Publications
245 results found
Howell J, Pinato DJ, Ramaswami R, et al., 2017, On-target sorafenib toxicity predicts improved survival in hepatocellular carcinoma: a multi-centre, prospective study, ALIMENTARY PHARMACOLOGY & THERAPEUTICS, Vol: 45, Pages: 1146-1155, ISSN: 0269-2813
Background:Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and has high mortality despite treatment. While sorafenib has a survival benefit for patients with advanced HCC, clinical response is highly variable.Aim:To determine whether development of sorafenib toxicity is a prognostic marker of survival in HCC.Methods:In this prospective multicentre cohort study, patients with advanced-stage HCC receiving sorafenib were recruited from five international specialist centres. Demographic and clinical data including development and grade of sorafenib toxicity during treatment, radiological response to sorafenib and survival time (months) were recorded prospectively.Results:A total of 634 patients with advanced-stage HCC receiving sorafenib were recruited to the study, with a median follow-up of 6692.3 person-months at risk. The majority of patients were male (81%) with Child–Pugh A stage liver disease (74%) and Barcelona Clinic Liver Cancer stage C HCC (64%). Median survival time was 8.1 months (IQR 3.8–18.6 months). 94% experienced at least one sorafenib-related toxicity: 34% diarrhoea, 16% hypertension and 37% hand-foot syndrome (HFS). Twenty-one per cent ceased sorafenib due to toxicity and 59% ceased treatment due to progressive disease or death. On multivariate analysis, sorafenib-related diarrhoea (HR 0.76, 95% CI 0.61–0.95, P = 0.017), hypertension (HR 0.531, 95% CI 0.37–0.76, P < 0.0001) and HFS (HR 0.65, 95% CI 0.51–0.81, P < 0.0001) were all significant independent predictors of overall survival after adjusting for age, severity of liver disease, tumour stage and sorafenib dose.Conclusion:Development of sorafenib-related toxicity including diarrhoea, hypertension and hand-foot syndrome is associated with prolonged overall survival in patients with advanced-stage HCC on sorafenib.
Howell J, Pinato DJ, Ramaswami R, et al., 2017, Integration of the cancer-related inflammatory response as a stratifying biomarker of survival in hepatocellular carcinoma treated with sorafenib., Oncotarget, Vol: 8, Pages: 36161-36170, ISSN: 1949-2553
BACKGROUND AND AIMS: Response to sorafenib is highly variable in hepatocellular carcinoma (HCC). Baseline inflammatory parameters and treatment toxicities may improve survival prediction in patients on sorafenib therapy. RESULTS: 442 patients with advanced stage HCC on sorafenib were recruited (follow-up 5096 person-months at risk). 88% had BCLC stage B or greater HCC and 72.3% had Child-Pugh A cirrhosis. On Cox multivariate regression, previously-treated HCC (HR 0.579, 95% CI 0.385-0.872, p=0.009), Cancer of Liver Italian Program (CLIP) score (HR 1.723, 95% CI 1.462-2.047, p<0.0001), baseline red cell distribution width (RDW; HR 1.234, 95% CI 1.115-1.290, p<0.0001) and neutrophil to lymphocyte ratio (NLR; HR 1.218, 95% CI 1.108-1.322, p<0.0001) were significant independent risks for shorter survival, whilst sorafenib-related diarrhoea was associated with prolonged survival (HR 0.533, 95% CI 0.373-0.763, p=0.001). The combination of RD-CLIP score (CLIP score multiplied by RDW) ≥ 70 and no treatment-related diarrhoea had good utility for predicting 3-month survival (AUC of 0.808 (95% CI 0.734-0.882), positive predictive value of 86.4% and negative predictive value of 83.3%), compared with CLIP (AUC=0.642) or BCLC score alone (AUC=0.579). RD-CLIP score ≥ 35 and no treatment-related diarrhoea had an AUC of 0.787 for predicting 12-month survival. METHODS: Patients with HCC were consecutively recruited from three tertiary centres (Japan, Italy and UK) and clinical data were prospectively collected. The primary study endpoint was overall survival (OS) after commencing sorafenib. CONCLUSION: The novel prognostic index of CLIP score combined with inflammatory marker RDW and treatment-related diarrhoea has good accuracy for predicting overall, 3 month and 12 month survival in patients on sorafenib.
Pinato DJ, Sharma R, Yen C, et al., 2017, The ALBI grade provides objective hepatic reserve phenotyping across each BCLC stage of hepatocellular carcinoma, Journal of Hepatology, Vol: 66, Pages: 338-346, ISSN: 1600-0641
BACKGROUND & AIMS: Overall survival (OS) is a composite clinical endpoint in hepatocellular carcinoma (HCC) due to the mutual influence of cirrhosis and active malignancy in dictating patient's mortality. The ALBI grade is a recently described index of liver dysfunction in hepatocellular carcinoma, based solely on albumin and bilirubin levels. Whilst accurate, this score lacks cross-validation, especially in intermediate stage HCC, where OS is highly heterogeneous. METHODS: We evaluated the prognostic accuracy of the ALBI grade in estimating OS in a large, multi-centre study of 2426 patients, including a large proportion of intermediate stage patients treated with chemoembolization (n=1461) accrued from Europe, the United States and Asia. RESULTS: Analysis of survival by primary treatment modality confirmed the ALBI grade as a significant predictor of patient OS after surgical resection (p<0.001), transarterial chemoembolization (p<0.001) and sorafenib (p<0.001). Stratification by Barcelona Clinic Liver Cancer stage confirmed the independent prognostic value of the ALBI across the diverse stages of the disease, geographical regions of origin and time of recruitment to the study (p<0.001). CONCLUSIONS: In this large, multi-centre retrospective study, the ALBI grade satisfied the criteria for accuracy and reproducibility following statistical validation in Eastern and Western HCC patients, including those treated with chemoembolization. Consideration should be given to the ALBI grade as a stratifying biomarker of liver reserve in routine clinical practice. LAY SUMMARY: Liver failure is a key determinant influencing the natural history of hepatocellular carcinoma (HCC). In this large multi-centre study we externally validate a novel biomarker of liver functional reserve, the ALBI grade, across all the stages of HCC.
Pinato DJ, Yen C, Bettinger D, et al., 2017, The albumin-bilirubin grade improves hepatic reserve estimation post-sorafenib failure: implications for drug development, Alimentary Pharmacology and Therapeutics, Vol: 45, Pages: 714-722, ISSN: 0269-2813
Background: Drug development in hepatocellular carcinoma (HCC) is limited by disease heterogeneity, with hepatic reserve being a major source of variation in survival outcomes. The albumin–bilirubin (ALBI) grade is a validated index of liver function in patients with HCC.Aim: To test the accuracy of the ALBI grade in predicting post-sorafenib overall survival (PSOS) in patients who permanently discontinued treatment.Methods: From a prospectively maintained international database of 447 consecutive referrals, we derived 386 eligible patients treated with sorafenib within Barcelona Clinic Liver Cancer C stage (62%), 75% of whom were of Child class A at initiation. Clinical variables at sorafenib discontinuation were analysed for their impact on post-sorafenib overall survival using uni- and multivariable analyses.Results: Median post-sorafenib overall survival of the 386 eligible patients was 3.4 months and median sorafenib duration was 2.9 months, with commonest causes of cessation being disease progression (68%) and toxicity (24%). At discontinuation, 92 patients (24%) progressed to terminal stage, due to worsening Child class to C in 40 (10%). Median post-sorafenib overall survival in patients eligible for second-line therapies (n = 294) was 17.5, 7.5 and 1.9 months according respectively to ALBI grade 1, 2 and 3 (P < 0.001).Conclusions: The ALBI grade at sorafenib discontinuation identifies a subset of patients with prolonged stability of hepatic reserve and superior survival. This may allow improved patient selection for second-line therapies in advanced HCC.
Gupta N, Banerjee S, Timitrov, et al., 2017, Osteomyelitis due to multiple rare infections in a patient with idiopathic CD4 lymphocytopenia, Intractable and Rare Diseases Research, Vol: 6, Pages: 206-210, ISSN: 2186-3644
A 26-year-old male patient presented with features suggestive of osteomyelitis involving the entire left femur, hip joint and knee joint. Culture from the debrided tissue grew Acinetobacter spp. and he was treated with sensitivity based antibiotics but the symptoms did not resolve. The synovial biopsy showed multinucleated giant cells and acid fast bacilli on Ziehl Neelsen stain. Cartridge based nucleic acid amplification test (GeneXpert) was negative. The Mycobacteria growth indicator tube culture was found to be positive for Mycobacterium abscessus. The patient was started on imipenem, amikacin and macrolide based therapy. There was partial response initially but the patient worsened again. A girdle stone arthroplasty with cemented nail (with tobramycin) insertion after debridement of the infected tissue was done. Potassium hydroxide (KOH) mount from the debridement sample was found to be positive for aseptate hyphae suggestive of mucormycosis. He was treated with liposomal amphotericin B. He was evaluated for immunodeficiency in view of multiple atypical infections and was found to have a low CD4 count. The patient was discharged on amikacin, azithromycin, trimethoprimsulfamethoxazole and posaconazole. Follow up showed considerable resolution both clinically and radiologically. To our knowledge, this is the first reported case of osteomyelitis with co-infection of Acinetobacter spp., M. abscessus and mucormycetes. We report this case to highlight the possibility of multiple rare infections in patients with immunodeficiency. Also, atypical complicated bone infections, such as Mycobacterium abscessus and mucormycetes might require combined medical and surgical treatment.
Yen C, Sharma R, Rimassa L, et al., 2017, Treatment Stage Migration Maximizes Survival Outcomes in Patients with Hepatocellular Carcinoma Treated with Sorafenib: An Observational Study, LIVER CANCER, Vol: 6, Pages: 313-324, ISSN: 2235-1795
Kumar S, Bopanna S, Kedia S, et al., 2017, Evaluation of Xpert MTB/RIF assay performance in the diagnosis of abdominal tuberculosis, Intestinal Research, Vol: 15, Pages: 187-194, ISSN: 1598-9100
The use of genetic probes for the diagnosis of pulmonary tuberculosis (TB) has been well described. However, the role of these assays in the diagnosis of intestinal tuberculosis is unclear. We therefore assessed the diagnostic utility of the Xpert Mycobacterium tuberculosis /rifampicin (MTB/RIF) assay, and estimated the prevalence of multidrug-resistant (MDR) TB in the Indian population Methods: Of 99 patients recruited, 37 had intestinal TB; two control groups comprised 43 with Crohn's disease (CD) and 19 with irritable bowel syndrome. Colonoscopy was performed before starting any therapy; mucosal biopsies were subjected to histopathology, acid-fast bacilli staining, Lowenstein-Jensen culture, and nucleic acid amplification testing using the Xpert MTB/RIF assay. Patients were followed up for 6 months to confirm the diagnosis and response to therapy. A composite reference standard was used for diagnosis of TB and assessment of the diagnostic utility of the Xpert MTB/RIF assay. Results: Of 37 intestinal TB patients, the Xpert MTB/RIF assay was positive in three of 37 (8.1%), but none had MDR-TB. The sensitivity, specificity, positive predictive value, and negative predictive value of the Xpert MTB/RIF assay was 8.1%, 100%, 100%, and, 64.2%, respectively. Conclusions: The Xpert MTB/RIF assay has low sensitivity but high specificity for intestinal TB, and may be helpful in endemic tuberculosis areas, when clinicians are faced with difficulty differentiating TB and CD. Based on the Xpert MTB/RIF assay, the prevalence of intestinal MDR-TB is low in the Indian population.
Pinato DJ, Victor S, Spina P, et al., 2017, Intra-tumour heterogeneity in the regulation of immune-tolerogenic pathways in primary and metastatic hepatocellular carcinoma, International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S224-S224, ISSN: 0168-8278
Pinato DJ, Merli M, Pria AD, et al., 2017, The systemic inflammatory response is a prognostic marker in human immunodeficiency virus-infected patients with hepatocellular carcinoma, International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S205-S206, ISSN: 0168-8278
Yen C, Sharma R, Rimassa L, et al., 2017, Treatment-stage migration maximizes survival outcomes in patients with hepatocellular carcinoma treated with sorafenib: an observational study, International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S223-S224, ISSN: 0168-8278
Howell J, Atkinson S, PInato DJ, et al., 2017, Identification of actionable mutations in circulating cell-free tumour DNA as a prognostic biomarker in hepatocellular carcinoma, International Liver Congress / 52nd Annual Meeting of the European-Association-for-the-Study-of-the-Liver, Publisher: ELSEVIER SCIENCE BV, Pages: S449-S449, ISSN: 0168-8278
Singh BK, Sharma SK, Sharma R, et al., 2017, Diagnostic utility of a line probe assay for multidrug resistant-TB in smear-negative pulmonary tuberculosis., PLoS One, Vol: 12
OBJECTIVE: To evaluate the performance of Genotype MTBDRplus VER 2.0 in the diagnosis of Mycobacterium tuberculosis (MTB) in sputum smear-negative pulmonary TB cases. METHODS: A total of 572 Ziehl-Neelsen sputum smear-negative samples were selected and subjected to line probe assay (Genotype MTBDRplus VER 2.0), and culture in mycobacterial growth indicator tube (MGIT-960). Immunochromatographic test was used to confirm the MTB-complex (MTBC) in culture-positive samples and phenotypic drug-susceptibility testing was done using MGIT-960. RESULTS: The line probe assay was able to diagnose MTBC in 38.2% (213/558) of specimens after excluding 14 nontuberculous mycobacteria. Sensitivity and specificity of the assay were 68.4% and 89.3% respectively, considering MGIT-960 culture as gold standard after excluding contaminated and invalid results. On comparing with composite reference standard, the assay had 71.5% sensitivity and 100% specificity in the diagnosis of tuberculosis. The sensitivity and specificity for detecting resistance to rifampicin (RMP) were 100% and 99.24% respectively and for resistance to isoniazid (INH) were 97.62% and 98.55%, respectively. CONCLUSION: Genotype MTBDRplus VER 2.0 is a rapid and precise diagnostic tool for detection of MTB in sputum smear-negative samples. It also facilitates accurate diagnosis of RMP and INH resistance within turn around-time.
Howell JA, Khan SA, Knapp S, et al., 2016, The clinical role of circulating free tumor DNA in gastrointestinal malignancy, Translational Research, Vol: 183, Pages: 137-154, ISSN: 1931-5244
Circulating cell-free DNA (cfDNA) is DNA released from necrotic or apoptotic cells into the bloodstream. While both healthy cells and cancer cells release cfDNA, tumors are associated with higher levels of tumor-derived circulating cell-free DNA (ctDNA) detectable in blood. Absolute levels of ctDNA and its genetic mutations and epigenetic changes show promise as potentially useful biomarkers of tumor biology, progression, and response to therapy. Moreover, studies have demonstrated the discriminative accuracy of ctDNA levels for diagnosis of gastrointestinal cancer compared with benign inflammatory diseases. Therefore, ctDNA detected in blood offers a minimally invasive and easily repeated "liquid biopsy" of cancer, facilitating real-time dynamic analysis of tumor behavior that could revolutionize both clinical and research practices in oncology. In this review, we provide a critical summary of the evidence for the utility of ctDNA as a diagnostic and prognostic biomarker in gastrointestinal malignancies.
Pinato DJ, Yen C, Sharma R, 2016, 'Validating the ALBI grade: Its current and future use in HCC prognostication' Reply, JOURNAL OF HEPATOLOGY, Vol: 66, Pages: 663-664, ISSN: 0168-8278
Sharma R, Mapelli P, Hanna GB, et al., 2016, Evaluation of F-18-fluorothymidine positron emission tomography ([F-18] FLT-PET/CT) methodology in assessing early response to chemotherapy in patients with gastro-oesophageal cancer, EJNMMI Research, Vol: 6, ISSN: 2191-219X
Background3’-Deoxy-3’-[18F]fluorothymidine ([18F]FLT) PET has limited utility in abdominal imaging due to high physiological hepatic uptake of a tracer. We evaluated [18F]FLT-PET/CT combined with a temporal-intensity information-based voxel-clustering approach termed kinetic spatial filtering (KSF) to improve tumour visualisation in patients with locally advanced and metastatic gastro-oesophageal cancer and as a marker of early response to chemotherapy.Dynamic [18F]FLT-PET/CT data were collected before and 3 weeks post first cycle of chemotherapy. Changes in tumour [18F]FLT-PET/CT variables were determined. Response was determined on contrast-enhanced CT after three cycles of therapy using RECIST 1.1.ResultsTen patients were included. Following application of the KSF, visual distinction of all oesophageal and/or gastric tumours was observed in [18F]FLT-PET images. Among the nine patients available for response evaluation (RECIST 1.1), three patients had responded (partial response) and six patients were non-responders (stable disease). There was a significant association between Ki-67 and all baseline [18F]FLT-PET parameters. Area under the curve (AUC) from 0 to 1 min was associated with treatment response.ConclusionsThe results of this study indicate that application of the KSF allowed accurate visualisation of both primary and metastatic lesions following imaging with the proliferation marker, [18F]FLT-PET/CT. However, [18F]FLT-PET uptake parameters did not correlate with response. Instead, we observe significant changes in tracer delivery following chemotherapy suggesting that further [18F]FLT-PET/CT studies in this tumour type should be undertaken with caution.
Dubash SR, Keat N, Mapelli P, et al., 2016, Biodistribution, radiation dosimetry and first preliminary results of a novel <SUP>18</SUP>F-fluoroethyl triazole [Tyr<SUP>3</SUP>] octreotate analogue for PET imaging in locally advanced and metastatic Neuroendocrine tumour patients, Annual Congress of the European-Association-of-Nuclear-Medicine (EANM), Publisher: SPRINGER, Pages: S105-S105, ISSN: 1619-7070
- Author Web Link
- Cite
- Citations: 1
Pinato DJ, Sharma R, 2016, Systemic inflammation: A new prognostic domain and source of therapeutic targets in hepatocellular carcinoma, Hepatocellular Carcinoma Diagnosis and Treatment, Editors: Carr, Publisher: Springer, Pages: 229-241, ISBN: 9783319342122
The pathogenesis of hepatocellular carcinoma (HCC) strongly relates to inflammation with chronic up-regulation of pro-inflammatory mediators standing as a potential unifying mechanism to justify the origin and progression of HCC independent of aetiology. Activation of the diverse pro-inflammatory mediators either within the tumour or its microenvironment is part of an active cross-talk between the progressive HCC and the host, which is known to influence clinical outcomes including recurrence after radical treatments and long-term survival. A number of clinical biomarkers to measure the severity of cancer-related inflammation are now available, most of which emerge from routine blood parameters including bone marrow function, albuminaemia and C-reactive protein. Cancer-related inflammation is an accurate prognostic indicator in both curative and palliative setting of care in HCC and a potential source of novel therapeutic strategies in advanced disease.
Howell J, Pinato D, Ramaswami R, et al., 2016, Integration of the cancer-related pro-inflammatory response as a stratifying biomarker of survival benefit with sorafenib in hepatocellular carcinoma, Journal of Hepatology, Vol: 64, Pages: S195-S195, ISSN: 1600-0641
Pinato DJ, Shiner RJ, White SDT, et al., 2016, Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer: Implications for immunotherapy, OncoImmunology, Vol: 5, ISSN: 2162-4011
Purpose: There is inconclusive evidence to suggest the expression of programmed cell death (PD) ligand 1 (PD-L1) is a putative predictor of response to PD-1/PD-L1-targeted therapies in lung cancer. We evaluated the heterogeneity in the expression of PD-1 ligands in isogeneic primary and metastatic LC specimens. Experimental Design: From 12,580 post mortem cases, we identified 214 patients with untreated metastatic LC, of which 98 had adequately preserved tissues to construct a syngeneic primary LC/metastasis tissue microarray. Immunostaining for PD-L1 and 2 was evaluated in paired primary and metastatic lesions and correlated with clinicopathologic features. Results: We included 98 patients with non-small cell (NSCLC, n = 65, 66%), small cell histology (SCLC, n = 29, 30%) and four (4%) atypical carcinoids (AC). In total 8/65 (12%) primary PD-L1 positive NSCLC, had discordant matched metastases (14/17, 82%). PD-L1 negative primaries had universally concordant distant metastases. SCLCs were universally PD-L1 negative across primary and metastatic disease. PD-L2 positive NSCLC (n = 11/65, 17%) had high rate of discordant metastases (n = 24/27, 88%) and four cases (6%) had PD-L2 positive metastases with negative primaries. 2/29 SCLC (7%) and 1/4 AC (25%) were PD-L2 positive with discordance in all the sampled metastatic sites (n = 5). We found no correlation between the expression of PD ligands and clinicopathologic features of LC. Conclusions: Intra-tumoral heterogeneity in the expression of PD ligands is common in NSCLC, while PD-L1 is homogeneously undetectable in primary and metastatic SCLC. This holds implications in the clinical development of immune response biomarkers in LC.
Ramaswami R, Pinato DJ, Kubota K, et al., 2016, Prognostic sub-classification of intermediate-stage hepatocellular carcinoma: a multicenter cohort study with propensity score analysis, Medical Oncology, Vol: 33, ISSN: 1559-131X
There is significant heterogeneity in the clini-copathological characteristics of intermediate hepatocellu-lar carcinoma (IHCC). This also translates to treatment astransarterial chemoembolization (TACE) is used as first-line therapy for patients with IHCC; however, in Asia liverresection (LR) is preferred. Prognostic tools are required tohelp guide clinicians in deciding treatment options. Thisstudy evaluates the prognostic impact of the IntermediateStage Score (ISS) on overall survival (OS) in a large,multicenter cohort study of patients with IHCC treated withTACE or surgery LR. Consecutive patients from centers inJapan, Korea, Italy and the United Kingdom who under-went TACE or LR between 2001 and 2015 were enrolled.Propensity score (PS) adjustment was used to removeresidual confounding and applied to LR (n=162) and TACE (n=449) to determine the prognostic significanceof ISS. Among 611 patients, 75 % were men and 25 %women, with a mean age of 70 years. ISS is a validprognostic tool in the BCLC-B population with a medianOS ISS 1–51, 2–38.3, 3–24.3, 4–15.6, 5–16 months(p\0.0001). ISS was analyzed within each treatmentmodality, and this was a valid prognostic score amongthose treated with TACE and LR (p\0.001 vs.p=0.008). In the PS-adjusted model, ISS retained itsprognostic utility in TACE and LR groups (p\0.001 vs.p=0.007). ISS optimizes prognostic prediction in IHCC,reducing clinical heterogeneity, and is a useful tool forpatients treated for TACE or LR.
Pinato DJ, Stebbing J, Ishizuka M, et al., 2016, Corrigendum to “A novel and validated prognostic index in hepatocellular carcinoma: The Inflammation Based Index (IBI)”, Journal of Hepatology, Vol: 65, Pages: 453-453, ISSN: 1600-0641
Pinato DJ, Arizumi T, Jang JW, et al., 2016, Combined sequential use of HAP and ART scores to predict survival outcome and treatment failure following chemoembolization in hepatocellular carcinoma: a multi-center comparative study, Oncotarget, Vol: 7, Pages: 44705-44718, ISSN: 1949-2553
BACKGROUND: The prognosis of patients with hepatocellular carcinoma (HCC) undergoing transarterial chemoembolization (TACE) is variable, despite a myriad of prognostic markers. We compared and integrated the established prognostic models, HAP and ART scores, for their accuracy of overall survival (OS) prediction. RESULTS: In both training and validation sets, HAP and ART scores emerged as independent predictors of OS (p<0.01) with HAP achieving better prognostic accuracy (c-index: 0.68) over ART (0.57). We tested both scores in combination to evaluate their combined ability to predict OS. Subgroup analysis of BCLC-C patients revealed favorable HAP stage (p<0.001) and radiological response after initial TACE (p<0.001) as positive prognostic factors. PATIENTS AND METHODS: Prognostic scores were studied using multivariable Cox regression and c-index analysis in 83 subjects with Barcelona Clinic Liver Cancer (BCLC) A/B stage from UK and Italy (training set), and 660 from Korea and Japan (validation set), all treated with conventional TACE. Scores were further validated in an separate analysis of patients with BCLC-C stage disease (n=63) receiving initial TACE. CONCLUSION: ART and HAP scores are validated indices in patients with intermediate stage HCC undergoing TACE. The HAP score is best suited for screening patients prior to initial TACE, whilst sequential ART assessment improves early detection of chemoembolization failure. BCLC-C patients with low HAP stage may be a subgroup where TACE should be explored in clinical studies.
Pinato DJ, Shiner RJ, White SDT, et al., 2016, Intra-tumoral heterogeneity in the expression of programmed-death (PD) ligands in isogeneic primary and metastatic lung cancer (LC): Implications for immunotherapy., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Pinato DJ, Brown M, White SDT, et al., 2016, Programmed cell death (PD-1) ligands expression in gastro-entero-pancreatic neuroendocrine tumours (GEP-NETs): relationship with angiogenesis and clinical outcome., Annual Meeting of the American-Society-of-Clinical-Oncology (ASCO), Publisher: AMER SOC CLINICAL ONCOLOGY, ISSN: 0732-183X
Sharma R, 2016, Reply to: "Survival data might be inappropriate in the paper by Pinato et al.": Survival data correct and appropriate by Pinato et al., Journal of Hepatology, Vol: 65, Pages: 449-449, ISSN: 1600-0641
Dubash S, Keat N, Mapelli P, et al., 2016, Clinical Translation of a Click-Labeled 18F-Octreotate Radioligand for Imaging Neuroendocrine Tumors, Journal of Nuclear Medicine, Vol: 57, Pages: 1207-1213, ISSN: 1535-5667
We conducted the first-in-human study of 18F-fluoroethyl triazole [Tyr3] octreotate (18F-FET-βAG-TOCA) in patients with neuroendocrine tumors (NETs) to evaluate biodistribution, dosimetry, and safety. Despite advances in clinical imaging, detection and quantification of NET activity remains a challenge, with no universally accepted imaging standard. Methods: Nine patients were enrolled. Eight patients had sporadic NETs, and 1 had multiple endocrine neoplasia type 1 syndrome. Patients received 137–163 MBq (mean ± SD, 155.7 ± 8 MBq) of 18F-FET-βAG-TOCA. Safety data were obtained during and 24 h after radioligand administration. Patients underwent detailed whole-body PET/CT multibed scanning over 4 h with sampling of venous bloods for radioactivity and radioactive metabolite quantification. Regions of interest were defined to derive individual and mean organ residence times; effective dose was calculated with OLINDA 1.1. Results: All patients tolerated 18F-FET-βAG-TOCA with no adverse events. Over 60% parent radioligand was present in plasma at 60 min. High tumor (primary and metastases)-to-background contrast images were observed. Physiologic distribution was seen in the pituitary, salivary glands, thyroid, and spleen, with low background distribution in the liver, an organ in which metastases commonly occur. The organs receiving highest absorbed dose were the gallbladder, spleen, stomach, liver, kidneys, and bladder. The calculated effective dose over all subjects (mean ± SD) was 0.029 ± 0.004 mSv/MBq. Conclusion: The favorable safety, imaging, and dosimetric profile makes 18F-FET-βAG-TOCA a promising candidate radioligand for staging and management of NETs. Clinical studies in an expanded cohort are ongoing to clinically qualify this agent.
Pinato DJ, Black JRM, Ramaswami R, et al., 2016, Peptide receptor radionuclide therapy for metastatic paragangliomas, Medical Oncology, Vol: 33, ISSN: 1559-131X
There is little evidence to direct the management of malignant paragangliomas (mPGL) beyond initial surgical treatment. Peptide receptor radionuclide therapy (PRRT), using somatostatin analogues, is effective in other neuroendocrine tumours, but data on its efficacy in treating mPGL are scarce. We report safety and efficacy outcomes from a case series of five patients with advanced mPGLs treated with 177Lu-DOTATATE PRRT. The mean age of our cohort was 34 years (range 16–47); 4 patients were male with bone disease being the most prevalent metastatic site. PRRT scheme varied between 1 and 4 cycles, with premature cessation due to suspected pneumonitis in one case and disease progression in another. Three patients with previously documented progressive disease achieved stabilization following treatment; one had partial response and one was treatment refractory. Median progression-free survival was 17 months (range 0–78 months). 177-Lu-DOTATATE is an effective therapy in mPGLs in this molecularly defined patient cohort, warranting further investigation in larger studies including hereditary and sporadic mPGL.
Howell J, Pinato DJ, Ramaswami R, et al., 2016, Integration of the cancer related inflammatory response as a stratifying biomarker of survival benefit with sorafenib, 51th International Liver Congress of the European-Association-for-the-Study-of-the-Liver
Pinato DJ, Yen C, Arizumi T, et al., 2016, An objective model to optimize treatment decisions in advanced hepatocellular carcinoma after sorafenib failure: the SORFA score., 51th International Liver Congress of the European-Association-for-the-Study-of-the-Liver
Brown M, Black JRM, Sharma R, et al., 2016, Gene of the month: Axl, Journal of Clinical Pathology, Vol: 69, Pages: 391-397, ISSN: 0021-9746
The interaction between Axl receptor tyrosine kinase and its main ligand Gas6 has been implicated in the progression of a wide number of malignancies. More recently, overexpression of Axl has emerged as a key molecular determinant underlying the development of acquired resistance to targeted anticancer agents. The activation of Axl is overexpression-dependent and controls a number of hallmarks of cancer progression including proliferation, migration, resistance to apoptosis and survival through a complex network of intracellular second messengers. Axl has been noted to influence clinically meaningful end points including metastatic recurrence and survival in the vast majority of tumour types. With Axl inhibitors having gained momentum as novel anticancer therapies, we provide an overview of the biological and clinical relevance of this molecular pathway, outlining the main directions of research.
This data is extracted from the Web of Science and reproduced under a licence from Thomson Reuters. You may not copy or re-distribute this data in whole or in part without the written consent of the Science business of Thomson Reuters.