolysis (TLG, highest: r = -0.547, = 0.002). Using optimized cut-off values, five MR FWC-TF identified a good prognostic group with zero mortality (lowest: = 0.017). For the most statistically significant prognostic marker, favorable prognosis was significantly associated with a higher number of GM per patient (medians: 7 vs. 1.5, = 0.009). FWC-TA derived from routine PET/MRI Dixon acquisitions shows good inter-operator agreement, generates biological relevant information related to TLG, GM count, and provides prognostic information that can unlock new clinical applications for CRC patients.
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http://dx.doi.org/10.3390/cancers13112715DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199380PMC
May 2021

Evaluation of PSA and PSA Density in a Multiparametric Magnetic Resonance Imaging-Directed Diagnostic Pathway for Suspected Prostate Cancer: The INNOVATE Trial.

Cancers (Basel) 2021 Apr 20;13(8). Epub 2021 Apr 20.

Centre for Medical Imaging, University College London, London WC1E 6BT, UK.

: To assess the clinical outcomes of mpMRI before biopsy and evaluate the space remaining for novel biomarkers. The INNOVATE study was set up to evaluate the validity of novel fluidic biomarkers in men with suspected prostate cancer who undergo pre-biopsy mpMRI. We report the characteristics of this clinical cohort, the distribution of clinical serum biomarkers, PSA and PSA density (PSAD), and compare the mpMRI Likert scoring system to the Prostate Imaging-Reporting and Data System v2.1 (PI-RADS) in men undergoing biopsy. : 340 men underwent mpMRI to evaluate suspected prostate cancer. 193/340 (57%) men had subsequent MRI-targeted prostate biopsy. Clinically significant prostate cancer (csigPCa), i.e., overall Gleason ≥ 3 + 4 of any length OR maximum cancer core length (MCCL) ≥4 mm of any grade including any 3 + 3, was found in 96/195 (49%) of biopsied patients. Median PSA (and PSAD) was 4.7 (0.20), 8.0 (0.17), and 9.7 (0.31) ng/mL (ng/mL/mL) in mpMRI scored Likert 3,4,5 respectively for men with csigPCa on biopsy. The space for novel biomarkers was shown to be within the group of men with mpMRI scored Likert3 (178/340) and 4 (70/350), in whom an additional of 40% (70/178) men with mpMRI-scored Likert3, and 37% (26/70) Likert4 could have been spared biopsy. PSAD is already considered clinically in this cohort to risk stratify patients for biopsy, despite this 67% (55/82) of men with mpMRI-scored Likert3, and 55% (36/65) Likert4, who underwent prostate biopsy had a PSAD below a clinical threshold of 0.15 (or 0.12 for men aged <50 years). Different thresholds of PSA and PSAD were assessed in mpMRI-scored Likert4 to predict csigPCa on biopsy, to achieve false negative levels of ≤5% the proportion of patients whom who test as above the threshold were unsuitably high at 86 and 92% of patients for PSAD and PSA respectively. When PSA was re tested in a sub cohort of men repeated PSAD showed its poor reproducibility with 43% (41/95) of patients being reclassified. After PI-RADS rescoring of the biopsied lesions, 66% (54/82) of the Likert3 lesions received a different PI-RADS score. : The addition of simple biochemical and radiological markers (Likert and PSAD) facilitate the streamlining of the mpMRI-diagnostic pathway for suspected prostate cancer but there remains scope for improvement, in the introduction of novel biomarkers for risk assessment in Likert3 and 4 patients, future application of novel biomarkers tested in a Likert cohort would also require re-optimization around Likert3/PI-RADS2, as well as reproducibility testing.
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http://dx.doi.org/10.3390/cancers13081985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8074769PMC
April 2021

FDG-PET/CT in colorectal cancer: potential for vascular-metabolic imaging to provide markers of prognosis.

Eur J Nucl Med Mol Imaging 2021 Apr 10. Epub 2021 Apr 10.

Division of Medicine, Research Department of Imaging, University College London (UCL), London, UK.

Purpose: This study assesses the potential for vascular-metabolic imaging with FluoroDeoxyGlucose (FDG)-Positron Emission Tomography/Computed Tomography (PET/CT) perfusion to provide markers of prognosis specific to the site and stage of colorectal cancer.

Methods: This prospective observational study comprised of participants with suspected colorectal cancer categorized as either (a) non-metastatic colon cancer (M0colon), (b) non-metastatic rectal cancer (M0rectum), or (c) metastatic colorectal cancer (M+). Combined FDG-PET/CT perfusion imaging was successfully performed in 286 participants (184 males, 102 females, age: 69.60 ± 10 years) deriving vascular and metabolic imaging parameters. Vascular and metabolic imaging parameters alone and in combination were investigated with respect to overall survival.

Results: A vascular-metabolic signature that was significantly associated with poorer survival was identified for each patient group: M0colon - high Total Lesion Glycolysis (TLG) with increased Permeability Surface Area Product/Blood Flow (PS/BF), Hazard Ratio (HR) 3.472 (95% CI: 1.441-8.333), p = 0.006; M0rectum - high Metabolic Tumour Volume (MTV) with increased PS/BF, HR 4.567 (95% CI: 1.901-10.970), p = 0.001; M+ participants, high MTV with longer Time To Peak (TTP) enhancement, HR 2.421 (95% CI: 1.162-5.045), p = 0.018. In participants with stage 2 colon cancer as well as those with stage 3 rectal cancer, the vascular-metabolic signature could stratify the prognosis of these participants.

Conclusion: Vascular and metabolic imaging using FDG-PET/CT can be used to synergise prognostic markers. The hazard ratios suggest that the technique may have clinical utility.
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http://dx.doi.org/10.1007/s00259-021-05318-yDOI Listing
April 2021

HACE1 blocks HIF1α accumulation under hypoxia in a RAC1 dependent manner.

Oncogene 2021 Mar 18;40(11):1988-2001. Epub 2021 Feb 18.

Department of Molecular Oncology, British Columbia Cancer Research Centre, Vancouver, Canada.

Uncovering the mechanisms that underpin how tumor cells adapt to microenvironmental stress is essential to better understand cancer progression. The HACE1 (HECT domain and ankyrin repeat-containing E3 ubiquitin-protein ligase) gene is a tumor suppressor that inhibits the growth, invasive capacity, and metastasis of cancer cells. However, the direct regulatory pathways whereby HACE1 confers this tumor-suppressive effect remain to be fully elucidated. In this report, we establish a link between HACE1 and the major stress factor, hypoxia-inducible factor 1 alpha (HIF1α). We find that HACE1 blocks the accumulation of HIF1α during cellular hypoxia through decreased protein stability. This property is dependent on HACE1 E3 ligase activity and loss of Ras-related C3 botulinum toxin substrate 1 (RAC1), an established target of HACE1 mediated ubiquitinylation and degradation. In vivo, genetic deletion of Rac1 reversed the increased HIF1α expression observed in Hace1 mice in murine KRas-driven lung tumors. An inverse relationship was observed between HACE1 and HIF1α levels in tumors compared to patient-matched normal kidney tissues, highlighting the potential pathophysiological significance of our findings. Together, our data uncover a previously unrecognized function for the HACE1 tumor suppressor in blocking HIF1α accumulation under hypoxia in a RAC1-dependent manner.
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http://dx.doi.org/10.1038/s41388-021-01680-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7979542PMC
March 2021

Perivascular lymphocytic aggregates in hip prosthesis-associated adverse local tissue reactions demonstrate Th1 and Th2 activity and exhausted CD8 cell responses.

J Orthop Res 2021 Jan 28. Epub 2021 Jan 28.

Vancouver Prostate Centre, Vancouver, British Columbia, Canada.

Hip implants are a successful solution for osteoarthritis; however, some individuals with metal-on-metal (MoM) and metal-on-polyethylene (MoP) prosthetics develop adverse local tissue reactions (ALTRs). While MoM and MoP ALTRs are presumed to be delayed hypersensitivity reactions to corrosion products, MoM- and MoP-associated ALTRs present with different histological characteristics. We compared MoM- and MoP-associated ALTRs histopathology with cobalt and chromium levels in serum and synovial fluid. We analyzed the gene expression levels of leukocyte aggregates and synovial fluid chemokines/cytokines to resolve potential pathophysiologic differences. In addition, we classified ALTRs from 79 patients according to their leukocyte infiltrates as macrophage-dominant, mixed, and lymphocyte-dominant. Immune-related transcript profiles from lymphocyte-dominant MoM- and MoP-associated ALTR patients with perivascular lymphocytic aggregates were similar. Cell signatures indicated predominantly macrophage, Th1 and Th2 lymphocytic infiltrate, with strong exhausted CD8 signature, and low Th17 and B cell, relative to healthy lymph nodes. Lymphocyte-dominant ALTR-associated synovial fluid contained higher levels of induced protein 10 (IP-10), interleukin-1 receptor antagonist (IL-1RN), IL-8, IL-6, IL-16, macrophage inflammatory protein 1 (MIP-1α), IL-18, MCP-2, and lower cell-attracting chemokine levels, when compared with prosthetic revisions lacking ALTRs. In addition, the higher levels of IP-10, IL-8, IL-6, MIP-1α, and MCP-2 were observed within the synovial fluid of the lymphocyte-dominant ALTRs relative to the macrophage-dominant ALTRs. Not all cytokines/chemokines were detected in the perivascular aggregate transcripts, suggesting the existence of other sources in the affected synovia. Our results support the hypothesis of common hypersensitivity pathogenesis in lymphocyte-dominant MoM and MoP ALTRs. The exhausted lymphocyte signature indicates chronic processes and an impaired immune response, although the cause of the persistent T-cell activation remains unclear. The cytokine/chemokine signature of lymphocyte-dominant-associated ATLRs may be of utility for diagnosing this more aggressive pathogenesis.
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http://dx.doi.org/10.1002/jor.24998DOI Listing
January 2021

Acute Immune Signatures and Their Legacies in Severe Acute Respiratory Syndrome Coronavirus-2 Infected Cancer Patients.

Cancer Cell 2021 02 5;39(2):257-275.e6. Epub 2021 Jan 5.

Targeted Therapy Team, The Institute of Cancer Research, London, UK.

Given the immune system's importance for cancer surveillance and treatment, we have investigated how it may be affected by SARS-CoV-2 infection of cancer patients. Across some heterogeneity in tumor type, stage, and treatment, virus-exposed solid cancer patients display a dominant impact of SARS-CoV-2, apparent from the resemblance of their immune signatures to those for COVID-19 non-cancer patients. This is not the case for hematological malignancies, with virus-exposed patients collectively displaying heterogeneous humoral responses, an exhausted T cell phenotype and a high prevalence of prolonged virus shedding. Furthermore, while recovered solid cancer patients' immunophenotypes resemble those of non-virus-exposed cancer patients, recovered hematological cancer patients display distinct, lingering immunological legacies. Thus, while solid cancer patients, including those with advanced disease, seem no more at risk of SARS-CoV-2-associated immune dysregulation than the general population, hematological cancer patients show complex immunological consequences of SARS-CoV-2 exposure that might usefully inform their care.
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http://dx.doi.org/10.1016/j.ccell.2021.01.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7833668PMC
February 2021

Localized plantar amyloidosis: case report and review of the literature.

Skeletal Radiol 2021 Jul 15;50(7):1467-1472. Epub 2021 Jan 15.

Department of Radiology, Vancouver General Hospital, Vancouver, Canada.

Amyloidosis may be hereditary or acquired and the deposits can be focal, localized, or systemic in distribution. A discrete mass of amyloid deposition is called an amyloidoma and is the least common presentation. Soft tissue amyloidoma in an extremity is exceedingly rare. Amyloidomas can mimic malignant neoplasms both clinically and radiologically. We report a case of an amyloidoma in the foot, which has not been previously described. Clinical history, pathology, and immunohistochemistry and appearance by MRI are described. Knowledge of this atypical lesion, in its various forms, is important for experts in musculoskeletal radiology, pathology, surgery, and oncology to appreciate as it can prevent confusion with more sinister disease processes such as malignancy. Early recognition can help guide appropriate management in a timely fashion.
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http://dx.doi.org/10.1007/s00256-020-03696-2DOI Listing
July 2021

Muscle invasion in oropharyngeal carcinoma undergoing transoral robotic surgery.

Head Neck 2021 04 23;43(4):1194-1201. Epub 2020 Dec 23.

Division of Otolaryngology - Head & Neck Surgery, University of British Columbia, Vancouver, British Columbia, Canada.

Backgrounds: Pathologic features of oropharyngeal squamous cell carcinoma (OPSCC) treated with trans-oral robotic surgery predict prognosis and adjuvant therapy. We hypothesized that pathologic muscle invasion (pMI) is associated with poor pathological markers.

Methods: Retrospective review of surgically treated OPSCC to identify pMI and its association with poor pathologic markers.

Results: pMI was present in 12/37 patients, and compared to non-pMI, was associated with higher rates of lymphovascular invasion (75% vs. 36%, p = 0.03), perineural invasion (16.7% vs. 0%, p = 0.04), extranodal extension (66.7% vs. 20%, p < 0.01), and tumor stage (8.3% vs. 48% pT1, 75% vs. 52% pT2 and 16.7% vs. 0% pT3). pMI was associated with having a positive margin on main specimen (41.7% vs. 12%, p = 0.04) but not after considering additional margins.

Conclusions: Muscle invasion was associated with higher pathologic tumor staging, poor pathologic factors, and higher rates of positive margin on main specimen.
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http://dx.doi.org/10.1002/hed.26582DOI Listing
April 2021

A Rapid and Cost-Effective Gene Expression Assay for the Diagnosis of Well-Differentiated and Dedifferentiated Liposarcomas.

J Mol Diagn 2021 03 17;23(3):274-284. Epub 2020 Dec 17.

Genetic Pathology Evaluation Centre, Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, British Columbia, Canada; Department of Pathology and Laboratory Medicine, Vancouver General Hospital, Vancouver, BC, Canada. Electronic address:

Histologic examination neither reliably distinguishes benign lipomas from atypical lipomatous tumor/well-differentiated liposarcoma, nor dedifferentiated liposarcoma from other pleomorphic sarcomas, entities with different prognoses and management. Molecular confirmation of pathognomonic 12q13-15 amplifications leading to MDM2 overexpression is a diagnostic gold standard. Currently the most commonly used assay for this purpose is fluorescence in situ hybridization (FISH), but this is labor intensive. This study assessed whether newer NanoString-based technology could allow for more rapid and cost-efficient diagnosis of liposarcomas on standard formalin-fixed tissues through gene expression. Leveraging large-scale transcriptome data from The Cancer Genome Atlas, 20 genes were identified, most from the 12q13-15 amplicon, that distinguish dedifferentiated liposarcoma from other sarcomas and can be measured within a single NanoString assay. Using 21 cases of histologically ambiguous low-grade adipocytic tumors with available MDM2 amplification status, a machine learning-based analytical pipeline was built that assigns a given sample as negative or positive for liposarcoma based on quantitative gene expression. The effectiveness of the assay was validated on an independent set of 100 sarcoma samples (including 40 incident prospective cases), where histologic examination was considered insufficient for clinical diagnosis. The NanoString assay had a 93% technical success rate, and an accuracy of 97.8% versus an MDM2 amplification FISH gold standard. NanoString had a considerably faster turnaround time and was cheaper than FISH.
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http://dx.doi.org/10.1016/j.jmoldx.2020.11.011DOI Listing
March 2021

Uncovering Clinically Relevant Gene Fusions with Integrated Genomic and Transcriptomic Profiling of Metastatic Cancers.

Clin Cancer Res 2021 Jan 4;27(2):522-531. Epub 2020 Nov 4.

Department of Medical Oncology, BC Cancer, Vancouver, Canada.

Purpose: Gene fusions are important oncogenic drivers and many are actionable. Whole-genome and transcriptome (WGS and RNA-seq, respectively) sequencing can discover novel clinically relevant fusions.

Experimental Design: Using WGS and RNA-seq, we reviewed the prevalence of fusions in a cohort of 570 patients with cancer, and compared prevalence to that predicted with commercially available panels. Fusions were annotated using a consensus variant calling pipeline (MAVIS) and required that a contig of the breakpoint could be constructed and supported from ≥2 structural variant detection approaches.

Results: In 570 patients with advanced cancer, MAVIS identified 81 recurrent fusions by WGS and 111 by RNA-seq, of which 18 fusions by WGS and 19 by RNA-seq were noted in at least 3 separate patients. The most common fusions were in thoracic malignancies (9/69, 13%), and in colorectal cancer (4/73, 5.5%). Combined genomic and transcriptomic analysis identified novel fusion partners for clinically relevant genes, such as (novel partners: , and (novel partners: ).

Conclusions: Utilizing WGS/RNA-seq facilitates identification of novel fusions in clinically relevant genes, and detected a greater proportion than commercially available panels are expected to find. A significant benefit of WGS and RNA-seq is the innate ability to retrospectively identify variants that becomes clinically relevant over time, without the need for additional testing, which is not possible with panel-based approaches.
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http://dx.doi.org/10.1158/1078-0432.CCR-20-1900DOI Listing
January 2021

p53 immunohistochemical analysis of fusion-positive uterine sarcomas.

Histopathology 2021 May 14;78(6):805-813. Epub 2021 Feb 14.

Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, BC, Canada.

Aims: Uterine sarcomas can be grouped into tumours with pathognomonic genetic fusions such as low-grade endometrial stromal sarcoma (LGESS), high-grade endometrial stromal sarcoma (HGESS), and inflammatory myofibroblastic tumour (IMT), and tumours lacking genetic fusions such as leiomyosarcoma (LMS) and undifferentiated uterine sarcoma (UUS). Members of the latter group frequently harbour TP53 mutations. The aim of this study was to evaluate TP53 mutations by the use of immunohistochemistry in fusion-positive uterine sarcomas.

Methods And Results: We performed p53 immunohistochemical staining on 124 uterine sarcomas harbouring genetic fusions and 38 fusion-negative LMSs and UUSs. These included 41 HGESSs with YWHAE, BCOR and BCORL1 fusions/rearrangements, 13 IMTs with ALK fusion, 12 sarcomas with NTRK1/3 fusion, three sarcomas with PDGFB fusion, and 55 LGESSs with JAZF1, SUZ12 and PHF1 fusions/rearrangements. All HGESSs, LGESSs, IMTs and sarcomas with PDGFB fusion showed wild-type p53 expression. Among NTRK1/3-positive sarcomas, a TPR-NTRK1-positive sarcoma with nuclear pleomorphism showed mutation-type p53 expression. The remaining 11 NTRK1/3-positive sarcomas showed wild-type p53 expression, except for the subclonal p53 mutation-type staining in a minor pleomorphic focus of an NTRK3-positive sarcoma. Twenty-one of 27 (78%) LMSs and six of nine (67%) UUSs showed mutation-type p53 expression.

Conclusion: p53 immunohistochemistry may be considered in the initial work-up of a uterine sarcoma, as mutation-type staining would make a fusion-positive sarcoma very unlikely. Mutation-type p53 expression, however, can be seen in a small subset of NTRK1/3-positive sarcomas showing pleomorphic round/ovoid cell histology, which may represent a mechanism of progression in these tumours.
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http://dx.doi.org/10.1111/his.14292DOI Listing
May 2021

A Unique Case of Primary EBV-Positive, HPV-Negative Nasopharyngeal Carcinoma Located in the Tonsil.

Head Neck Pathol 2020 Oct 21. Epub 2020 Oct 21.

Division of Otolaryngology-Head and Neck Surgery, Department of Surgery, Vancouver General Hospital, Vancouver, BC, Canada.

Nasopharyngeal carcinomas (NPC) are non-keratinizing squamous cell carcinomas of the nasopharynx associated with Epstein-Barr virus (EBV). When occurring outside of the nasopharynx, they are referred to as lymphoepithelioma-like carcinomas (LELCs) and present the same morphology as NPC. LELC have been described in other head and neck regions such as the salivary glands and the soft palate. LELC can also occur in the oropharynx, are associated with human papillomavirus (HPV) and are typically negative for EBV. We herein present a unique case of a 78-year-old Chinese male with EBV-positive, HPV-negative NPC of the left tonsil. His presenting symptom was a left-sided lymph node. There was no evidence of nasopharyngeal lesion seen on physical examination, PET and MRI. The patient was treated with curative-intent external beam radiotherapy which delivered 70 Gy (Gy) to the gross tumour and lymph nodes, and 56 Gy electively to the ipsilateral neck using a volumetric modulated arc therapy technique. This is the first case of primary tonsil EBV-positive NPC described in the literature.
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http://dx.doi.org/10.1007/s12105-020-01237-wDOI Listing
October 2020

Breast cancer-associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells.

Sci Signal 2020 10 6;13(652). Epub 2020 Oct 6.

UCL Cancer Institute, University College London, London WC1E 6DD, UK.

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.
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http://dx.doi.org/10.1126/scisignal.aax4585DOI Listing
October 2020

Identification of Autophagy-Inhibiting Factors of Mycobacterium tuberculosis by High-Throughput Loss-of-Function Screening.

Infect Immun 2020 11 16;88(12). Epub 2020 Nov 16.

Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, Texas, USA

The interaction of host cells with mycobacteria is complex and can lead to multiple outcomes ranging from bacterial clearance to progressive or latent infection. Autophagy is recognized as one component of host cell responses that has an essential role in innate and adaptive immunity to intracellular bacteria. Many microbes, including , have evolved to evade or exploit autophagy, but the precise mechanisms and virulence factors are mostly unknown. Through a loss-of-function screening of an transposon mutant library, we identified 16 genes that contribute to autophagy inhibition, six of which encoded the PE/PPE protein family. Their expression in confirmed that these PE/PPE proteins inhibit autophagy and increase intracellular bacterial persistence or replication in infected cells. These effects were associated with increased mammalian target of rapamycin (mTOR) activity and also with decreased production of tumor necrosis factor alpha (TNF-α) and interleukin-1β (IL-1β). We also confirmed that the targeted deletion of the / genes in resulted in enhanced autophagy and improved intracellular survival rates compared to those of wild-type bacteria in the infected macrophages. Differential expression of these PE/PPE proteins was observed in response to various stress conditions, suggesting that they may confer advantages to by modulating its interactions with host cells under various conditions. Our findings demonstrated that multiple PE/PPE proteins are involved in inhibiting autophagy during infection of host phagocytes and may provide strategic targets in developing therapeutics or vaccines against tuberculosis.
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http://dx.doi.org/10.1128/IAI.00269-20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7671894PMC
November 2020

A small molecule inhibitor of HER3: a proof-of-concept study.

Biochem J 2020 09;477(17):3329-3347

Protein Phosphorylation Laboratory, The Francis Crick Institute, London, U.K.

Despite being catalytically defective, pseudokinases are typically essential players of cellular signalling, acting as allosteric regulators of their active counterparts. Deregulation of a growing number of pseudokinases has been linked to human diseases, making pseudokinases therapeutic targets of interest. Pseudokinases can be dynamic, adopting specific conformations critical for their allosteric function. Interfering with their allosteric role, with small molecules that would lock pseudokinases in a conformation preventing their productive partner interactions, is an attractive therapeutic strategy to explore. As a well-known allosteric activator of epidermal growth factor receptor family members, and playing a major part in cancer progression, the pseudokinase HER3 is a relevant context in which to address the potential of pseudokinases as drug targets for the development of allosteric inhibitors. In this proof-of-concept study, we developed a multiplex, medium-throughput thermal shift assay screening strategy to assess over 100 000 compounds and identify selective small molecule inhibitors that would trap HER3 in a conformation which is unfavourable for the formation of an active HER2-HER3 heterodimer. As a proof-of-concept compound, AC3573 bound with some specificity to HER3 and abrogated HER2-HER3 complex formation and downstream signalling in cells. Our study highlights the opportunity to identify new molecular mechanisms of action interfering with the biological function of pseudokinases.
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http://dx.doi.org/10.1042/BCJ20200496DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7489893PMC
September 2020

Pathology data set for reporting parathyroid carcinoma and atypical parathyroid neoplasm: recommendations from the International Collaboration on Cancer Reporting.

Hum Pathol 2021 Apr 17;110:73-82. Epub 2020 Jul 17.

University of Sydney, Sydney, New South Wales, 2006, Australia; Cancer Diagnosis and Pathology Group Kolling Institute of Medical Research, Royal North Shore Hospital, St Leonards; NSW Health Pathology, Department of Anatomical Pathology, Royal North Shore Hospital, St Leonards, New South Wales, 2065, Australia.

Standardized pathologic reporting for cancers improves patient care and prognostic determination. However, access in many countries is limited. To address this issue, the International Collaboration on Cancer Reporting (ICCR), a not-for-profit organization, has the mission to develop and disseminate standardized data sets for global use. Within endocrine organs, the parathyroid gland has rarely been included in formal pathologic data sets. Utilizing an expert international panel of eleven members, an evidence-based data set was developed for parathyroid carcinoma and atypical parathyroid neoplasms. This data set consists of sixteen core (required) elements viewed as essential for documentation of these conditions. Characterizing parathyroid carcinomas and atypical neoplasms begins with correlative clinical information, the operative procedure, specimens submitted, and site of the disease. The pathologic features essential to document include parathyroid weight, size, classification, and, when a carcinoma, the tumor grade. Histologic grade of parathyroid carcinoma incorporates other core elements including necrosis, mitotic count, perineural invasion, and lymphovascular invasion. Documenting the extent of disease locally into adjacent organs, regionally, and distally is critical for staging. Pathologic staging is now included as part of the American Joint Committee on Cancer 8th edition and is included in this data set. Ancillary studies should be recorded when performed as noncore elements. Standardized pathologic data sets for endocrine organs including the parathyroid gland are now available through the ICCR website. These essential resources enhance international standardization for documenting these rare tumors for both patient care and future guidelines.
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http://dx.doi.org/10.1016/j.humpath.2020.07.008DOI Listing
April 2021

Differential expression and prognostic relevance of autophagy-related markers ATG4B, GABARAP, and LC3B in breast cancer.

Breast Cancer Res Treat 2020 Oct 20;183(3):525-547. Epub 2020 Jul 20.

Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada.

Purpose: Previous studies indicate that breast cancer molecular subtypes differ with respect to their dependency on autophagy, but our knowledge of the differential expression and prognostic significance of autophagy-related biomarkers in breast cancer is limited.

Methods: Immunohistochemistry (IHC) was performed on tissue microarrays from a large population of 3992 breast cancer patients divided into training and validation cohorts. Consensus staining scores were used to evaluate the expression levels of autophagy proteins LC3B, ATG4B, and GABARAP and determine the associations with clinicopathological variables and molecular biomarkers. Survival analyses were performed using the Kaplan-Meier function and Cox proportional hazards regression models.

Results: We found subtype-specific expression differences for ATG4B, with its expression lowest in basal-like breast cancer and highest in Luminal A, but there were no significant associations with patient prognosis. LC3B and GABARAP levels were highest in basal-like breast cancers, and high levels were associated with worse outcomes across all subtypes (DSS; GABARAP: HR 1.43, LC3B puncta: HR 1.43). High ATG4B levels were associated with ER, PR, and BCL2 positivity, while high LC3B and GABARAP levels were associated with ER, PR, and BCL2 negativity, as well as EGFR, HER2, HER3, CA-IX, PD-L1 positivity, and high Ki67 index (p < 0.05 for all associations). Exploratory multi-marker analysis indicated that the combination of ATG4B and GABARAP with LC3B could be useful for further stratifying patient outcomes.

Conclusions: ATG4B levels varied across breast cancer subtypes but did not show prognostic significance. High LC3B expression and high GABARAP expression were both associated with poor prognosis and with clinicopathological characteristics of aggressive disease phenotypes in all breast cancer subtypes.
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http://dx.doi.org/10.1007/s10549-020-05795-zDOI Listing
October 2020

Prevention and management of aggressive behaviour in patients at psychiatric hospitals: a document analysis of clinical practice guidelines in Hong Kong.

Int J Ment Health Nurs 2020 Dec 29;29(6):1079-1091. Epub 2020 Jun 29.

Department of Nursing Science, University of Turku, Turku, Finland.

Patient aggressive behaviour remains a significant public health concern worldwide. The use of restraint and seclusion remains a last resort but not an uncommon practice in clinical psychiatry in the management of aggressive events. There seems to be a paucity of evidenced-based research examining the policy framework guiding the use of restraint and seclusion in Asia contexts. The purpose of this study was to conduct an analysis on the guidelines in psychiatric hospitals in Hong Kong, and to explore the extent to which these guidelines were aligned with the international clinical guidelines for the prevention and management of patient aggression in psychiatry. A descriptive document analysis was used to analyse the guidelines from four psychiatric hospitals in Hong Kong in comparison with the NICE (National Institute of Health and Care Excellence UK) guidelines. Data were collected from December 2017 to June 2018. A total of 91 written documents were retrieved. Preventing violence and aggression has the highest level of agreement (31%,) while the use of restrictive interventions has the lowest level of agreement (12%). The sub-recommendation with most in line with the NICE guidelines were restrictive interventions, de-escalation, and improving service users' experiences. However, for example, staff training, working with police, and reduced use of restrictive interventions seemed to have no agreement with the NICE guidelines. Variation exists between the Asian (Hong Kong) local policy framework/guidelines and the European (UK) national policy framework. There are also large discrepancies in the written guidelines on patient aggressive behaviour when comparing local policy frameworks, cluster-based documents, and departmental practices.
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http://dx.doi.org/10.1111/inm.12742DOI Listing
December 2020

Exploiting Pre-Existing CD4 T Cell Help from Bacille Calmette-Guérin Vaccination to Improve Antiviral Antibody Responses.

J Immunol 2020 07 8;205(2):425-437. Epub 2020 Jun 8.

Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461;

The continuing emergence of viral pathogens and their rapid spread into heavily populated areas around the world underscore the urgency for development of highly effective vaccines to generate protective antiviral Ab responses. Many established and newly emerging viral pathogens, including HIV and Ebola viruses, are most prevalent in regions of the world in which infection remains endemic and vaccination at birth with bacille Calmette-Guérin (BCG) is widely used. We have investigated the potential for using CD4 T cells arising in response to BCG as a source of help for driving Ab responses against viral vaccines. To test this approach, we designed vaccines comprised of protein immunogens fused to an immunodominant CD4 T cell epitope of the secreted Ag 85B protein of BCG. Proof-of-concept experiments showed that the presence of BCG-specific Th cells in previously BCG-vaccinated mice had a dose-sparing effect for subsequent vaccination with fusion proteins containing the Ag 85B epitope and consistently induced isotype switching to the IgG2c subclass. Studies using an Ebola virus glycoprotein fused to the Ag 85B epitope showed that prior BCG vaccination promoted high-affinity IgG1 responses that neutralized viral infection. The design of fusion protein vaccines with the ability to recruit BCG-specific CD4 Th cells may be a useful and broadly applicable approach to generating improved vaccines against a range of established and newly emergent viral pathogens.
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http://dx.doi.org/10.4049/jimmunol.2000191DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7343599PMC
July 2020

Radiation therapy and the innate immune response: Clinical implications for immunotherapy approaches.

Br J Clin Pharmacol 2020 09 3;86(9):1726-1735. Epub 2020 Jun 3.

UCL Cancer Institute, University College London, London, UK.

Radiation therapy is an essential component of cancer care, contributing up to 40% of curative cancer treatment regimens. It creates DNA double-strand breaks causing cell death in highly replicating tumour cells. However, tumours can develop acquired resistance to therapy. The efficiency of radiation treatment has been increased by means of combining it with other approaches such as chemotherapy, molecule-targeted therapies and, in recent years, immunotherapy (IT). Cancer-cell apoptosis after radiation treatment causes an immunological reaction that contributes to eradicating the tumour via antigen presentation and subsequent T-cell activation. By contrast, radiotherapy also contributes to the formation of an immunosuppressive environment that hinders the efficacy of the therapy. Innate immune cells from myeloid and lymphoid origin show a very active role in both acquired resistance and antitumourigenic mechanisms. Therefore, many efforts are being made in order to reach a better understanding of the innate immunity reactions after radiation therapy (RT) and the design of new combinatorial IT strategies focused in these particular populations.
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http://dx.doi.org/10.1111/bcp.14351DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7444780PMC
September 2020

Primary Parotid Merkel Type Small Cell Neuroendocrine Carcinoma with Oligometastasis to the Brain and Adrenal Gland: Case Report and Review of Literature.

Head Neck Pathol 2021 Mar 29;15(1):311-318. Epub 2020 Apr 29.

Department of Radiation Oncology, BC Cancer, Vancouver, BC, Canada.

Oligometastatic disease is a hypothesized intermediate stage of disease between localized and widespread metastatic cancer. Localized treatment of oligometastatic lesions may offer survival advantages in addition to systemic treatment. In this case report, we describe a patient who presented with small cell neuroendocrine carcinoma "Merkel type" (SNECM) of the parotid gland which had metastasized to the brain and adrenal gland. He was treated with chemotherapy followed by stereotactic radiotherapy and volumetric modulated arc therapy for oligometastasis. He maintains good functional status with low burden of disease at 20-months after diagnosis. SNECM is a rare and aggressive parotid cancer with immunohistochemical and morphologic similarities to Merkel cell carcinoma (MCC). There are only 44 cases of parotid SNECM in the English literature. This is the first case to describe management of oligometastatic SNECM and we review literature on management of both SNECM and metastatic MCC.
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http://dx.doi.org/10.1007/s12105-020-01164-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8010043PMC
March 2021

HER2-Mediated Internalization of Cytotoxic Agents in Amplified or Mutant Lung Cancers.

Cancer Discov 2020 05 25;10(5):674-687. Epub 2020 Mar 25.

mProbe Inc., Rockville, Maryland.

Amplification of and oncogenic mutations in , the gene encoding the HER2 receptor tyrosine kinase, promote receptor hyperactivation and tumor growth. Here we demonstrate that HER2 ubiquitination and internalization, rather than its overexpression, are key mechanisms underlying endocytosis and consequent efficacy of the anti-HER2 antibody-drug conjugates (ADC) ado-trastuzumab emtansine (T-DM1) and trastuzumab deruxtecan (T-DXd) in lung cancer cell lines and patient-derived xenograft models. These data translated into a 51% response rate in a clinical trial of T-DM1 in 49 patients with -amplified or -mutant lung cancers. We show that cotreatment with irreversible pan-HER inhibitors enhances receptor ubiquitination and consequent ADC internalization and efficacy. We also demonstrate that ADC switching to T-DXd, which harbors a different cytotoxic payload, achieves durable responses in a patient with lung cancer and corresponding xenograft model developing resistance to T-DM1. Our findings may help guide future clinical trials and expand the field of ADC as cancer therapy. SIGNIFICANCE: T-DM1 is clinically effective in lung cancers with amplification of or mutations in . This activity is enhanced by cotreatment with irreversible pan-HER inhibitors, or ADC switching to T-DXd. These results may help address unmet needs of patients with HER2-activated tumors and no approved targeted therapy...
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http://dx.doi.org/10.1158/2159-8290.CD-20-0215DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7196485PMC
May 2020

Pleiotropic Role and Bidirectional Immunomodulation of Innate Lymphoid Cells in Cancer.

Front Immunol 2019 4;10:3111. Epub 2020 Feb 4.

KCL Breast Cancer Now Research Unit, Guys Cancer Centre, King's College London, London, United Kingdom.

Innate lymphoid cells (ILCs) are largely tissue resident and respond rapidly toward the environmental signals from surrounding tissues and other immune cells. The pleiotropic function of ILCs in diverse contexts underpins its importance in the innate arm of immune system in human health and disease. ILCs derive from common lymphoid progenitors but lack adaptive antigen receptors and functionally act as the innate counterpart to T-cell subsets. The classification of different subtypes is based on their distinct transcription factor requirement for development as well as signature cytokines that they produce. The discovery and subsequent characterization of ILCs over the past decade have mainly focused on the regulation of inflammation, tissue remodeling, and homeostasis, whereas the understanding of the multiple roles and mechanisms of ILCs in cancer is still limited. Emerging evidence of the potent immunomodulatory properties of ILCs in early host defense signifies a major advance in the use of ILCs as promising targets in cancer immunotherapy. In this review, we will decipher the non-exclusive roles of ILCs associated with both protumor and antitumor activities. We will also dissect the heterogeneity, plasticity, genetic evidence, and dysregulation in different cancer contexts, providing a comprehensive understanding of the complexity and diversity. These will have implications for the therapeutic targeting in cancer.
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http://dx.doi.org/10.3389/fimmu.2019.03111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010811PMC
November 2020

Complex interrelationships between nitro-alkene-dependent inhibition of soluble epoxide hydrolase, inflammation and tumor growth.

Redox Biol 2020 01 16;29:101405. Epub 2019 Dec 16.

William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, EC1M6BQ, UK. Electronic address:

Nitro-oleate (10-nitro-octadec-9-enoic acid), which inhibits soluble epoxide hydrolase (sEH) by covalently adducting to C521, increases the abundance of epoxyeicosatrienoic acids (EETs) that can be health promoting, for example by lowering blood pressure or their anti-inflammatory actions. However, perhaps consistent with their impact on angiogenesis, increases in EETs may exacerbate progression of some cancers. To assess this, Lewis lung carcinoma (LLc1) cells were exposed to oleate or nitro-oleate, with the latter inhibiting the hydrolase and increasing their proliferation and migration in vitro. The enhanced proliferation induced by nitro-oleate was EET-dependent, being attenuated by the ETT-receptor antagonist 14,15-EE-5(Z)-E. LLc1 cells were engineered to stably overexpress wild-type or C521S sEH, with the latter exhibiting resistance to nitro-oleate-dependent hydrolase inhibition and the associated stimulation of tumor growth in vitro or in vivo. Nitro-oleate also increased migration in endothelial cells isolated from wild-type (WT) mice, but not those from C521S sEH knock-in (KI) transgenic mice genetically modified to render the hydrolase electrophile-resistant. These observations were consistent with nitro-oleate promoting cancer progression, and so the impact of this electrophile was examined in vivo again, but this time comparing growth of LLc1 cells expressing constitutive levels of wild-type hydrolase when implanted into WT or KI mice. Nitro-oleate inhibited tumor sEH (P < 0.05), with a trend for elevated plasma 11(12)-EET/DHET and 8(9)EET/DHET (dihydroxyeicosatrienoic acid) ratios when administered to WT, but not KI, mice. Although in vitro studies with LLc1 cells supported a role for nitro-oleate in cancer cell proliferation, it failed to significantly stimulate tumor growth in WT mice implanted with the same LLc1 cells in vivo, perhaps due to its well-established anti-inflammatory actions. Indeed, pro-inflammatory cytokines were significantly down-regulated in nitro-oleate treated WT mice, potentially countering any impact of the concomitant inhibition of sEH.
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http://dx.doi.org/10.1016/j.redox.2019.101405DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6928308PMC
January 2020

HER2-HER3 Heterodimer Quantification by FRET-FLIM and Patient Subclass Analysis of the COIN Colorectal Trial.

J Natl Cancer Inst 2020 09;112(9):944-954

UCL Cancer Institute, Paul O'Gorman Building, University College London, London, UK.

Background: The phase III MRC COIN trial showed no statistically significant benefit from adding the EGFR-target cetuximab to oxaliplatin-based chemotherapy in first-line treatment of advanced colorectal cancer. This study exploits additional information on HER2-HER3 dimerization to achieve patient stratification and reveal previously hidden subgroups of patients who had differing disease progression and treatment response.

Methods: HER2-HER3 dimerization was quantified by fluorescence lifetime imaging microscopy in primary tumor samples from 550 COIN trial patients receiving oxaliplatin and fluoropyrimidine chemotherapy with or without cetuximab. Bayesian latent class analysis and covariate reduction was performed to analyze the effects of HER2-HER3 dimer, RAS mutation, and cetuximab on progression-free survival and overall survival (OS). All statistical tests were two-sided.

Results: Latent class analysis on a cohort of 398 patients revealed two patient subclasses with differing prognoses (median OS = 1624 days [95% confidence interval [CI] = 1466 to 1816 days] vs 461 days [95% CI = 431 to 504 days]): Class 1 (15.6%) showed a benefit from cetuximab in OS (hazard ratio = 0.43, 95% CI = 0.25 to 0.76, P = .004). Class 2 showed an association of increased HER2-HER3 with better OS (hazard ratio = 0.64, 95% CI = 0.44 to 0.94, P = .02). A class prediction signature was formed and tested on an independent validation cohort (n = 152) validating the prognostic utility of the dimer assay. Similar subclasses were also discovered in full trial dataset (n = 1630) based on 10 baseline clinicopathological and genetic covariates.

Conclusions: Our work suggests that the combined use of HER dimer imaging and conventional mutation analyses will be able to identify a small subclass of patients (>10%) who will have better prognosis following chemotherapy. A larger prospective cohort will be required to confirm its utility in predicting the outcome of anti-EGFR treatment.
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http://dx.doi.org/10.1093/jnci/djz231DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7492762PMC
September 2020

Localising occult prostate cancer metastasis with advanced imaging techniques (LOCATE trial): a prospective cohort, observational diagnostic accuracy trial investigating whole-body magnetic resonance imaging in radio-recurrent prostate cancer.

BMC Med Imaging 2019 11 15;19(1):90. Epub 2019 Nov 15.

Centre for Medical Imaging, University College London, 2nd floor Charles Bell house, 43-45 Foley Street, London, W1W 7TS, UK.

Background: Accurate whole-body staging following biochemical relapse in prostate cancer is vital in determining the optimum disease management. Current imaging guidelines recommend various imaging platforms such as computed tomography (CT), Technetium 99 m (Tc) bone scan and F-choline and recently Ga-PSMA positron emission tomography (PET) for the evaluation of the extent of disease. Such approach requires multiple hospital attendances and can be time and resource intensive. Recently, whole-body magnetic resonance imaging (WB-MRI) has been used in a single visit scanning session for several malignancies, including prostate cancer, with promising results, providing similar accuracy compared to the combined conventional imaging techniques. The LOCATE trial aims to investigate the application of WB-MRI for re-staging of patients with biochemical relapse (BCR) following external beam radiotherapy and brachytherapy in patients with prostate cancer.

Methods/design: The LOCATE trial is a prospective cohort, multi-centre, non-randomised, diagnostic accuracy study comparing WB-MRI and conventional imaging. Eligible patients will undergo WB-MRI in addition to conventional imaging investigations at the time of BCR and will be asked to attend a second WB-MRI exam, 12-months following the initial scan. WB-MRI results will be compared to an enhanced reference standard comprising all the initial, follow-up imaging and non-imaging investigations. The diagnostic performance (sensitivity and specificity analysis) of WB-MRI for re-staging of BCR will be investigated against the enhanced reference standard on a per-patient basis. An economic analysis of WB-MRI compared to conventional imaging pathways will be performed to inform the cost-effectiveness of the WB-MRI imaging pathway. Additionally, an exploratory sub-study will be performed on blood samples and exosome-derived human epidermal growth factor receptor (HER) dimer measurements will be taken to investigate its significance in this cohort.

Discussion: The LOCATE trial will compare WB-MRI versus the conventional imaging pathway including its cost-effectiveness, therefore informing the most accurate and efficient imaging pathway.

Trial Registration: LOCATE trial was registered on ClinicalTrial.gov on 18th of October 2016 with registration reference number NCT02935816.
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http://dx.doi.org/10.1186/s12880-019-0380-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6858718PMC
November 2019

NanoString nCounter Technology: High-Throughput RNA Validation.

Methods Mol Biol 2020 ;2079:125-139

Department of Pathology, University of British Columbia, Vancouver, BC, Canada.

NanoString nCounter is a multiplex nucleic acid hybridization technology that enables reliable and reproducible assessment of the expression of up to 800 genes or 228 gene fusions in 12 samples in a single assay. The technique works well with a variety of starting materials from fresh or formalin-fixed tissues, cell lysates or biological fluid samples. As low as 1 ng RNA input per sample is needed. In addition to gene expression, copy number variation, single nucleotide variation and chimeric RNAs can be analyzed. In this chapter, we discuss the design, setup, and performance of a NanoString-based RNA assay for gene expression or fusion transcript assessment.
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http://dx.doi.org/10.1007/978-1-4939-9904-0_10DOI Listing
December 2020

Vaccine innovations for emerging infectious diseases-a symposium report.

Ann N Y Acad Sci 2020 02 28;1462(1):14-26. Epub 2019 Oct 28.

GlaxoSmithKline, Brentford, United Kingdom.

Vaccines have been incredibly successful at stemming the morbidity and mortality of infectious diseases worldwide. However, there are still no effective vaccines for many serious and potentially preventable infectious diseases. Advances in vaccine technology, including new delivery methods and adjuvants, as well as progress in systems biology and an increased understanding of the human immune system, hold the potential to address these issues. In addition, maternal immunization has opened an avenue to address infectious diseases in neonates and very young infants. This report summarizes the presentations from a 1-day symposium at the New York Academy of Sciences entitled "Innovative Vaccines against Resistant Infectious Diseases and Emerging Threats," held on May 20, 2019.
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http://dx.doi.org/10.1111/nyas.14235DOI Listing
February 2020
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