Publications by authors named "Ravindran Kanesvaran"

109 Publications

Evaluation of Clear Cell, Papillary, and Chromophobe Renal Cell Carcinoma Metastasis Sites and Association With Survival.

JAMA Netw Open 2021 Jan 4;4(1):e2021869. Epub 2021 Jan 4.

Tom Baker Cancer Centre, University of Calgary, Calgary, Alberta, Canada.

Importance: There exists considerable biological and clinical variability between histologic variants of metastatic renal cell carcinoma (mRCC). Data reporting on patterns of metastasis in histologic variants of mRCC are sparse.

Objective: To characterize sites of metastasis and their association with survival across the 3 most common histologic variants of mRCC: clear cell (ccRCC), papillary (pRCC), and chromophobe (chrRCC).

Design, Setting, And Participants: In this multicenter, international cohort study, the International mRCC Database Consortium (IMDC) database was used to identify consecutive patients starting systemic therapy for mRCC between 2002 and 2019. Patients with mixed histologic subtype were excluded. Statistical analysis was performed from February to June 2020.

Exposures: Data regarding histologic subtype and sites of metastatic involvement at the time of first systemic therapy initiation were collected.

Main Outcomes And Measures: The primary outcomes were prevalence of metastatic site involvement and overall survival (OS) from time of systemic therapy initiation. Patients with multiple sites of metastatic involvement were included in analyses of all groups to which they had metastases.

Results: A total of 10 105 patients were eligible for analysis. Median (interquartile range) age at diagnosis was 60 (53-67) years, 7310 (72.4%) were men and 8526 (84.5%) underwent nephrectomy. Of these, 9252 (92%) had ccRCC, 667 (7%) had pRCC, and 186 (2%) had chrRCC. The median number of sites of metastasis was 2 (range, 0-7). In ccRCC, the most common sites of metastasis were lung (70%; 6189 of 8804 patients [448 missing]), lymph nodes (45%; 3874 of 8655 patients [597 missing]), bone (32%; 2847 of 8817 patients [435 missing]), liver (18%; 1560 of 8804 [448 missing]), and adrenal gland (10%; 678 of 6673 patients [2579 missing]). Sites of metastasis varied between subtypes. Lung, adrenal, brain, and pancreatic metastases were more frequent in ccRCC, lymph node involvement was more common in pRCC, and liver metastases were more frequent in chrRCC. Median OS for ccRCC varied by site of metastatic involvement, ranging between 16 months (95% CI, 13.7-18.8 months) for the pleura and 50 months (95% CI, 41.1-55.5 months) for the pancreas. Compared with ccRCC, patients with pRCC tended to have lower OS, regardless of metastatic site.

Conclusions And Relevance: Sites of metastatic involvement differ according to histologic subtype in mRCC and are associated with OS. These data highlight the clinical and biological variability between histologic subtypes of mRCC. Patterns of metastatic spread may reflect differences in underlying disease biology. Further work to investigate differences in immune, molecular, and genetic profiles between metastatic sites and histologic subtypes is encouraged.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.21869DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821027PMC
January 2021

Early Outcomes of a National Cancer Center's Strategy Against COVID-19 Executed Through a Disease Outbreak Response Taskforce.

JCO Oncol Pract 2021 Jan 13:OP2000535. Epub 2021 Jan 13.

Oncology Academic Clinical Program, Duke-NUS Medical School, Singapore.

Purpose: We present the strategy of a comprehensive cancer center organized to make operations pandemic proof and achieve continuity of cancer care during the COVID-19 pandemic.

Methods: Disease Outbreak Response (DORS) measures implemented at our center and its satellite clinics included strict infection prevention, manpower preservation, prudent resource allocation, and adaptation of standard-of-care treatments. Critical day-to-day clinical operations, number of persons screened before entry, staff temperature monitoring, and personal protection equipment stockpile were reviewed as a dashboard at daily DORS taskforce huddles. Polymerase chain reaction swab tests performed for patients and staff who met defined criteria for testing of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection were tracked. Descriptive statistics of outpatient attendances and treatment caseloads from February 3 to May 23, 2020, were compared with the corresponding period in 2019.

Results: We performed COVID-19 swabs for 80 patients and 93 staff, detecting three cancer patients with community-acquired COVID-19 infections with no nosocomial transmission. Patients who required chemotherapy, radiotherapy, or surgery and patients who are on maintenance treatment continued to receive timely treatment without disruption. The number of intravenous chemotherapy treatments was maintained at 97.8% compared with 2019, whereas that of weekly radiotherapy treatments remained stable since December 2019. All cancer-related surgeries proceeded without delay, with a 0.3% increase in workload. Surveillance follow-ups were conducted via teleconsultation, accounting for a 30.7% decrease in total face-to-face clinic consultations.

Conclusion: Through the coordinated efforts of a DORS taskforce, it is possible to avoid nosocomial SARS-CoV-2 transmissions among patients and staff without compromising on care delivery at a national cancer center.
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http://dx.doi.org/10.1200/OP.20.00535DOI Listing
January 2021

Priorities for the global advancement of care for older adults with cancer: an update of the International Society of Geriatric Oncology Priorities Initiative.

Lancet Oncol 2021 01;22(1):e29-e36

Department of Medical Oncology University Hospitals Leuven, Leuven, Belgium.

In 2011, the International Society of Geriatric Oncology (SIOG) published the SIOG 10 Priorities Initiative, which defined top priorities for the improvement of the care of older adults with cancer worldwide. Substantial scientific, clinical, and educational progress has been made in line with these priorities and international health policy developments have occurred, such as the shift of emphasis by WHO from communicable to non-communicable diseases and the adoption by the UN of its Sustainable Development Goals 2030. Therefore, SIOG has updated its priority list. The present document addresses four priority domains: education, clinical practice, research, and strengthening collaborations and partnerships. In this Policy Review, we reflect on how these priorities would apply in different economic settings, namely in high-income countries versus low-income and middle-income countries. SIOG hopes that it will offer guidance for international and national endeavours to provide adequate universal health coverage for older adults with cancer, who represent a major and rapidly growing group in global epidemiology.
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http://dx.doi.org/10.1016/S1470-2045(20)30473-3DOI Listing
January 2021

Computerized Image Analysis of Tumor Cell Nuclear Morphology Can Improve Patient Selection for Clinical Trials in Localized Clear Cell Renal Cell Carcinoma.

J Pathol Inform 2020 6;11:35. Epub 2020 Nov 6.

School of Medicine, University of St Andrews and Lothian NHS University Hospitals, St Andrews, Scotland.

Background: Clinicopathological scores are used to predict the likelihood of recurrence-free survival for patients with clear cell renal cell carcinoma (ccRCC) after surgery. These are fallible, particularly in the middle range. This inevitably means that a significant proportion of ccRCC patients who will not develop recurrent disease enroll into clinical trials. As an exemplar of using digital pathology, we sought to improve the predictive power of "recurrence free" designation in localized ccRCC patients, by precise measurement of ccRCC nuclear morphological features using computational image analysis, thereby replacing manual nuclear grade assessment.

Materials And Methods: TNM 8 UICC pathological stage pT1-pT3 ccRCC cases were recruited in Scotland and in Singapore. A Leibovich score (LS) was calculated. Definiens Tissue studio® (Definiens GmbH, Munich) image analysis platform was used to measure tumor nuclear morphological features in digitized hematoxylin and eosin (H&E) images.

Results: Replacing human-defined nuclear grade with computer-defined mean perimeter generated a modified Leibovich algorithm, improved overall specificity 0.86 from 0.76 in the training cohort. The greatest increase in specificity was seen in LS 5 and 6, which went from 0 to 0.57 and 0.40, respectively. The modified Leibovich algorithm increased the specificity from 0.84 to 0.94 in the validation cohort.

Conclusions: CcRCC nuclear mean perimeter, measured by computational image analysis, together with tumor stage and size, node status and necrosis improved the accuracy of predicting recurrence-free in the localized ccRCC patients. This finding was validated in an ethnically different Singaporean cohort, despite the different H and E staining protocol and scanner used. This may be a useful patient selection tool for recruitment to multicenter studies, preventing some patients from receiving unnecessary additional treatment while reducing the number of patients required to achieve adequate power within neoadjuvant and adjuvant clinical studies.
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http://dx.doi.org/10.4103/jpi.jpi_13_20DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7737492PMC
November 2020

Cancer Versus COVID-19: A Coordinated Disease Outbreak Response System (DORS) to Combat COVID-19 at the National Cancer Centre Singapore.

Ann Acad Med Singap 2020 Oct;49(10):807-809

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

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October 2020

Winning the Fight Against Cancer.

Ann Acad Med Singap 2020 Oct;49(10):779-788

Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore.

Advances in cytotoxic chemotherapy, surgical oncology, genomic medicine, targeted small molecule treatment, cancer immunotherapy and biology-driven precision radiation oncology have resulted in significant improvements in outcomes of cancer treatment, with an increasing number of patients achieving long-term disease control or even being potentially cured. Concurrent advances in palliative care and geriatric oncology have also helped to ensure that patients are managed holistically by considering their physical, social, psychological and emotional needs in a personalised manner.
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October 2020

Regional registration of whole slide image stacks containing major histological artifacts.

BMC Bioinformatics 2020 Dec 4;21(1):558. Epub 2020 Dec 4.

Imaging Informatics Division, Bioinformatics Institute (BII), Agency for Science, Technology and Research (A*STAR), 30 Biopolis Street, 07-01, Matrix, 138671, Singapore, Singapore.

Background: High resolution 2D whole slide imaging provides rich information about the tissue structure. This information can be a lot richer if these 2D images can be stacked into a 3D tissue volume. A 3D analysis, however, requires accurate reconstruction of the tissue volume from the 2D image stack. This task is not trivial due to the distortions such as tissue tearing, folding and missing at each slide. Performing registration for the whole tissue slices may be adversely affected by distorted tissue regions. Consequently, regional registration is found to be more effective. In this paper, we propose a new approach to an accurate and robust registration of regions of interest for whole slide images. We introduce the idea of multi-scale attention for registration.

Results: Using mean similarity index as the metric, the proposed algorithm (mean ± SD [Formula: see text]) followed by a fine registration algorithm ([Formula: see text]) outperformed the state-of-the-art linear whole tissue registration algorithm ([Formula: see text]) and the regional version of this algorithm ([Formula: see text]). The proposed algorithm also outperforms the state-of-the-art nonlinear registration algorithm (original: [Formula: see text], regional: [Formula: see text]) for whole slide images and a recently proposed patch-based registration algorithm (patch size 256: [Formula: see text] , patch size 512: [Formula: see text]) for medical images.

Conclusion: Using multi-scale attention mechanism leads to a more robust and accurate solution to the problem of regional registration of whole slide images corrupted in some parts by major histological artifacts in the imaged tissue.
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http://dx.doi.org/10.1186/s12859-020-03907-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7718714PMC
December 2020

Overall Survival in Heart Disease-Related Death in Non-Small Cell Lung Cancer Patients: Nonimmunotherapy Versus Immunotherapy Era: Population-Based Study.

Front Oncol 2020 22;10:572380. Epub 2020 Oct 22.

Department of Oncology, First Affiliated Hospital of Dalian Medical University, Dalian, China.

The cardiotoxicity during immunotherapy administration leads to mortality by more than 42% and heart disease-related mortality among immunotherapy-linked cancers is still considered to be underestimated. In this study, the advanced stage of non-small cell lung cancer (NSCLC) with heart disease-related death was selected in accordance with immunotherapy approval time. NSCLC was searched on the Surveillance, Epidemiology, and End Results (SEER) program. Results show that 538 advanced NSCLC cases, those dominated by men and elderly people aged more than 70 years, had a high percentage of heart disease-related death in both eras. The difference between contemporary groups was fairly nonsignificant ( = > 0.05). The overall survival (OS) of all-cause mortality difference showed improved survival in the immunotherapy group ( = 0.0001). In the study of heart disease-related death survival with adjusted data, the NSCLC patients show significant lower survival in the immunotherapy era compared with the nonimmunotherapy era ( = 0.003; hazard ratio [HR] = 1.31; 95% CI = 1.099-1.57). In the multivariate analysis of NSCLC-related immunotherapy, histology revealed that the non-squamous cell type had an independent risk for lower OS than the squamous cell type ( = 0.04; HR= 0.74; CI = 0, 55- 0.99). The results demonstrate the survival benefits for NSCLC in immunotherapy; however, in heart disease-related death, immunotherapy in patients with NSCLC shows decreased OS. This study highlights that NSCLC patients should be highly monitored during immunotherapy administration, and further assessment is needed.
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http://dx.doi.org/10.3389/fonc.2020.572380DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643546PMC
October 2020

Immune checkpoint inhibitor-associated myositis and myasthenia gravis overlap: Understanding the diversity in a case series.

Asia Pac J Clin Oncol 2020 Sep 27. Epub 2020 Sep 27.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

Immune checkpoint inhibitors (ICI) have improved survival across tumor types however they cause immune-related toxicities through removal of the inhibition of auto-reactive T cells. In this case review, we present 4 patients with metastatic cancer who developed de-novo neuromuscular side effects of myositis with overlapping seropositive myasthenia gravis after ICI treatment. Declaration: This study was performed in accordance to the ethical standards set by the SingHealth Institutional Review Board, with consent taken from living patients and waiver of consent from deceased patients (CIRB Ref 2019/2485). Supporting data were collected from our institution's digital medical records system.
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http://dx.doi.org/10.1111/ajco.13442DOI Listing
September 2020

Sequencing of PD-1/L1 Inhibitors and Carboplatin Based Chemotherapy for Cisplatin Ineligible Metastatic Urothelial Carcinoma.

J Urol 2021 02 16;205(2):414-419. Epub 2020 Sep 16.

Dana-Farber Cancer Institute, Boston, Massachusetts.

Purpose: Current first line treatment options in patients with metastatic urothelial carcinoma unfit to receive cisplatin containing chemotherapy include PD-1/L1 inhibitors and carboplatin containing chemotherapy. However, the optimal sequencing of these therapies remains unclear.

Materials And Methods: We conducted a multicenter retrospective analysis. Consecutive cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line carboplatin containing chemotherapy followed sequentially by second line PD-1/L1 inhibitor, or the reverse order, were included. Patient demographics, objective response, time to treatment failure for first line and second line therapy, interval between end of first line and initiation of second line treatment (Interval) and overall survival were collected. Multivariate analysis was conducted to examine the association of sequencing on overall survival.

Results: In this multicenter retrospective study we identified 146 cisplatin ineligible patients with metastatic urothelial carcinoma treated with first line PD-1/L1 inhibitor therapy followed by second line carboplatin containing chemotherapy (group 1, 43) or the reverse sequence (group 2, 103). In the overall cohort median age was 72, 76% were men and 18% had liver metastasis. In both groups objective response rates were higher with carboplatin containing chemotherapy (45.6% first line, 44.2% second line) compared to PD-1/L1 inhibitors (9.3% first line, 21.3% second line). On multivariate analysis treatment sequence was not associated with overall survival (HR 1.05, p=0.85). Site of metastasis was the only factor significantly associated with overall survival (p=0.002).

Conclusions: In this biomarker unselected cohort of cisplatin ineligible patients with metastatic urothelial carcinoma, PD-1/L1 inhibitor followed by carboplatin containing chemotherapy and the reverse sequence had comparable overall survival.
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http://dx.doi.org/10.1097/JU.0000000000001371DOI Listing
February 2021

Molecular Characterization and Clinical Outcomes in RET-Rearranged NSCLC.

J Thorac Oncol 2020 12 28;15(12):1928-1934. Epub 2020 Aug 28.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore, Singapore. Electronic address:

Introduction: RET rearrangements are an emerging targetable oncogenic fusion driver in NSCLC. However, the natural history of disease and activity of different classes of systemic therapy remain to be defined. Furthermore, molecular testing for RET is not yet routine, and the optimal method of testing is unclear. We present a comparative analysis of molecular profiling with fluorescence in situ hybridization (FISH) or next-generation sequencing (NGS) and treatment outcomes.

Methods: This study was a retrospective analysis of patients treated at the National Cancer Centre Singapore. Baseline demographics and treatment outcomes were collected.

Results: A total of 64 patients were included, with a median age of 62 years (range: 25-85), 56% were women, 77% were of Chinese ethnicity, 95% had adenocarcinoma, and 69% were never smokers. RET rearrangement was detected by FISH in 30 of 34 patients (88%), NGS in 40 of 43 patients (93%), and with discordant results in seven of 13 patients (54%) tested with both methods. Of 61 patients with stage IIIB/IV or recurrent disease, prevalence of central nervous system metastases was 31% and 92% received palliative systemic therapy. Overall survival was prolonged in patients treated with a selective RET tyrosine kinase inhibitor versus untreated patients (median 49.3 versus 15.3 mo; hazard ratio [HR]: 0.16, 95% confidence interval [CI]: 0.06-0.40, p < 0.001). However, it was not different in patients treated with immunotherapy versus untreated patients (median 37.7 versus 49.3 mo; HR: 1.30, 95% CI: 0.53-3.19, p = 0.53). Overall survival was also prolonged in patients with CCDC6-RET fusion versus those with KIF5B-RET fusion (median 113.5 versus 37.7 mo; HR: 0.12, 95% CI: 0.04-0.38, p = 0.009).

Conclusions: In RET-rearranged NSCLC, selective RET tyrosine kinase inhibitor therapy is associated with improved survival outcomes, especially in patients with CCDC6-RET fusion. However, immunotherapy has poor efficacy. NGS and FISH testing methods may also result in substantial discordance.
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http://dx.doi.org/10.1016/j.jtho.2020.08.011DOI Listing
December 2020

Protocol for a scoping review of digital health for older adults with cancer and their families.

BMJ Open 2020 08 26;10(8):e038876. Epub 2020 Aug 26.

School of Health Sciences, Faculty of Health and Medical Sciences, University of Surrey, Guildford, Surrey, UK.

Introduction: The potential for digital medicine and healthcare in geriatric oncology settings has received much attention. This scoping review will summarise the nature and extent of the existing literature that describes and examines digital health development, implementation, evaluation, outcome and experience for older adults with cancer, their families and their healthcare providers.

Methods And Analysis: Arksey and O'Malley's six stages of scoping review methodology framework will be used. Searches will be conducted in Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Embase via OvidSP, Cumulative Index to Nursing and Allied Health Literature (CINAHL) Plus via EBSCO, Scopus and PsycINFO via OvidSP for published articles in peer-reviewed scientific journals from year 2000 onwards. In addition, we will screen databases for all prospectively registered trials. Research articles using quantitative or qualitative study design or reviews will be included if they describe or report the design, development or usability of digital health interventions in the treatment and care of patients 65 years of age or older with cancer and their families before, during and after cancer treatment. Grey literature will not be searched and included. Two investigators will independently perform the literature search, eligibility assessments and study selection. A Preferred Reporting Items for Systematic Reviews and Meta-Analyses flow diagram for the scoping reviews (PRISMA-ScR) will be used to delineate the search decision process. For included articles, the extracted results will be synthesised both quantitatively and qualitatively and reported under key conceptual categories of this scoping review. Research gaps and opportunities will be identified and summarised.

Ethics And Dissemination: Since this review will only include published data, ethics approval will not be sought. The results of the review will be published in peer-reviewed scientific journals. We will also engage with relevant stakeholders within research team's networks to determine suitable approaches for dissemination.
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http://dx.doi.org/10.1136/bmjopen-2020-038876DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7451461PMC
August 2020

Minimizing transmission of COVID-19 while delivering optimal cancer care in a National Cancer Centre.

J Cancer Policy 2020 Sep 9;25:100241. Epub 2020 Jul 9.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore.

The COVID-19 pandemic has disrupted current models of healthcare and adaptations will likely continue. With the gradual easing of lockdown measures worldwide, cancer centres must be prepared to implement novel means to prevent repeated waves of infection. There are two limitations unique to oncology - a higher susceptibility of patients to COVID-19 and the multidisciplinary approach required of cancer management. We describe the measures implemented in the largest cancer centre in Singapore to continue optimal cancer care in spite of the ongoing pandemic, with no nosocomial infections reported in our centre to date. We adopted a multipronged approach, with an overall committee supervising the entire COVID-19 management effort. A screening clinic was setup to triage patients prior to entry to the centre. Each Oncology Division within the cancer centre designed solutions tailored to the specific needs of their discipline. We explore in detail the screening criteria and workflow of the screening clinic, as well as modifications by individual divisions to reduce infection risk to patients and healthcare professionals. This approach can be modelled by other cancer centres during this prolonged COVID-19 pandemic.
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http://dx.doi.org/10.1016/j.jcpo.2020.100241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7346798PMC
September 2020

Factors associated with falls in older women with breast cancer: the use of a brief geriatric screening tool in clinic.

Breast Cancer Res Treat 2020 Nov 13;184(2):445-457. Epub 2020 Aug 13.

Duke University Medical Center, Durham, NC, USA.

Purpose: Unintentional falls and breast cancer are common among older women, but the associations between them are understudied. We aimed to identify factors associated with falls in older women with breast cancer.

Methods: We retrospectively reviewed clinical records of older women with breast cancer at Duke Medical Center who had completed the Senior Adult Oncology Program geriatric assessment. Characteristics were compared between women had had at least one fall in the past year and those who did not. Pearson's Chi-square tests and t tests were used for comparison of groups' characteristics. Logistic regression determined factors associated with falling.

Results: We identified 425 women, age 76.2 years (range 65-89 years), at the time of the assessment. 118 (27.8%) women reported a fall in the prior year. Age, race, ethnicity, and time since diagnosis (all p > 0.05) were similar between groups. In univariate analyses, metastatic disease (p = 0.023) and history of endocrine therapy (p = 0.042) were more common among women who fell. Women who fell had lower systolic (p = 0.001), diastolic (p < 0.001) blood pressures, and SpO (p = 0.018). Women who had fallen had a higher Charlson Comorbidity Index (CCI: p = 0.033), and were more likely to report using a walking aide (p < 0.001), nutritional issues (p = 0.006), and depression symptoms (p = 0.038). In multivariate analysis, falling was associated with low DBP (OR 0.93; p = 0.0017), low SpO (OR 0.79; p = 0.0169), a higher CCI (OR 1.23; p = 0.0076), and depression symptoms (OR 1.61; p = 0.039).

Conclusions: Among older women with breast cancer, depressive symptoms, higher comorbidity level, and vital sign measurements were associated with having fallen.
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http://dx.doi.org/10.1007/s10549-020-05862-5DOI Listing
November 2020

Adapting care for older cancer patients during the COVID-19 pandemic: Recommendations from the International Society of Geriatric Oncology (SIOG) COVID-19 Working Group.

J Geriatr Oncol 2020 11 16;11(8):1190-1198. Epub 2020 Jul 16.

Department of General Medical Oncology, University Hospitals Leuven, Leuven, Belgium. Electronic address:

The COVID-19 pandemic poses a barrier to equal and evidence-based management of cancer in older adults. The International Society of Geriatric Oncology (SIOG) formed a panel of experts to develop consensus recommendations on the implications of the pandemic on several aspects of cancer care in this age group including geriatric assessment (GA), surgery, radiotherapy, systemic treatment, palliative care and research. Age and cancer diagnosis are significant predictors of adverse outcomes of the COVID-19 infection. In this setting, GA is particularly valuable to drive decision-making. GA may aid estimating physiologic reserve and adaptive capability, assessing risk-benefits of either providing or temporarily withholding treatments, and determining patient preferences to help inform treatment decisions. In a resource-constrained setting, geriatric screening tools may be administered remotely to identify patients requiring comprehensive GA. Tele-health is also crucial to ensure adequate continuity of care and minimize the risk of infection exposure. In general, therapeutic decisions should favor the most effective and least invasive approach with the lowest risk of adverse outcomes. In selected cases, this might require deferring or omitting surgery, radiotherapy or systemic treatments especially where benefits are marginal and alternative safe therapeutic options are available. Ongoing research is necessary to expand knowledge of the management of cancer in older adults. However, the pandemic presents a significant barrier and efforts should be made to ensure equitable access to clinical trials and prospective data collection to elucidate the outcomes of COVID-19 in this population.
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http://dx.doi.org/10.1016/j.jgo.2020.07.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7365054PMC
November 2020

High-Dimensional Characterization of the Systemic Immune Landscape Informs on Synergism Between Radiation Therapy and Immune Checkpoint Blockade.

Int J Radiat Oncol Biol Phys 2020 Sep 13;108(1):70-80. Epub 2020 Jun 13.

Division of Radiation Oncology, National Cancer Centre Singapore, Singapore; Oncology Academic Programme, Duke-NUS Medical School, Singapore; Division of Medical Sciences, National Cancer Centre Singapore, Singapore. Electronic address:

Purpose: Improved antitumor responses have been observed in patients after combination radiation therapy (RT) and immune checkpoint blockade (ICB). Whether these clinical responses are linked to the host systemic immune system has not been elucidated.

Methods And Materials: In this single-institution prospective observational study, peripheral blood was longitudinally collected from 10 patients with metastatic disease who had responded to anti-PD-1/anti-PD-L1 ICB and received RT (8-50 Gy in 1-5 fractions) upon disease progression at the following timepoints: baseline (pre-RT), 1 to 2 weeks post-RT, and post-ICB (cycle 1) on reintroduction post-RT. To thoroughly characterize the interaction between combined RT-ICB and the host immune system, we performed high-dimensional, mass cytometry-based immunophenotyping of circulating lymphocytes using a 40-marker panel addressing lineage, differentiation, activation, trafficking, cytotoxicity, and costimulatory and inhibitory functions. Phenotypic expression of circulating lymphocytes was compared across patients and time points and correlated with post-RT tumor responses.

Results: Foremost, we demonstrated excellent posttreatment clinical responses, including 4 local responses with >50% reduction in radiated tumor size, 1 out-of-field response, and 4 patients who resumed ICB for >1 year. Baseline and post-RT immune states were highly heterogeneous among patients. Despite this interindividual heterogeneity in baseline immune states, we observed a systemic immune reaction to RT-ICB common across patients, histology, and radiation sites; a subset of pre-existing Ki-67+ CD8+ T cells were increased post-RT and further expanded upon reintroduction of ICB post-RT (2.3-fold increase, P = .02). Importantly, RT did not alter the phenotypic profile of these Ki-67+ CD8+ T cells, which was characterized by a distinct activated and differentiated effector phenotype.

Conclusions: Collectively, these findings point toward a sustained reinvigoration of host antitumor immunity after RT-ICB and suggest an expansion in activated Ki-67+ CD8+ T cells as a possible demonstration of this synergy, thereby providing new insights that may support the development of optimal sequencing strategies.
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http://dx.doi.org/10.1016/j.ijrobp.2020.06.007DOI Listing
September 2020

Combined novice, near-peer, e-mentoring palliative medicine program: A mixed method study in Singapore.

PLoS One 2020 5;15(6):e0234322. Epub 2020 Jun 5.

Department of Family Medicine, National University Health System, Singapore, Singapore.

Introduction: An acute shortage of senior mentors saw the Palliative Medicine Initiative (PMI) combine its novice mentoring program with electronic and peer mentoring to overcome insufficient mentoring support of medical students and junior doctors by senior clinicians. A three-phased evaluation was carried out to evaluate mentees' experiences within the new CNEP mentoring program.

Methods: Phase 1 saw use of a Delphi process to create a content-valid questionnaire from data drawn from 9 systematic reviews of key aspects of novice mentoring. In Phase 2 Cognitive Interviews were used to evaluate the tool. The tool was then piloted amongst mentees in the CNEP program. Phase 3 compared mentee's experiences in the CNEP program with those from the PMI's novice mentoring program.

Results: Thematic analysis of open-ended responses revealed three themes-the CNEP mentoring process, its benefits and challenges that expound on the descriptive statistical analysis of specific close-ended and Likert scale responses of the survey. The results show mentee experiences in the PMI's novice mentoring program and the CNEP program to be similar and that the addition of near peer and e-mentoring processes enhance communications and support of mentees.

Conclusion: CNEP mentoring is an evolved form of novice mentoring built on a consistent mentoring approach supported by an effective host organization. The host organization marshals assessment, support and oversight of the program and allows flexibility within the approach to meet the particular needs of mentees, mentors and senior mentors. Whilst near-peer mentors and e-mentoring can make up for the lack of senior mentor availability, their effectiveness hinges upon a common mentoring approach. To better support the CNEP program deeper understanding of the mentoring dynamics, policing and mentor and mentee training processes are required. The CNEP mentoring tool too needs to be validated.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0234322PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274408PMC
September 2020

Assessing mentoring: A scoping review of mentoring assessment tools in internal medicine between 1990 and 2019.

PLoS One 2020 8;15(5):e0232511. Epub 2020 May 8.

Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.

Background: Mentoring's success in enhancing a mentee's professional and personal development, and a host organisations' reputation has been called into question, amidst a lack of effective tools to evaluate mentoring relationships and guide oversight of mentoring programs. A scoping review is proposed to map available literature on mentoring assessment tools in Internal Medicine to guide design of new tools.

Objective: The review aims to explore how novice mentoring is assessed in Internal Medicine, including the domains assessed, and the strengths and limitations of the assessment methods.

Methods: Guided by Levac et al.'s framework for scoping reviews, 12 reviewers conducted independent literature reviews of assessment tools in novice mentoring in PubMed, Embase, Scopus, ERIC, Cochrane, GreyLit, Web of Science, Open Dissertations and British Education Index databases. A 'split approach' saw research members adopting either Braun and Clarke's approach to thematic analysis or directed content analysis to independently evaluate the data and improve validity and objectivity of the findings.

Results: 9662 abstracts were identified, 187 full-text articles reviewed, and 54 full-text articles included. There was consensus on the themes and categories identified through the use of the split approach, which were the domains assessed and methods of assessment.

Conclusion: Most tools fail to contend with mentoring's evolving nature and provide mere snap shots of the mentoring process largely from the mentee's perspective. The lack of holistic, longitudinal and validated assessments propagate fears that ethical issues in mentoring are poorly recognized and addressed. To this end, we forward a framework for the design of 'fit for purpose' multi-dimensional tools.

Practice Points: Most tools focus on the mentee's perspective, do not consider mentoring's evolving nature and fail to consider mentoring holistically nor longitudinallyA new tool capable of addressing these gaps must also consider inputs from all stakeholders and take a longitudinal perspective of mentoring.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0232511PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7209188PMC
July 2020

HPLC-MS/MS coupled with equilibrium dialysis method for quantification of free drug concentration of pazopanib in plasma.

Heliyon 2020 Apr 27;6(4):e03813. Epub 2020 Apr 27.

Department of Pharmacy, Faculty of Science, National University of Singapore, Singapore.

Background: The selective occurrence of hepatotoxicity observed with use of pazopanib may be attributed to its high level of plasma protein binding and low hepatic extraction ratio. The primary objective was to investigate changes in free drug concentration amongst patients with varying albumin concentrations.

Methods: A HPLC-MS/MS method using C18 column (4.6 × 150 mm, 5 μm) with ESI source in positive mode had been developed and validated for the quantitative determination of free pazaopanib concentration in human plasma. Prior to sample preparation, patient samples were subjected to 6-hour equilibrium dialysis with molecular weight cut-off set at 8000 Da.

Results: The calibration curves were linear over the range of 5-1000 ng/mL, with a lower limit of quantification of 5 ng/mL. The intra-day and inter-day precisions and accuracies were all within ± 15 %, at 3 different quality controls. Higher median fraction unbound of pazopanib were observed in patients (n = 17) with lower than normal albumin concentrations.

Conclusion: With the developed assay, monitoring of plasma free concentrations may be evaluated as an indicator of pazopanib exposure in patients.
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http://dx.doi.org/10.1016/j.heliyon.2020.e03813DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7191207PMC
April 2020

Deferred Cytoreductive Nephrectomy in Patients with Newly Diagnosed Metastatic Renal Cell Carcinoma.

Eur Urol 2020 10 30;78(4):615-623. Epub 2020 Apr 30.

Tom Baker Cancer Centre, University of Calgary, Calgary, AB, Canada.

Background: The use of cytoreductive nephrectomy (CN) selectively for patients who show a favorable response to upfront systemic therapy may be an approach to select optimal candidates with metastatic renal cell carcinoma (mRCC) who are most likely to benefit.

Objective: We sought to characterize outcomes of deferred CN (dCN) after upfront sunitinib, outcomes relative to sunitinib alone, and outcomes of CN followed by sunitinib.

Design, Setting, And Participants: We used the prospectively maintained International mRCC Database Consortium (IMDC) database to identify patients with newly diagnosed mRCC (2006-2018).

Intervention: Sunitinib alone, upfront CN followed by sunitinib, sunitinib followed by dCN.

Outcome Measurements And Statistical Analysis: Outcomes were overall survival (OS) and time to sunitinib treatment failure (TTF). Kaplan-Meier and multivariable Cox regression analyses were performed; dCN was analyzed as a time-varying covariate to account for immortal time bias.

Results And Limitations: We evaluated 1541 patients, of whom 651 (42%) received sunitinib alone, 805 (52%) underwent CN followed by sunitinib, and 85 (5.5%) received sunitinib followed by dCN, at a median of 7.8 mo from diagnosis. Median OS periods for patients treated with sunitinib alone, CN followed by sunitinib, and sunitinib followed by dCN were 10, 19, and 46 mo, respectively, while the median TTF values were 4, 8, and 13 mo, respectively. In multivariable regression analyses, sunitinib followed by dCN was significantly associated with improved OS (hazard ratio [HR] = 0.45, 95% confidence interval [CI] 0.33-0.60, p < 0.001) and TTF (HR = 0.62, 95% CI 0.46-0.85, p = 0.003) versus sunitinib alone. Among CN-treated patients, sunitinib followed by dCN was associated with improved OS (HR = 0.52, 95% CI 0.39-0.70, p < 0.001) and TTF (HR = 0.71, 95% CI 0.56-0.90, p = 0.005) compared with upfront CN followed by sunitinib. In various sensitivity analyses, dCN remained significantly associated with improved OS and TTF.

Conclusions: Patients who received dCN were carefully selected and achieved long OS. With these benchmark outcomes, optimal selection criteria need to be identified and confirmation of the role of dCN in a clinical trial is warranted.

Patient Summary: We characterized benchmark survival outcomes for patients with metastatic kidney cancer treated with sunitinib alone, nephrectomy (kidney removal) followed by sunitinib, and sunitinib followed by nephrectomy. Patients who had their nephrectomy after an initial course of sunitinib had prolonged survival.
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http://dx.doi.org/10.1016/j.eururo.2020.04.038DOI Listing
October 2020

The Globalization of Geriatric Oncology: From Data to Practice.

Am Soc Clin Oncol Educ Book 2020 Mar;40:1-9

Division of Oncology 2, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, Silver Spring, MD.

Older adults with cancer are a unique group of patients who require specialized care and treatment. The field of geriatric oncology (GO) was born more than 3 decades ago to address the needs of this growing group of patients. Some challenges in the GO field include establishing a GO clinical service, educating and training personnel, and conducting research in GO. These issues are addressed to varying extents with global initiatives in GO, which are largely dependent on the socioeconomic status of the countries involved. To overcome disparities seen globally, scientific journals that reach an international cancer audience should publish content related to improving care of older adults with cancer around the world, develop an organizational structure that encourages global dissemination of GO knowledge, and advance reporting policies that encourage higher-quality reporting of data relevant to older adults with cancer worldwide. A number of international scientific journals have risen to the occasion to address these disparities. A key battle in enabling access of this vulnerable group of patients to clinical trials is now being fought and won on the global front with numerous regulatory initiatives. The U.S. Food and Drug Administration (FDA) Oncology Center of Excellence (OCE) recently issued draft guidance on the inclusion of older adults in cancer clinical trials. This and other global initiatives led by the FDA have the potential to further improve the evidence base for older adults with cancer.
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http://dx.doi.org/10.1200/EDBK_279513DOI Listing
March 2020

Clinical outcomes of 177lutetium-prostate-specific membrane antigen therapy in advanced prostate cancer-a prospective pilot study in an Asian population.

Nucl Med Commun 2020 Jul;41(7):618-628

Department of Nuclear Medicine and Molecular Imaging, Singapore General Hospital.

Objective: Metastatic castration-resistant prostate cancers are aggressive tumors with poor prognosis. Prostate-specific membrane antigen-targeted radionuclide therapy is a potential treatment for these patients. Here, we report our initial experience in Singapore.

Methods: Twenty men (median age 70) with progressive disease were prospectively recruited. Prostate-specific membrane antigen and fluorodeoxyglucose-PET/computed tomography were performed to confirm high prostate-specific membrane antigen-expression. Up to four cycles of lutetium-prostate-specific membrane antigen-I&T at 6-8 weekly intervals were administered. Patients were restaged 3 months following treatment. Primary endpoints were prostate-specific antigen decline ≥50% and treatment-related toxicity. Additional endpoints included radiological and clinical response as well as progression-free survival and overall survival from first cycle.

Results: Sixty-seven cycles were administered (median 4 cycles per patient, mean 6.5 GBq per cycle). Sixty five percent had ≥1 line of prior chemotherapy, 90% abiraterone, enzalutamide or both, and 30% radium-223 radionuclide therapy. All had bone metastases and 35% had visceral metastases. Prostate-specific antigen decline ≥50% was achieved in 50%. Grade 3-4 hematotoxicity was seen in up to 15%. Grade 3-4 non-hematotoxicity was not observed. Eleven patients had restaging scans 3 months post-treatment (5 = partial response, 6 = progressive disease). Fifty-seven percent (4/7) with bone pain had pain improvement. Median progression-free survival was 5.9 months and median overall survival 13.1 months. Patients with prostate-specific antigen decline ≥50% had longer progression-free survival and overall survival.

Conclusion: Lutetium-prostate-specific membrane antigen-I&T therapy is effective with tolerable side effects in our local setting. Prostate-specific antigen decline ≥50% is associated with longer progression-free survival and overall survival.
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http://dx.doi.org/10.1097/MNM.0000000000001179DOI Listing
July 2020

Synchronous Versus Metachronous Metastatic Disease: Impact of Time to Metastasis on Patient Outcome-Results from the International Metastatic Renal Cell Carcinoma Database Consortium.

Eur Urol Oncol 2020 08 6;3(4):530-539. Epub 2020 Feb 6.

Tom Baker Cancer Center, Calgary, Canada.

Background: Patients with metastatic renal cell carcinoma (mRCC) may present with primary metastases (synchronous disease) or develop metastases during follow-up (metachronous disease). The impact of time to metastasis on patient outcome is poorly characterised.

Objective: To characterise overall survival (OS) and time to treatment failure (TTF) based on time to metastasis in mRCC patients treated with targeted therapy (tyrosine kinase inhibitors [TKIs]).

Design, Setting, And Participants: We used the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) to compare synchronous (metastases within ≤3 mo of initial diagnosis of cancer) versus metachronous disease (evaluated by >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr intervals).

Outcome Measurements And Statistical Analysis: OS and TFF were assessed using Kaplan-Meier curves. Cox multivariable regressions analyses (MVAs) were adjusted for baseline factors.

Results And Limitations: Of 7386 patients with mRCC treated with first-line TKIs, 3906 (53%) and 3480 (47%) had synchronous and metachronous metastasis, respectively. More patients with synchronous versus metachronous disease had higher T stage (T1-2: 19% vs 34%), N1 disease (21% vs 6%), presence of sarcomatoid differentiation (15.8% vs 7.9%), Karnofsky performance status <80 (25.9% vs 15.1%), anaemia (62.5% vs 42.3%), elevated neutrophils (18.9% vs 10.9%), elevated platelets (21.6% vs 11.4%), bone metastases (40.4% vs 29.8%), and IMDC poor risk (40.6% vs 11.3%). Synchronous versus metachronous disease by intervals >3-12 mo, >1-2 yr, >2-7 yr, and >7 yr correlated with poor TTF (5.6 mo vs 7.3, 8.0, 10.8, and 13.3 mo, p <  0.0001) and poor OS (median 16.7 mo vs 23.8, 30.2, 34.8, and 41.7 mo, p <  0.0001). In MVAs, the adjusted hazard ratios (95% confidence intervals) were 1.00 (reference), 0.98 (0.90-1.06), 0.81 (0.73-0.91), 0.74 (0.68-0.81), and 0.60 (0.54-0.67), respectively, for OS (p <  0.0001), and 1.00 (reference), 0.99 (0.92-1.06), 0.98 (0.90-1.07), 0.83 (0.77-0.89), and 0.66 (0.60-0.72), respectively, for TTF (p <  0.0001). Data were collected retrospectively.

Conclusions: Timing of metastases after initial RCC diagnosis may impact the outcomes from targeted therapy in mRCC.

Patient Summary: We looked at the impact of the timing of metastatic outbreak on survival outcomes in kidney cancer patients treated with targeted therapy. We found that the longer time to metastatic development was associated with improved outcome.
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http://dx.doi.org/10.1016/j.euo.2020.01.001DOI Listing
August 2020

The role of immune checkpoint inhibitors (ICI) in the treatment of metastatic non-small cell lung carcinoma in the elderly.

Ann Transl Med 2019 Dec;7(Suppl 8):S383

National Cancer Centre Singapore, 11, Hospital Drive, Singapore 169610, Singapore.

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http://dx.doi.org/10.21037/atm.2019.12.76DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6976496PMC
December 2019

Management of Patients with Advanced Prostate Cancer: Report of the Advanced Prostate Cancer Consensus Conference 2019.

Eur Urol 2020 04 27;77(4):508-547. Epub 2020 Jan 27.

University of Bern, Bern, Switzerland; Department of Medical Oncology and Haematology, Cantonal Hospital St. Gallen, St. Gallen, Switzerland.

Background: Innovations in treatments, imaging, and molecular characterisation in advanced prostate cancer have improved outcomes, but there are still many aspects of management that lack high-level evidence to inform clinical practice. The Advanced Prostate Cancer Consensus Conference (APCCC) 2019 addressed some of these topics to supplement guidelines that are based on level 1 evidence.

Objective: To present the results from the APCCC 2019.

Design, Setting, And Participants: Similar to prior conferences, experts identified 10 important areas of controversy regarding the management of advanced prostate cancer: locally advanced disease, biochemical recurrence after local therapy, treating the primary tumour in the metastatic setting, metastatic hormone-sensitive/naïve prostate cancer, nonmetastatic castration-resistant prostate cancer, metastatic castration-resistant prostate cancer, bone health and bone metastases, molecular characterisation of tissue and blood, inter- and intrapatient heterogeneity, and adverse effects of hormonal therapy and their management. A panel of 72 international prostate cancer experts developed the programme and the consensus questions.

Outcome Measurements And Statistical Analysis: The panel voted publicly but anonymously on 123 predefined questions, which were developed by both voting and nonvoting panel members prior to the conference following a modified Delphi process.

Results And Limitations: Panellists voted based on their opinions rather than a standard literature review or formal meta-analysis. The answer options for the consensus questions had varying degrees of support by the panel, as reflected in this article and the detailed voting results reported in the Supplementary material.

Conclusions: These voting results from a panel of prostate cancer experts can help clinicians and patients navigate controversial areas of advanced prostate management for which high-level evidence is sparse. However, diagnostic and treatment decisions should always be individualised based on patient-specific factors, such as disease extent and location, prior lines of therapy, comorbidities, and treatment preferences, together with current and emerging clinical evidence and logistic and economic constraints. Clinical trial enrolment for men with advanced prostate cancer should be strongly encouraged. Importantly, APCCC 2019 once again identified important questions that merit assessment in specifically designed trials.

Patient Summary: The Advanced Prostate Cancer Consensus Conference provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference, which has been held three times since 2015, aims to share the knowledge of world experts in prostate cancer management with health care providers worldwide. At the end of the conference, an expert panel discusses and votes on predefined consensus questions that target the most clinically relevant areas of advanced prostate cancer treatment. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients as part of shared and multidisciplinary decision making.
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http://dx.doi.org/10.1016/j.eururo.2020.01.012DOI Listing
April 2020

PD-L1 expression is an unfavourable prognostic indicator in Asian renal cell carcinomas.

J Clin Pathol 2020 Aug 24;73(8):463-469. Epub 2020 Jan 24.

Anatomical Pathology, Singapore General Hospital, Singapore

Background/aims: The programmed cell death receptor 1 (PD-1) checkpoint inhibitor, nivolumab, has been approved for the treatment of metastatic renal cell carcinoma (RCC). However, the understanding of the expression and distribution of PD ligand 1 (PD-L1) in the tumour immune microenvironment and its prognostic role in an Asian cohort is limited. Our group investigated PD-L1 protein expression in a cohort of Asian patients with RCC of mixed ethnicity, using two commercially available antibody clones.

Methods: E1L3N and SP263 anti-PD-L1 clones were used to categorise RCCs of various histological subtypes, diagnosed at our institution between 1995 and 2008, into PD-L1-positive or PD-L1-negative groups, based on a 1% Tumour Proportion Score (TPS) cut-off.

Results: In total, 267 (83%) clear cell (cc)RCC and 55 (17%) non-ccRCC cases were studied. Overall PD-L1 protein expression rates for the entire cohort were 13% and 8% for the E1L3N and SP263 clones, respectively. Patients bearing PD-L1-positive tumours experienced significantly decreased disease-free survival (DFS; E1L3N: p=0.01; SP263: p=0.03) but not overall survival, compared with those with PD-L1-negative tumours. Multivariate survival analysis further confirmed the results of the E1L3N clone (HR 1.85, 95% CI 1.10 to 3.13, p=0.02), but not SP263, after adjusting for pathological stage, histological subtype and grade. The addition of PD-L1 (E1L3N) TPS to clinicopathological features significantly increased the prognostic value for DFS (∆LRχ=5.25; p=0.022), compared with clinicopathological features alone.

Conclusions: PD-L1 protein expression was associated with an unfavourable prognosis in our study cohort. PD-L1 (E1L3N) expression was an independent prognostic indicator of clinical outcome in all RCCs when using a 1% cut-off.
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http://dx.doi.org/10.1136/jclinpath-2019-206092DOI Listing
August 2020

Pilot Trial of a Combined Oncologist-Patient-Caregiver Communication Intervention in Singapore.

JCO Oncol Pract 2020 02 27;16(2):e190-e200. Epub 2019 Dec 27.

Department of Population Health Sciences, Duke University School of Medicine, Singapore.

Purpose: High-quality end-of-life cancer care requires oncologists to communicate effectively and patients/caregivers to be participatory. However, most communication interventions target either but not both. We aimed to pilot a potentially disseminable combined oncologist-patient/caregiver intervention to improve oncologist empathic responses, discussions of prognosis and goals of care, and patient/caregiver participation. We assessed its feasibility, acceptability, and preliminary efficacy.

Methods: Between June 2018 and January 2019, we conducted a pilot 2-arm cluster trial in Singapore, randomly assigning 10 oncologists in a 1:1 ratio to receive the combined intervention or usual care. Intervention arm oncologists received online communication skills training, and their patients received a brief prompt sheet before consultations. We audio recorded consultations with 60 patients with stage IV solid malignancy and analyzed 30 in the postintervention phase. The study was not powered for statistical significance.

Results: Participation rates for oncologists and patients were 100% and 63%, respectively. All oncologists completed the online training within an average of 4.5 weeks; 73% of the patients selected at least 1 question in the prompt sheet. Compared with the control arm, intervention arm oncologists had more empathic responses in total (relative risk [RR], 1.66) and for every patient/caregiver negative emotion (RR, 2.01). Their consultations were more likely to involve discussions of prognosis (RR, 3.00) and goals of care, and their patients were more likely to ask a prognosis-related question (RR, 2.00; > .05 for all).

Conclusion: The combined oncologist-patient/caregiver intervention is feasible and acceptable and has the potential to improve communication within consultations.
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http://dx.doi.org/10.1200/JOP.19.00412DOI Listing
February 2020

United in Fight against prOstate cancer (UFO) registry: first results from a large, multi-centre, prospective, longitudinal cohort study of advanced prostate cancer in Asia.

BJU Int 2020 04 30;125(4):541-552. Epub 2020 Jan 30.

Janssen Medical Affairs, Asia Pacific, Singapore.

Objectives: To document the management of advanced prostate cancer including diagnosis, prognosis, treatment, and care, in real-world practice in Asia using the United in Fight against prOstate cancer (UFO) registry.

Patients And Methods: We established a multi-national, longitudinal, observational registry of patients with prostate cancer presenting to participating tertiary care hospitals in eight Asian countries. A total of 3636 eligible patients with existing or newly diagnosed high-risk localised prostate cancer (HRL), non-metastatic biochemically recurrent prostate cancer (M0), or metastatic prostate cancer (M1), were consecutively enrolled and are being followed-up for 5 years. Patient history, demographic and disease characteristics, treatment and treatment decisions, were collected at first prostate cancer diagnosis and at enrolment. Patient-reported quality of life was prospectively assessed using the European Quality of Life-five Dimensions, five Levels (EQ-5D-5L) and Functional Assessment of Cancer Therapy for Prostate Cancer questionnaires. In the present study, we report the first interim analysis of 2063 patients enrolled from study start (15 September 2015) until 18 May 2017.

Results: Of the 2063 enrolled patients, 357 (17%), 378 (19%), and 1328 (64%) had HRL, M0 or M1 prostate cancer, respectively. The mean age at first diagnosis was similar in each group, 56% of all patients had extracapsular extension of their tumour, 28% had regional lymph node metastasis, and 53% had distant metastases. At enrolment, 62% of patients had at least one co-morbidity (mainly cardiovascular disease or diabetes), 91.8% of M1 patients had an Eastern Cooperative Oncology Group performance score of <2 and the mean EQ-5D-5L visual analogue score was 74.6-79.6 across cohorts. Treatment of M1 patients was primarily with combined androgen blockade (58%) or androgen-deprivation therapy (either orchidectomy or luteinising hormone-releasing hormone analogues) (32%). Decisions to start therapy were mainly driven by treatment guidelines and disease progression. Decision to discontinue therapy was most often due to disease progression (hormonal drug therapy) or completion of therapy (chemotherapy).

Conclusion: In the UFO registry of advanced prostate cancer in Asia, regional differences exist in prostate cancer treatment patterns that will be explored more deeply during the follow-up period; prospective follow-up is ongoing. The UFO registry will provide valuable descriptive data on current disease characteristics and treatment landscape amongst patients with prostate cancer in Asia.
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http://dx.doi.org/10.1111/bju.14980DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7187217PMC
April 2020

Utility of incorporating next-generation sequencing (NGS) in an Asian non-small cell lung cancer (NSCLC) population: Incremental yield of actionable alterations and cost-effectiveness analysis.

Lung Cancer 2020 01 26;139:207-215. Epub 2019 Nov 26.

Division of Medical Oncology, National Cancer Centre Singapore, Singapore; Duke-NUS Medical School, National University of Singapore, Singapore. Electronic address:

Objectives: There is an expanding list of therapeutically relevant biomarkers for non-small cell lung cancer (NSCLC), and molecular profiling at diagnosis is paramount. Tissue attrition in scaling traditional single biomarker assays from small biopsies is an increasingly encountered problem. We sought to compare the performance of targeted next-generation sequencing (NGS) panels with traditional assays and correlate the mutational landscape with PD-L1 status in Singaporean patients.

Materials And Methods: We identified consecutive patients diagnosed between Jan 2016 to Sep 2017 with residual tissue after standard molecular testing. Tissue samples were tested using a targeted NGS panel for DNA alterations (29 selected genes including BRAF, EGFR, ERBB2 and TP53) and an RNA fusion panel (ALK, ROS1 and RET). PD-L1 immunohistochemistry was also performed. A cost-effectiveness analysis of NGS compared to standard molecular testing was conducted.

Results: A total of 174 samples were evaluated: PD-L1 (n = 169), NGS DNA panel (n = 173) and RNA fusion (n = 119) testing. Median age was 68 years, 53 % were male, 58 % were never smokers, 85 % were Chinese, 66 % had stage IV disease and 95 % had adenocarcinoma histology. In patients profiled with NGS on DNA, EGFR (56 %), KRAS (14 %), BRAF (2 %) and ERBB2 (1 %) mutations were found. RNA fusion testing revealed fusions in ALK (6 %), RET (3 %) and ROS1 (1 %). Cost-effectiveness analysis demonstrated that compared to sequential testing in EGFR negative patients, upfront NGS testing would result in an additional 1 % of patients with actionable alterations for targeted therapy being identified without significant increases in testing cost or turnaround time.

Conclusions: This study demonstrates that even in an EGFR mutant predominant population, upfront NGS represents a feasible, cost-effective method of diagnostic molecular profiling compared with sequential testing strategies. Our results support the implementation of diagnostic NGS in non-squamous NSCLC in Asia to allow patients access to the most appropriate personalized therapy.
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http://dx.doi.org/10.1016/j.lungcan.2019.11.022DOI Listing
January 2020

Financial difficulties are associated with greater total pain and suffering among patients with advanced cancer: results from the COMPASS study.

Support Care Cancer 2020 Aug 12;28(8):3781-3789. Epub 2019 Dec 12.

Lien Centre for Palliative Care, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.

Background: The Universal Health Coverage goals call for access to affordable palliative care to reduce inequities in "total pain" and suffering. To achieve this, a patient-centred understanding of these inequities is required.

Aim: To assess association of total pain and suffering (i.e. physical, psychological, social, and spiritual health outcomes) and perceived health care quality with financial difficulties among stage IV solid malignancy patients.

Design: Using baseline data from the COMPASS cohort study, we assessed total pain and suffering including physical (physical and functional well-being, pain, symptom burden), psychological (anxiety, depression, emotional well-being), social (social well-being), and spiritual (spiritual well-being, hope) outcomes and perceived health care quality (physician communication, nursing care, and coordination/responsiveness). Financial difficulties were scored by assessing patient perception of the extent to which their resources were meeting expenses for their treatments, daily living, and other obligations. We used multivariable linear/logistic regression to test association between financial difficulties and each patient-reported outcome.

Setting/participants: Six hundred stage IV solid malignancy patients in Singapore.

Results: Thirty-five percent reported difficulty in meeting expenses. A higher financial difficulties score was associated with worse physical, psychological, social, spiritual outcomes, and lower perceived quality of health care coordination and responsiveness (i.e. greater total pain and suffering) (all p < 0.05). These associations persisted after adjustment for socio-economic indicators.

Conclusion: Results identify advanced cancer patients with financial difficulties to be a vulnerable group with greater reported total pain and suffering. A holistic patient-centred approach to care at end-of-life may help meet goals for Universal Health Coverage.
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http://dx.doi.org/10.1007/s00520-019-05208-yDOI Listing
August 2020