Publications
246 results found
Singh BK, Sharma R, Chaubey J, et al., 2020, Evaluation of genotype MTBDRplus V2 and genotype MTBDRsl V2 for the diagnosis of extrapulmonary tuberculosis in India., Tuberculosis (Edinb), Vol: 125
Microbiological diagnosis of extra-pulmonary tuberculosis (EPTB) has been one of the most difficult aspects of tuberculosis (TB) management. Availability of better imaging and diagnostic modalities has led to an increase in the number of diagnosed cases. The current upsurge in multidrug-resistant tuberculosis warrants routine testing of EPTB samples for resistance at baseline with shorter turn-around time. A total of 369 EPTB specimens were subjected to Ziehl-Neelsen (ZN) stain, liquid culture (LC) with phenotypic drug susceptibility testing, MTBDRplus V.2 and MTBDRsl V.2. The molecular categorisation of resistant specimens was further reconfirmed with sequencing. The sensitivity and specificity of MTBDRplus V.2 to detect Mycobacterium tuberculosis (MTB) when compared to ZN stain was 97.9% and 89.2%, respectively while it was 73.4% and 83.8%, respectively when compared to LC. Similarly, for MTBDRsl V.2, the sensitivity and specificity for detection of MTB when compared with ZN was 95.6% and 91.9%, respectively and 75% and 89.2%, respectively when compared to LC. In smear-positive specimens, 94% (141/150) and 86% (129/150) valid results were observed in MTBDRplus V.2 and MTBDRsl V.2, respectively. The utilisation of both MTBDRplus V.2 and MTBDRsl V.2 for the diagnosis of smear-positive EPTB specimens would be useful in programmatic management of TB in high-burden settings.
Schuette K, Schinner R, Fabritius MP, et al., 2020, Impact of Extrahepatic Metastases on Overall Survival in Patients with Advanced Liver Dominant Hepatocellular Carcinoma: A Subanalysis of the SORAMIC Trial, LIVER CANCER, Vol: 9, Pages: 771-786, ISSN: 2235-1795
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- Citations: 13
Motedayen Aval L, Pease JE, Sharma R, et al., 2020, Challenges and opportunities in the clinical development of STING agonists for cancer immunotherapy, Journal of Clinical Medicine, Vol: 9, ISSN: 2077-0383
Immune checkpoint inhibitors (ICI) have revolutionised cancer therapy. However, they have been effective in only a small subset of patients and a principal mechanism underlying immune-refractoriness is a 'cold' tumour microenvironment, that is, lack of a T-cell-rich, spontaneously inflamed phenotype. As such, there is a demand to develop strategies to transform the tumour milieu of non-responsive patients to one supporting T-cell-based inflammation. The cyclic guanosine monophosphate-adenosine monophosphate synthase-stimulator of interferon genes (cGAS-STING) pathway is a fundamental regulator of innate immune sensing of cancer, with potential to enhance tumour rejection through the induction of a pro-inflammatory response dominated by Type I interferons. Recognition of these positive immune-modulatory properties has rapidly elevated the STING pathway as a putative target for immunotherapy, leading to a myriad of preclinical and clinical studies assessing natural and synthetic cyclic dinucleotides and non-nucleotidyl STING agonists. Despite pre-clinical evidence of efficacy, clinical translation has resulted into disappointingly modest efficacy. Poor pharmacokinetic and physiochemical properties of cyclic dinucleotides are key barriers to the development of STING agonists, most of which require intra-tumoral dosing. Development of systemically administered non-nucleotidyl STING agonists, or conjugation with liposomes, polymers and hydrogels may overcome pharmacokinetic limitations and improve drug delivery. In this review, we summarise the body of evidence supporting a synergistic role of STING agonists with currently approved ICI therapies and discuss whether, despite the numerous obstacles encountered to date, the clinical development of STING agonist as novel anti-cancer therapeutics may still hold the promise of broadening the reach of cancer immunotherapy.
Lythgoe M, Julve M, Pinato D, et al., 2020, "Regorafenib therapy for hepatocellular carcinoma in a HIV-1 infected patient: a case report", Liver Cancer International, Vol: 1, Pages: 51-54, ISSN: 2642-3561
Sharma R, Pinato DJ, 2020, Management of Hepatocellular CAncer in the time of SARS-CoV-2, Liver International, Vol: 40, Pages: 1823-1825, ISSN: 1478-3223
As COVID-19 the disease caused by SARS-CoV-2 continues to have a profound impact on global health, there have been a number of guidelines recently published addressing the management of patients with liver disease during the COVID-19 pandemic including the recently published EASL-ESCMID Position Paper, guidelines issued by the International Liver Cancer Association and the American Association for the Study of Liver Diseases (1-3). All publications present a sound discussion regarding the challenges face by both patients and clinicians alike in the management of chronic liver disease in the setting of this ongoing pandemic.
Sarker D, Plummer R, Meyer T, et al., 2020, MTL-CEBPA, a small activating RNA therapeutic upregulating C/EBP-α, in patients with advanced liver cancer: a first-in-human, multicenter, open-label, phase I trial, Clinical Cancer Research, Vol: 26, Pages: 3936-3946, ISSN: 1078-0432
PURPOSE: Transcription factor C/EBP-α (CCAAT/enhancer-binding protein alpha) acts as a master regulator of hepatic and myeloid functions and multiple oncogenic processes. MTL-CEBPA is a first-in-class small activating RNA oligonucleotide drug that upregulates C/EBP-α. PATIENTS AND METHODS: We conducted a phase I, open-label, dose-escalation trial of MTL-CEBPA in adults with advanced hepatocellular carcinoma (HCC) with cirrhosis, or resulting from nonalcoholic steatohepatitis or with liver metastases. Patients received intravenous MTL-CEBPA once a week for 3 weeks followed by a rest period of 1 week per treatment cycle in the dose-escalation phase (3+3 design). RESULTS: Thirty-eight participants have been treated across six dose levels (28-160 mg/m2) and three dosing schedules. Thirty-four patients were evaluable for safety endpoints at 28 days. MTL-CEBPA treatment-related adverse events were not associated with dose, and no maximum dose was reached across the three schedules evaluated. Grade 3 treatment-related adverse events occurred in nine (24%) patients. In 24 patients with HCC evaluable for efficacy, an objective tumor response was achieved in one patient [4%; partial response (PR) for over 2 years] and stable disease (SD) in 12 (50%). After discontinuation of MTL-CEBPA, seven patients were treated with tyrosine kinase inhibitors (TKIs); three patients had a complete response with one further PR and two with SD. CONCLUSIONS: MTL-CEBPA is the first saRNA in clinical trials and demonstrates an acceptable safety profile and potential synergistic efficacy with TKIs in HCC. These encouraging phase I data validate targeting of C/EBP-α and have prompted MTL-CEBPA + sorafenib combination studies in HCC.
Hoogenboom T, Lim A, Sharma R, et al., 2020, Ultrasound small vessel imaging and deep learning; a novel approach to FLD screening, Publisher: ELSEVIER, Pages: S436-S437, ISSN: 0168-8278
Stickel F, Lutz P, Buch S, et al., 2020, Genetic variation in HSD17B13 reduces the risk of developing cirrhosis and hepatocellular carcinoma in alcohol misusers, Hepatology, Vol: 72, Pages: 88-102, ISSN: 0270-9139
BACKGROUND & AIMS: Carriage of rs738409:G in patatin-like phospholipase domain-containing 3 (PNPLA3) is associated with an increased risk for developing alcohol-related cirrhosis and hepatocellular carcinoma (HCC). Recently, rs72613567:TA in hydroxysteroid 17-beta dehydrogenase 13 (HSD17B13) was shown to be associated with a reduced risk for developing alcohol-related liver disease and to attenuate the risk associated with PNPLA3 rs738409:G. This study explores the risk-associations between these two genetic variants and the development of alcohol-related cirrhosis and HCC. APPROACH AND RESULTS: Variants in HSD17B13 and PNPLA3 were genotyped in 6,171 participants, including: 1,031 with alcohol-related cirrhosis and HCC; 1,653 with alcohol-related cirrhosis without HCC; 2,588 alcohol misusers with no liver disease; and 899 healthy controls. Genetic associations with the risks for alcohol-related cirrhosis and HCC were determined using logistic regression analysis. Carriage of HSD17B13 rs72613567:TA was associated with a lower risk for both cirrhosis (OR 0.79 [95% CI 0.72-0.88], p=8.13×10-6) and HCC (OR 0.77 [95% CI 0.68-0.89], p=2.27×10-4), while carriage of PNPLA3 rs738409:G was associated with an increased risk for developing cirrhosis (OR 1.70 [95% CI 1.54-1.88], p=1.52x10-26) and HCC (OR 1.77 [95% CI 1.58-1.98], p=2.31×10-23). These associations remained significant after adjusting for age, sex, body mass index, type II diabetes mellitus and country. Carriage of HSD17B13 rs72613567:TA attenuated the risk for developing cirrhosis associated with PNPLA3 rs738409:G in both men and women but the protective effect against the subsequent development of HCC was only observed in men (p=1.72×10-4; ORallelic, 0.75; 95% CI, 0.64-0.87). CONCLUSIONS: Carriage of variants in PNPLA3 and HSD17B13 differentially affect the risk for developing advanced alcohol-related liver disease. A genotypic/phenotypic risk score might facilitate earlier diagnosis of
Han G, Berhane S, Toyoda H, et al., 2020, Prediction of survival among patients receiving transarterial chemoembolization for hepatocellular carcinoma: a response-based approach, Hepatology, Vol: 72, Pages: 198-212, ISSN: 0270-9139
The heterogeneity of intermediate-stage hepatocellular carcinoma (HCC) and the widespread use of transarterial chemoembolization (TACE) outside recommended guidelines have encouraged the development of scoring systems that predict patient survival. The aim of this study was to build and validate statistical models that offer individualized patient survival prediction using response to TACE as a variable. Clinically relevant baseline parameters were collected for 4,621 patients with HCC treated with TACE at 19 centers in 11 countries. In some of the centers, radiological response (as assessed by modified Response Evaluation Criteria in Solid Tumors [mRECIST]) was also accrued. The data set was divided into a training set, an internal validation set, and two external validation sets. A new pre-TACE model ("Pre-TACE-Predict") and a post-TACE model ("Post-TACE-Predict") that included response were built. The performance of the models in predicting overall survival (OS) was compared with existing ones. Median OS was 19.9 months. The factors influencing survival were tumor number and size, alpha-fetoprotein, albumin, bilirubin, vascular invasion, etiology, and response as assessed by mRECIST. The proposed models showed superior predictive accuracy compared to existing models (the HAP score and its various modifications) and allowed for patient stratification into four distinct risk categories whose median OS ranged from 7 months to more than 4 years. Conclusion: A TACE-specific and extensively validated model based on routinely available clinical features and response after first TACE permitted patient-level prognostication.
Evans J, Wang WM, Newsom-Davis T, et al., 2020, 141 - Peptide receptor radionuclide therapy for metastatic bronchopulmonary carcinoid tumours: A single ENETS Centre of Excellence experience (vol 127, pg S59, 2019), LUNG CANCER, Vol: 145, Pages: 227-227, ISSN: 0169-5002
Sharma R, Hajiev S, Aval LM, et al., 2020, An international cohort study investigating the impact of age on clinical outcome in patients with hepatocellular carcinoma treated with sorafenib., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0732-183X
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Sharma R, Valls PO, Inglese M, et al., 2020, [18F]Fluciclatide PET as a biomarker of response to combination therapy of pazopanib and paclitaxel in platinum-resistant/refractory ovarian cancer, European Journal of Nuclear Medicine and Molecular Imaging, Vol: 47, Pages: 1239-1251, ISSN: 0340-6997
BACKGROUND: Angiogenesis is a driver of platinum resistance in ovarian cancer. We assessed the effect of combination pazopanib and paclitaxel followed by maintenance pazopanib in patients with platinum-resistant/refractory ovarian cancer. Integrins αvβ3 and αvβ5 are both upregulated in tumor-associated vasculature. [18F]Fluciclatide is a novel PET tracer that has high affinity for integrins αvβ3/5, and was used to assess the anti-angiogenic effect of pazopanib. PATIENTS AND METHODS: We conducted an open-label, phase Ib study in patients with platinum-resistant/refractory ovarian cancer. Patients received 1 week of single-agent pazopanib (800 mg daily) followed by combination therapy with weekly paclitaxel (80 mg/m2). Following completion of 18 weeks of combination therapy, patients continued with single-agent pazopanib until disease progression. Dynamic [18F]fluciclatide-PET imaging was conducted at baseline and after 1 week of pazopanib. Response (RECIST 1.1), toxicities, and survival outcomes were recorded. Circulating markers of angiogenesis were assessed with therapy. RESULTS: Fourteen patients were included in the intention-to-treat analysis. Complete and partial responses were seen in seven patients (54%). Median progression-free survival (PFS) was 10.63 months, and overall survival (OS) was 18.5 months. Baseline [18F]fluciclatide uptake was predictive of long PFS. Elevated baseline circulating angiopoietin and fibroblast growth factor (FGF) were predictive of greater reduction in SUV60,mean following pazopanib. Kinetic modeling of PET data indicated a reduction in K1 and Ki following pazopanib indicating reduced radioligand delivery and retention. CONCLUSIONS: Combination therapy followed by maintenance pazopanib is effective and tolerable in platinum-resistant/refractory ovarian cancer. [18F]Fluciclatide-PET uptake parameters predict clinical outcome with pazopanib therapy indicating an anti
Pinato DJ, Guerra N, Fessas P, et al., 2020, Immune-based therapies for hepatocellular carcinoma, Oncogene, Vol: 39, Pages: 3620-3637, ISSN: 0950-9232
Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.
Pinato DJ, Vallipuram A, Evans JS, et al., 2020, Programmed cell death ligands expression drives immune tolerogenesis across the diverse subtypes of neuroendocrine tumours, Neuroendocrinology: international journal for basic and clinical studies on neuroendocrine relationships, Vol: 111, Pages: 465-474, ISSN: 0028-3835
INTRODUCTION: A comprehensive characterisation of the tumour microenvironment is lacking in neuroendocrine tumours (NETs), where programmed cell death-1 receptor-ligand (PD-1/PD-L1) inhibitors are undergoing efficacy testing. OBJECTIVE: We investigated drivers of cancer-related immunosuppression across NETs of various sites and grade using multi-parameter immunohistochemistry and targeted transcriptomic profiling. METHODS: Tissue microarrays (n=102) were stained for PD-L1 & 2, Indoleamine-deoxygenase-1 (IDO-1) and evaluated in relationship to functional characteristics of tumor-infiltrating T-lymphocytes (TILs) and biomarkers of hypoxia/angiogenesis. PD-L1 expression was tested in circulating tumour cell (CTCs, n=12) to evaluate its relationship with metastatic dissemination. RESULTS: PD-L1 expression was highest in lung NETs (n=30, p=0.007), whereas PD-L2 was highest in pNETs (n=53, p<0.001) with no correlation with grade or hypoxia/angiogenesis. PD-L1+ NETs (n=26, 25%) had greater CD4+/FOXP3+ and CD8+/PD1+ TILs (p<0.001) and necrosis (p=0.02). CD4+/FOXP3+ infiltrate was highest PD-L1/IDO-1 co-expressing tumours (p=0.006). Grade 3 well-differentiated NETs had lower CD4+/FOXP3+ and CD8+/PD1+ TILs density (p<0.001) and Nanostring immune-profiling revealed enrichment of macrophage-related transcripts in cases with poorer prognosis. We identified PD-L1(+) CTC subpopulations in 75% of evaluated patients (n=12). CONCLUSIONS: PD-L1 expression correlates with T-cell exhaustion independent of tumour hypoxia and is enhanced in a subpopulation of CTCs, suggesting its relevance to the progression of NETs. These findings support a potential therapeutic role for PD-L1 inhibitors in a subset of NETs.
Craig Z, Swain J, Batman E, et al., 2020, NET-02 trial protocol: a multicentre, randomised, parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI) and 5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive poorly differentiated extrapulmonary neuroendocrine carcinoma (NEC)., BMJ Open, Vol: 10, Pages: e034527-e034527, ISSN: 2044-6055
INTRODUCTION: Poorly differentiated (PD), extrapulmonary (EP), neuroendocrine carcinomas (NECs) are rare but aggressive neuroendocrine neoplasms. First-line treatment for advanced disease is an etoposide and platinum-based chemotherapy combination. There is no established second-line treatment for patients with PD-EP-NEC, and this is an area of unmet need. METHODS AND ANALYSIS: NET-02 is a UK, multicentre, randomised (1:1), parallel group, open-label, phase II, single-stage selection trial of liposomal irinotecan (nal-IRI)/5-fluorouracil (5-FU)/folinic acid or docetaxel as second-line therapy in patients with progressive PD-EP-NEC. One hundred and two eligible participants will be randomised to receive either nal-IRI/5-FU/folinic acid or docetaxel. The primary objective is to determine the 6-month progression-free survival (PFS) rate. The secondary objectives of this study are to determine PFS, overall survival, objective response rate, toxicity, quality of life and whether neuron-specific enolase is predictive of treatment response. If either treatment is found to have a 6-month PFS rate of at least 25%, that treatment will be considered for a phase III trial. If both treatments meet this target, prespecified selection criteria will be applied to establish which treatment to take forward. ETHICS AND DISSEMINATION: This study has ethical approval from the Greater Manchester Central Research Ethics Committee (reference no. 18/NW/0031) and clinical trial authorisation from the Medicine and Healthcare Products Regulatory Agency. Results will be published in peer-reviewed journals and uploaded to the European Union Clinical Trials Register. TRIAL REGISTRATION NUMBERS: ISRCTN10996604, NCT03837977, EudraCT Number: 2017-002453-11.
Ross PJ, Ma YT, Palmer DH, et al., 2020, Real-world experience of regorafenib in patients with hepatocellular carcinoma: A multicenter United Kingdom study, Gastrointestinal Cancers Symposium of the American-Society-of-Clinical-Oncology, Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
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Singh BK, Sharma R, Kodan P, et al., 2020, Diagnostic evaluation of non-Interpretable results associated with rpoB gene in genotype MTBDRplus ver 2.0, Tuberculosis and Respiratory Diseases, Vol: 83, Pages: 289-294, ISSN: 1738-3536
Background: Line probe assay (LPA) is standard diagnostic tool to detect multidrug resistant tuberculosis. Non-interpretable (NI) results in LPA (complete missing or light wild-type 3 and 8 bands with no mutation band inrpoB gene region) poses a diagnostic challenge. Methods: Sputum samples obtained between October 2016 and July 2017 at the Intermediate Reference Laboratory, All India Institute of Medical Sciences Hospital, New Delhi, India were screened. Smear-positive and smear-negative culture-positive specimens were subjected to LPA Genotype MTBDRplus Ver 2.0. Smear-negative with culture-negative and culture contamination were excluded. LPA NI samples were subjected to phenotypic drug susceptibility testing (pDST) using MGIT-960 and sequencing. Results: A total of 1,614 sputum specimens were screened and 1,340 were included for the study (smear-positive [n=1,188] and smear-negative culture-positive [n=152]). LPA demonstrated 1,306 (97.5%) valid results with TUB (Mycobacterium tuberculosis) band, 24 (1.8%) NI, three (0.2%) valid results without TUB band, and seven (0.5%) invalid results. Among the NI results, 22 isolates (91.7%) were found to be rifampicin (RIF) resistant and two (8.3%) were RIF sensitive in the pDST. Sequencing revealed thatrpoB mutations were noted in all 22 cases with RIF resistance, whereas the remaining two cases had wild-type strains. Of the 22 cases with rpoB mutations, the most frequent mutation was S531W (n=10, 45.5%), followed by S531F (n=6, 27.2%), L530P (n=2, 9.1%), A532V (n=2, 9.1%), and L533P (n=2, 9.1%). Conclusion: The present study showed that the results of the Genotype MTBDRplus assay were NI in a small proportion of isolates. pDST andrpoB sequencing were useful in elucidating the cause and clinical meaning of the NI results.
Singh BK, Soneja M, Sharma R, et al., 2020, Mutation in atpE and Rv0678 genes associated with bedaquline resistance among drug-resistant tuberculosis patients: A pilot study from a high-burden setting in Northern India., Int J Mycobacteriol, Vol: 9, Pages: 212-215
BACKGROUND: Mutations in atpE gene or transcriptional repressor Rv0678 gene associated with inhibition of adenosine 5'-triphosphate synthase and upregulation of efflux pumps, respectively, may potentially lead to in vitro resistance to bedaquiline. This is the first study from India, which looks at mutations associated with this novel drug. METHODS: In 2019 (January to June), a total of 68 laboratory-confirmed pre-extensively drug-resistant tuberculosis (XDR-TB) (fluoroquinolone resistant [n = 52] and second-line injectables resistant [n = 12]) and 4 × DR-TB culture specimens were included. All specimens were evaluated for genetic analysis using predesigned primers of atpE and Rv0678 genes. RESULTS: Among the pre-XDR-TB isolates (n = 64), there were no mutations found in either atpE or Rv0678. However, among the XDR-TB isolates (n = 4), one specimen (25%) was found to be associated with a mutation in atpE gene at position 49, resulting in the amino acid leucine replaced by proline (L-49-P). No mutations were observed with the Rv0678 gene. CONCLUSION: In this study, genetic analysis showed that only one-fourth XDR-TB isolates had a mutation in the atpE gene; there were no other mutations found in the Rv0678 gene. To the best of our knowledge, this novel mutation (L-49-P) in atpE gene is being reported for the first time in northern India.
Bayet J, Hoogenboom T, Sharma R, et al., 2020, MACHINE-LEARNING ON LIVER ULTRASOUND TO STRATIFY MULTIPLE DISEASES VIA BLOOD-VESSELS AND PERFUSION CHARACTERISTICS, IEEE 17th International Symposium on Biomedical Imaging (ISBI), Publisher: IEEE, Pages: 1351-1354, ISSN: 1945-7928
Sharma R, Wang WM, Yusuf S, et al., 2019, 68Ga-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, Radiotherapy and Oncology, Vol: 141, Pages: 108-115, ISSN: 0167-8140
PURPOSE: [177Lu]DOTATATE prolongs progression free survival (PFS) in metastatic neuroendocrine tumours (NETs). However, objective response rate is low. This, coupled with long duration of therapy and expense suggest need for better selection. We aim to assess whether baseline [68Ga]DOTATATE-PET/CT parameters, and whether response assessment by PET accurately predicts clinical outcome to [177Lu]DOTATATE. EXPERIMENTAL DESIGN: Retrospective study of patients receiving [177Lu]DOTATATE was conducted. Patients were followed 3-monthly until disease progression. Four [68Ga]DOTATATE-PET parameters (single lesion SUVmax, tumour to spleen and liver SUV ratios, and SUVmax-av using up to five target lesions in multiple organ sites) were determined at baseline and follow-up. The association between these PET parameters either at baseline, or any changes following treatment, and PET response criteria (PERCIST and modified PERCIST) to predict PFS were determined. Patients were followed 3-monthly until disease progression. Response was determined using RECIST 1.1. Baseline SSTR2 expression was assessed and compared with PET parameters. RESULTS: 55 patients with metastatic NETs were identified predominantly small bowel (N = 18) and pancreatic (N = 8) in origin. 16 were low grade, 15 intermediate and 3 high grade. Response to PRRT (N = 47): partial response (PR) 28%, stable disease (SD) 60% progressive disease (PD) 13%. Response to PRRT predicted PFS: PR 71.8 months (95%CI: not achieved), SD 29.1 months (95%CI: 15.2-43.1), and PD 9.7 months (95%CI: 0-21.02). Baseline, single lesion SUVmax predicted both response and PFS with SUV cut-off of 13.0 giving high sensitivity and specificity. Tumoural SUVmax correlated with SSTR2 expression, Spearman's rho - 0.69, p < 0.01. CONCLUSIONS: Baseline single lesion SUVmax and SUVmax-av predicts response to [177Lu]DOTATATE. Objective response following PRRT defines a subset of patients with markedly improved PFSBaseline SUVmax 13.0 defines a thre
Sharma SK, Sharma R, Singh BK, et al., 2019, A prospective study of non-tuberculous mycobacterial disease among tuberculosis suspects at a tertiary care centre in north India., Indian J Med Res, Vol: 150, Pages: 458-467, ISSN: 0971-5916
BACKGROUND & OBJECTIVES: The burden of non-tuberculous mycobacterial (NTM) disease is increasing worldwide. The disease shares clinicoradiological features with tuberculosis (TB), Nocardia and several fungal diseases, and its diagnosis is frequently delayed. The present study was performed to determine the frequency of NTM disease among TB suspects in a tertiary care centre in north India. METHODS: In this prospective study, mycobacterial culture isolates from pulmonary and extrapulmonary specimens among TB suspects were tested with immunochromatographic assay (ICA). All ICA-negative isolates were considered as NTM suspects and further subjected to 16S-23S rRNA internal transcribed spacer gene sequencing for confirmation and species identification. Patients with active disease were treated with drug regimen as per the identified NTM species. Follow up of patients was done to determine clinical, radiological and microbiological outcomes. RESULTS: Of the 5409 TB suspects, 42 (0.77%) were diagnosed with NTM disease. Patients with active disease consenting for treatment were treated and followed up. Thirty four patients had NTM pulmonary disease (NTM-PD) and the remaining eight had extrapulmonary NTM (EP-NTM) disease. Mycobacterium intracellulare and M. abscessus, respectively, were most frequently isolated from NTM-PD and EP-NTM patients. Fifteen NTM-PD and seven EP-NTM patients successfully completed the treatment. Ten patients died due to unrelated causes, five were lost to follow up and another four declined the treatment. INTERPRETATION & CONCLUSIONS: Our study showed that the frequency of NTM disease was low among TB suspects at a large tertiary care centre in north India and this finding was similar to other Indian studies. More studies need to be done in other parts of the country to know the geographical variation in NTM disease, if any.
Sharma R, Wang W, Yusuf S, et al., 2019, [<SUP>68</SUP>Ga]-DOTATATE PET/CT parameters predict response to peptide receptor radionuclide therapy in neuroendocrine tumours, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S640-S640, ISSN: 1619-7070
Sharma R, Valls PO, Inglese M, et al., 2019, [<SUP>18</SUP>F]fluciclatide Pet As A Biomarker Of Response To Combination Therapy Of Pazopanib And Paclitaxel In Platinum-resistant/refractory Ovarian Cancer, 32nd Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S223-S223, ISSN: 1619-7070
Trousil S, Lee P, Edwards RJ, et al., 2019, Altered cytochrome 2E1 and 3A P450-dependent drug metabolism in advanced ovarian cancer correlates to tumour-associated inflammation, British Journal of Pharmacology, Vol: 176, Pages: 3712-3722, ISSN: 0007-1188
Background and PurposePrevious work has focussed on changes in drug metabolism caused by altered activity of CYP3A in the presence of inflammation and, in particular, inflammation associated with malignancy. However, drug metabolism involves a number of other P450s, and therefore, we assessed the effect of cancer‐related inflammation on multiple CYP enzymes using a validated drug cocktail.Experimental ApproachPatients with advanced stage ovarian cancer and healthy volunteers were recruited. Participants received caffeine, chlorzoxazone, dextromethorphan, and omeprazole as in vivo probes for CYP1A2, CYP2E1, CYP2D6, CYP3A, and CYP2C19. Blood was collected for serum C‐reactive protein and cytokine analysis.Key ResultsCYP2E1 activity was markedly up‐regulated in cancer (6‐hydroxychlorzoxazone/chlorzoxazone ratio of 1.30 vs. 2.75), while CYP3A phenotypic activity was repressed in cancer (omeprazole sulfone/omeprazole ratio of 0.23 vs. 0.49). Increased activity of CYP2E1 was associated with raised serum levels of IL‐6, IL‐8, and TNF‐α. Repression of CYP3A correlated with raised levels of serum C‐reactive protein, IL‐6, IL‐8, and TNF‐α.Conclusions and ImplicationsCYP enzyme activity is differentially affected by the presence of tumour‐associated inflammation, affecting particularly CYP2E1‐ and CYP3A‐mediated drug metabolism, and may have profound implications for drug development and prescribing in oncological settings.
Sharma R, Singh BK, Kumar P, et al., 2019, Presence of Fluoroquinolone mono-resistance among drug-sensitive Mycobacterium tuberculosis isolates: An alarming trend and implications, Clinical Epidemiology and Global Health, Vol: 7, Pages: 363-366
Background: The phenomenon of Drug Resistant Tuberculosis (DRTB) has been evolving aggressively and is posing great threat to tuberculosis control programs worldwide. But what really is fueling drug resistance in high disease burden countries apart from other well known risk factors, with this intent in mind the present study was developed and carried out to. The aim was to capture the presence of Fluoroquinolone (FQ) mono-resistance among drug-sensitive TB cases. Methods: A total of 1280 sputum smear-positive patients were enrolled in the study and were subjected for Drug Susceptibility Testing (DST) using First-Line Drugs (FLD's; Rifampicin, Streptomycin, Isoniazid and Ethambutol) using liquid culture DST and Line Probe Assay. These samples were further subjected to second-line drugs DST (ofloxacin and kanamycin) and DNA sequencing to confirm FQ mono-resistance. Results: The occurrence of FQ mono-resistance among FLD sensitive cases was found to be 3.2% (35/1099). Xpert MTB/RIF assay and rpoB gene sequencing were showed 100% concordance with FLD DST. A total of 35 FQ mono-resistant isolates were further sequenced for gyrA, gyrB and rrs genes. The gene sequencing was found to be in agreement with the DST results for 34 (3.1%) isolates with gyrA and gyrB genes. Conclusion: Presence of FQ resistance among drug sensitive TB cases is a red flag sign. The findings of the present study suggest that, second-line DST should be routinely performed not only for drug-resistant cases but also for drug-sensitive cases so as to capture prevailing true drug resistance at an initial stage.
Chambers E, Byrne C, Rugyendo A, et al., 2019, The effects of dietary supplementation with inulin and inulin-propionate ester on hepatic steatosis in adults with non-alcoholic fatty liver disease, Diabetes, Obesity and Metabolism, Vol: 21, Pages: 372-376, ISSN: 1462-8902
The short chain fatty acid (SCFA) propionate, produced through fermentation of dietary fibre by the gut microbiota, has been shown to alter hepatic metabolic processes that reduce lipid storage. We aimed to investigate the impact of raising colonic propionate production on hepatic steatosis in adults with non‐alcoholic fatty liver disease (NAFLD). Eighteen adults were randomised to receive 20g/day of an inulin‐propionate ester (IPE), designed to deliver propionate to the colon, or an inulin‐control for 42‐days in a parallel design. The change in intrahepatocellular lipid (IHCL) following the supplementation period was not different between groups (P=0.082), however IHCL significantly increased within the inulin‐control group (20.9±2.9 to 26.8±3.9%; P=0.012; n=9), which was not observed within the IPE group (22.6±6.9 to 23.5±6.8%; P=0.635; n=9). The predominant SCFA from colonic fermentation of inulin is acetate, which in a background of NAFLD and a hepatic metabolic profile that promotes fat accretion, may provide surplus lipogenic substrate to the liver. The increased colonic delivery of propionate from IPE appears to attenuate this acetate‐mediated increase in IHCL.
Howell J, Atkinson SR, Pinato DJ, et al., 2019, Identification of mutations in circulating cell-free tumour DNA as a biomarker in hepatocellular carcinoma, European Journal of Cancer, Vol: 116, Pages: 56-66, ISSN: 0959-8049
BACKGROUND: Hepatocellular carcinoma (HCC) is increasing globally. Prognostic biomarkers are urgently needed to guide treatment and reduce mortality. Tumour-derived circulating cell-free DNA (ctDNA) is a novel, minimally invasive means of determining genetic alterations in cancer. We evaluate the accuracy of ctDNA as a biomarker in HCC. METHODS: Plasma cell-free DNA, matched germline DNA and HCC tissue DNA were isolated from patients with HCC (n = 51) and liver cirrhosis (n = 10). Targeted, multiplex polymerase chain reaction ultra-deep sequencing was performed using a liver cancer-specific primer panel for genes ARID1A, ARID2, AXIN1, ATM, CTNNB1, HNF1A and TP53. Concordance of mutations in plasma ctDNA and HCC tissue DNA was determined, and associations with clinical outcomes were analysed. RESULTS: Plasma cell-free DNA was detected in all samples. Lower plasma cell-free DNA levels were seen in Barcelona Clinic Liver Cancer (BCLC A compared with BCLC stage B/C/D (median concentration 122.89 ng/mL versus 168.21 ng/mL, p = 0.041). 29 mutations in the eight genes (21 unique mutations) were detected in 18/51 patients (35%), median 1.5 mutations per patient (interquartile range 1-2). Mutations were most frequently detected in ARID1A (11.7%), followed by CTNNB1 (7.8%) and TP53 (7.8%). In patients with matched tissue DNA, all mutations detected in plasma ctDNA detected were confirmed in HCC DNA; however, 71% of patients had mutations identified in HCC tissue DNA that were not detected in matched ctDNA. CONCLUSION: ctDNA is quantifiable across all HCC stages and allows detection of mutations in key driver genes of hepatic carcinogenesis. This study demonstrates high specificity but low sensitivity of plasma ctDNA for detecting mutations in matched HCC tissue.
Bettinger D, Pinato DJ, Schultheiss M, et al., 2019, Stereotactic body radiation therapy as an alternative treatment for patients with hepatocellular carcinoma compared to sorafenib: a propensity score analysis, Liver Cancer, Vol: 8, Pages: 281-294, ISSN: 2235-1795
Background and Aims: Stereotactic body radiation therapy (SBRT) has emerged as a safe and effective treatment for patients with hepatocellular carcinoma (HCC), but its role in patients with advanced HCC is not yet defined. In this study, we aim to assess the efficacy and safety of SBRT in comparison to sorafenib treatment in patients with advanced HCC. Methods: We included 901 patients treated with sorafenib at six tertiary centers in Europe and Asia and 122 patients treated with SBRT from 13 centers in Germany and Switzerland. Medical records were reviewed including laboratory parameters, treatment characteristics and development of adverse events. Propensity score matching was performed to adjust for differences in baseline characteristics. The primary endpoint was overall survival (OS) and progression-free survival. Results: Median OS of SBRT patients was 18.1 (10.3–25.9) months compared to 8.8 (8.2–9.5) in sorafenib patients. After adjusting for different baseline characteristics, the survival benefit for patients treated with SBRT was still preserved with a median OS of 17.0 (10.8–23.2) months compared to 9.6 (8.6–10.7) months in sorafenib patients. SBRT treatment of intrahepatic lesions in patients with extrahepatic metastases was also associated with improved OS compared to patients treated with sorafenib in the same setting (17.0 vs. 10.0 months, p = 0.012), whereas in patients with portal vein thrombosis there was no survival benefit in patients with SBRT. Conclusions: In this retrospective comparative study, SBRT showed superior efficacy in HCC patients compared to patients treated with sorafenib.
Pinato D, Mauri F, Spina P, et al., 2019, Clinical implications of heterogeniety in PD-L1 immuno-histochemical detection in hepatocellular carcinoma: the Blueprint-HCC study, British Journal of Cancer, Vol: 120, Pages: 1033-1036, ISSN: 0007-0920
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.
Flynn MJ, Sayed AA, Sharma R, et al., 2019, Challenges and opportunities in the clinical development of immune checkpoint inhibitors for hepatocellular carcinoma, Hepatology, Vol: 69, Pages: 2258-2270, ISSN: 0270-9139
After a decade of stagnation in drug development, therapeutic reversal of immune-exhaustion with immune checkpoint inhibitors (ICPI) 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 biologic foundations supporting the development of ICPI across the advancing stages of HCC, focusing in particular on the proposal of a rational positioning of ICPI across the various Barcelona-Clinic Liver Cancer stages of the disease. Translational studies should guide adequate prioritisation of those therapeutic agents and combination strategies which are most likely to achieve patient benefit based on solid mechanistic and clinical justifications.
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