Publications by authors named "M Teo"

338 Publications

A review of the current evidence on the sensitivity and specificity of the Ipswich touch test for the screening of loss of protective sensation in patients with diabetes mellitus.

Diabetol Int 2021 Apr 29;12(2):145-150. Epub 2020 Jun 29.

Podiatry Department, Ng Teng Fong General Hospital, National University Health System, 1 Jurong East Street 21, Singapore, 609606 Singapore.

Aims: To evaluate the sensitivity and specificity of the Ipswich touch test for the screening of loss of protective sensation in patients with diabetes mellitus based on the current literature.

Methods: Three electronic databases were searched for eligible studies that investigated the sensitivity and specificity of the Ipswich touch test. Methodological quality was assessed using the QUADAS-2 tool.

Results: Five studies that reported the sensitivity and specificity of the Ipswich touch test were included. When compared to the 10 g monofilament, the sensitivity ranges from 51 to 83.3% and the specificity ranges from 96.4 to 98%. When compared to the vibration perception test ≥25 V, Ipswich touch test sensitivity ranges from 76 to 100% and specificity ranges from 90 to 96.6%.

Conclusions: The Ipswich touch test has a high specificity in screening for loss of protective sensation in the feet of patients with diabetes mellitus. It is a useful test to be included in diabetic foot screenings, especially when other sensory tools are not available. However, more rigorous studies need to be conducted as there is currently only a limited pool of research evidence to substantiate it as a screening tool for loss of protective sensation in the diabetic foot.
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http://dx.doi.org/10.1007/s13340-020-00451-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7943667PMC
April 2021

ASO Author Reflections: Postoperative Inflammatory Markers as a Surveillance Tool in Colorectal Peritoneal Carcinomatosis.

Ann Surg Oncol 2021 Mar 17. Epub 2021 Mar 17.

Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.

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http://dx.doi.org/10.1245/s10434-021-09733-1DOI Listing
March 2021

Postoperative Inflammatory Marker Surveillance in Colorectal Peritoneal Carcinomatosis.

Ann Surg Oncol 2021 Mar 2. Epub 2021 Mar 2.

Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, Singapore, Singapore.

Background: The prognostic significance of inflammatory markers in solid cancers is well-established, albeit with considerable heterogeneity. This study sought to investigate the postoperative inflammatory marker trend in peritoneal carcinomatosis (PC), with a focus on colorectal PC (CPC), and to propose optimal surveillance periods and cutoffs.

Methods: Data were collected from a prospectively maintained database of PC patients treated at the authors' institution from April 2001 to March 2019. The platelet-lymphocyte ratio (PLR), the neutrophil-lymphocyte ratio (NLR), and the lymphocyte-monocyte ratio (LMR) were collected preoperatively and on postoperative days 0, 1 to 3, 4 to 7, 8 to 21, 22 to 56, and 57 to 90 as averages. Optimal surveillance periods and cutoffs for each marker were determined by maximally selected rank statistics. The Kaplan-Meier method and Cox proportional hazard regression models were used to investigate the association of inflammatory markers with 1-year overall survival (OS) and recurrence-free survival (RFS) using clinicopathologic parameters.

Results: The postoperative inflammatory marker trend and levels did not differ between the patients with and those without hyperthermic intraperitoneal chemotherapy (HIPEC). Low postoperative LMR (days 4-7), high postoperative NLR (days 8-21), and high postoperative PLR (days 22-56) were optimal for prognosticating poor 1-year OS, whereas high postoperative PLR and NLR (days 57-90) and low postoperative LMR (days 8-21) were associated with poor 1-year RFS. A composite score of these three markers was prognostic for OS in CPC.

Conclusions: The reported cutoffs should be validated in a larger population of CPC patients. Future studies should account for the inflammatory response profile when selecting appropriate surveillance periods.
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http://dx.doi.org/10.1245/s10434-020-09544-wDOI Listing
March 2021

The asymmetry of antimatter in the proton.

Nature 2021 02 24;590(7847):561-565. Epub 2021 Feb 24.

Physics Division, Argonne National Laboratory, Lemont, IL, USA.

The fundamental building blocks of the proton-quarks and gluons-have been known for decades. However, we still have an incomplete theoretical and experimental understanding of how these particles and their dynamics give rise to the quantum bound state of the proton and its physical properties, such as its spin. The two up quarks and the single down quark that comprise the proton in the simplest picture account only for a few per cent of the proton mass, the bulk of which is in the form of quark kinetic and potential energy and gluon energy from the strong force. An essential feature of this force, as described by quantum chromodynamics, is its ability to create matter-antimatter quark pairs inside the proton that exist only for a very short time. Their fleeting existence makes the antimatter quarks within protons difficult to study, but their existence is discernible in reactions in which a matter-antimatter quark pair annihilates. In this picture of quark-antiquark creation by the strong force, the probability distributions as a function of momentum for the presence of up and down antimatter quarks should be nearly identical, given that their masses are very similar and small compared to the mass of the proton. Here we provide evidence from muon pair production measurements that these distributions are considerably different, with more abundant down antimatter quarks than up antimatter quarks over a wide range of momenta. These results are expected to revive interest in several proposed mechanisms for the origin of this antimatter asymmetry in the proton that had been disfavoured by previous results, and point to future measurements that can distinguish between these mechanisms.
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http://dx.doi.org/10.1038/s41586-021-03282-zDOI Listing
February 2021

Cost-effectiveness of two technology-assisted manual medication picking systems versus traditional manual picking in a hospital outpatient pharmacy.

Eur J Hosp Pharm 2021 Mar 14;28(2):100-105. Epub 2019 Nov 14.

Pharmacy, Singapore General Hospital Department of Pharmacy, Singapore

Objective: To evaluate the cost-effectiveness of two technology assisted manual medication picking systems vs traditional manual picking.

Methods: This was a retrospective observational study comparing three outpatient pharmacies of a tertiary referral hospital in Singapore, where a light-emitting diode (LED-guided) manual picking system, an LED-guided manual picking plus lockable drawer (LED-LD) system, and traditional manual picking were implemented, respectively. The primary outcome measure was the incidence of medication near-misses over the observation period. The incremental cost-effectiveness ratio (ICER) per near-miss avoided was also determined. Data on medications picked and near-misses reported between September 2017 and June 2018 were retrieved from electronic databases. The incidence of medication near-misses from the LED-guided and LED-LD systems, relative to traditional picking, was compared using logistic regression. We compared annual operating costs between manual medication picking systems, and reported ICERs per near-miss avoided, to evaluate the cost-effectiveness of each picking system.

Results: A total of 358 144, 397 343 and 254 162 medications were picked by traditional manual picking, LED-guided and LED-LD systems, respectively. The corresponding near-miss rates were 8.32, 4.08 and 0.69 per 10 000 medications picked, respectively. Medication near-miss rates were significantly lower for the LED-guided (OR 0.49, 95% CI 0.40 to 0.59, p<0.001) and LED-LD systems (OR 0.08, 95% CI 0.05 to 0.13, p<0.001) compared with traditional picking. The annual operating costs of traditional picking, LED-guided and LED-LD systems were S$60 912, S$129 832 and S$152 894, respectively. The LED-guided and LED-LD systems yielded ICERs of S$189 and S$140 per near-miss avoided, respectively, compared with traditional manual picking.

Conclusion: The LED-LD system is more cost-effective than both the LED-guided and manual medication picking systems in reducing medication picking near-misses.
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http://dx.doi.org/10.1136/ejhpharm-2019-001997DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7907698PMC
March 2021

Trial of dexamethasone for chronic subdural hematoma.

Br J Neurosurg 2021 Feb 19. Epub 2021 Feb 19.

North Bristol NHS Trust, Westbury on Trym, UK.

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http://dx.doi.org/10.1080/02688697.2021.1886245DOI Listing
February 2021

Neoadjuvant tyrosine kinase inhibitors in rectal gastrointestinal stromal tumours: a provision for enhanced oncological and functional outcomes.

Int J Clin Oncol 2021 May 2;26(5):913-921. Epub 2021 Feb 2.

Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore.

Background: The role of tyrosine kinase inhibitors (TKI) in the neoadjuvant setting and the optimal duration of therapy remains poorly defined. As such, we aim to evaluate the impact of neoadjuvant TKI on oncological and functional outcomes in our cohort of patients with rectal GISTs.

Methods: A retrospective analysis of 36 consecutive patients who underwent treatment for rectal GIST at the National Cancer Centre Singapore from February 1996 to October 2017 was analysed. Surgical, recurrence and survival outcomes between the groups who underwent neoadjuvant therapy and those who underwent upfront surgery were compared.

Results: Patients who received neoadjuvant treatment had significantly larger tumours (median size 7.1 vs. 6.0 cm, p = 0.04) and lower mitotic count (> 10 per 50 HPF, 14 vs. 70%, p = 0.03) when compared with the non-neoadjuvant group. With TKI pre-treatment (median duration 8.8 months), majority of patients (82%) achieved at least partial response to the therapy coupled with a significant downsizing effect of up to 39% (median size of 7.1-3.6 cm), resulting in similar rates of sphincter-sparing surgery (75 vs. 76%, p = 0.94) when compared with the non-neoadjuvant group. In general, neoadjuvant group had lower rates of local recurrence (0 vs. 69%, p = 0.04) and higher overall survival (7.4 vs. 5.7 years, p = 0.03) as compared to the non-neoadjuvant group.

Conclusions: Neoadjuvant TKI has the benefit of downsizing unresectable rectal GIST to benefit from sphincter-sparing procedure and also confers protection against local recurrence and improves overall survival.
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http://dx.doi.org/10.1007/s10147-021-01867-2DOI Listing
May 2021

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

Acta Oncol 2021 Apr 24;60(4):505-512. Epub 2021 Jan 24.

Department of Medical Physics, Leeds Teaching Hospitals, NHS trust, Leeds, UK.

Purpose/objectives: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes.

Material And Methods: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes.

Results: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1.

Conclusion: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.
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http://dx.doi.org/10.1080/0284186X.2021.1874617DOI Listing
April 2021

Natural history, response to systemic therapy, and genomic landscape of plasmacytoid urothelial carcinoma.

Br J Cancer 2021 Mar 21;124(7):1214-1221. Epub 2021 Jan 21.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Plasmacytoid urothelial carcinoma (PUC) is a rare, aggressive histologic variant of urothelial cancer characterised by a diffuse growth pattern and CDH1 mutation. We studied the efficacy of preoperative platinum-based chemotherapy in nonmetastatic PUC and immune checkpoint inhibitors (ICIs) in advanced PUC.

Methods: Cases of nonmetastatic PUC and advanced PUC treated with ICIs at our institution were identified. Outcomes were compared to those of a published cohort of patients with urothelial carcinoma not otherwise specified.

Results: We identified 81 patients with nonmetastatic PUC. Of the patients with localised disease who underwent neoadjuvant chemotherapy, pathologic complete response and downstaging rates were 12 and 21%, respectively. Pathologic downstaging was not associated with significant improvement in clinical outcomes. Up to 18% of localised disease and 28% of locally advanced cases had unresectable disease at the time of surgery. ICI-treated advanced PUC (N = 21) had progression-free and overall survival of 4.5 and 10.5 months, respectively, and a 38% response rate. FGFR3 and DNA damage response gene alterations were observed in 3 and 15% of cases, respectively.

Conclusions: PUC is associated with high disease burden and poor chemosensitivity. Increased awareness and recognition of this disease variant will allow for new treatment strategies.
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http://dx.doi.org/10.1038/s41416-020-01244-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8007750PMC
March 2021

Identification and separation of rigid image registration error sources, demonstrated for MRI-only image guided radiotherapy.

Biomed Phys Eng Express 2020 04 27;6(3):035032. Epub 2020 Apr 27.

Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, Leeds, United Kingdom.

Purpose: Rigid image registration (RIR) accuracy is crucial for image guided radiotherapy (IGRT). However, existing clinical image registration assessment methods cannot separate and quantify RIR error sources. Herein, we develop an extension of the 'full circle method' for RIR consistency. Paired registration circuits are used to isolate sources of RIR error caused by reference dataset substitution, from those inherent to the underlying RIR. This approach was demonstrated in the context of MRI-only IGRT, assessing substitution of MRI-derived synthetic-CT (sCT) for conventional CT, in a cohort of rectal cancer patients.

Materials And Methods: Planning CT, MRI-derived sCT, and two CBCTs from seven rectal cancer patients were retrospectively registered with global and soft tissue clipbox based RIR. Paired registration circuits were constructed using two moving (cone beam CT) images and two reference images (CT and sCT), per patient. Differences between inconsistencies in registration circuits containing CT and sCT were used to determine changes in registration accuracy due to substitution of sCT for CT.

Results: sCT was found to be equivalent to CT under global RIR, with median differences of 0.05 mm and 0.01°. Soft tissue clipbox based RIR with sCT exhibited gross misregistration (>5 mm or 3°) for 3 patients. Registration consistency was degraded compared to CT across the cohort, with median differences of 0.54 mm and 0.15°.

Conclusion: A paired registration circuit methodology for assessing RIR accuracy without ground truth information was developed and demonstrated for MRI-only IGRT in rectal cancer. This highlighted a reduction in clipbox based RIR consistency when sCT was substituted for conventional CT. The developed method enabled separation of degraded registration accuracy, from other error sources within the overall registration inconsistency. This novel methodology is applicable to any RIR scenario and enables analysis of the change in RIR performance on modification of image data or process.
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http://dx.doi.org/10.1088/2057-1976/ab81adDOI Listing
April 2020

Fibulin-2: A Novel Biomarker for Differentiating Grade II from Grade I Meningiomas.

Int J Mol Sci 2021 Jan 8;22(2). Epub 2021 Jan 8.

Faculty of Health, Medicine, Dentistry and Human Sciences, The Institute of Translational and Stratified Medicine, University of Plymouth, The John Bull Building, Plymouth Science Park, Research Way, Plymouth PL6 8BU, UK.

There is an unmet need for the identification of biomarkers to aid in the diagnosis, clinical management, prognosis and follow-up of meningiomas. There is currently no consensus on the optimum management of WHO grade II meningiomas. In this study, we identified the calcium binding extracellular matrix glycoprotein, Fibulin-2, via mass-spectrometry-based proteomics, assessed its expression in grade I and II meningiomas and explored its potential as a grade II biomarker. A total of 87 grade I and 91 grade II different meningioma cells, tissue and plasma samples were used for the various experimental techniques employed to assess Fibulin-2 expression. The tumours were reviewed and classified according to the 2016 edition of the Classification of the Tumours of the central nervous system (CNS). Mass spectrometry proteomic analysis identified Fibulin-2 as a differentially expressed protein between grade I and II meningioma cell cultures. Fibulin-2 levels were further evaluated in meningioma cells using Western blotting and Real-time Quantitative Polymerase Chain Reaction (RT-qPCR); in meningioma tissues via immunohistochemistry and RT-qPCR; and in plasma via Enzyme-Linked Immunosorbent Assay (ELISA). Proteomic analyses ( < 0.05), Western blotting ( < 0.05) and RT-qPCR ( < 0.01) confirmed significantly higher Fibulin-2 (FBLN2) expression levels in grade II meningiomas compared to grade I. Fibulin-2 blood plasma levels were also significantly higher in grade II meningioma patients compared to grade I patients. This study suggests that elevated Fibulin-2 might be a novel grade II meningioma biomarker, when differentiating them from the grade I tumours. The trend of Fibulin-2 expression observed in plasma may serve as a useful non-invasive biomarker.
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http://dx.doi.org/10.3390/ijms22020560DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7827565PMC
January 2021

Intensity-modulated Radiotherapy for Rectal Cancer in the UK in 2020.

Clin Oncol (R Coll Radiol) 2021 Apr 8;33(4):214-223. Epub 2021 Jan 8.

Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Aims: Preoperative (chemo)radiotherapy followed by total mesorectal excision is the current standard of care for patients with locally advanced rectal cancer. The use of intensity-modulated radiotherapy (IMRT) for rectal cancer is increasing in the UK. However, the extent of IMRT implementation and current practice was not previously known. A national survey was commissioned to investigate the landscape of IMRT use for rectal cancer and to inform the development of national rectal cancer IMRT guidance.

Materials And Methods: A web-based survey was developed by the National Rectal Cancer IMRT Guidance working group in collaboration with the Royal College of Radiologists and disseminated to all UK radiotherapy centres. The survey enquired about the implementation of IMRT with a focus on the following aspects of the workflow: dose fractionation schedules and use of a boost; pre-treatment preparation and simulation; target volume/organ at risk definition; treatment planning and treatment verification. A descriptive statistical analysis was carried out.

Results: In total, 44 of 63 centres (70%) responded to the survey; 30/44 (68%) and 36/44 (82%) centres currently use IMRT to treat all patients and selected patients with rectal cancer, respectively. There was general agreement concerning several aspects of the IMRT workflow, including patient positioning, use of intravenous contrast and bladder protocols. Greater variation in practice was identified regarding rectal protocols; use of a boost to primary/nodal disease; target volume delineation; organ at risk delineation and dose constraints and treatment verification. Delineation of individual small bowel loops and daily volumetric treatment verification were considered potentially feasible by most centres.

Conclusion: This survey identified that IMRT is already used to treat rectal cancer in many UK radiotherapy centres, but there is heterogeneity between centres in its implementation and practice. These results have been a valuable aid in framing the recommendations within the new National Rectal Cancer IMRT Guidance.
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http://dx.doi.org/10.1016/j.clon.2020.12.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7985673PMC
April 2021

A phase II trial of durvalumab and tremelimumab in metastatic, non-urothelial carcinoma of the urinary tract.

Cancer Med 2021 Feb 31;10(3):1074-1083. Epub 2020 Dec 31.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Background: Immune checkpoint blockade has made a significant impact on the clinical outcomes of patients with metastatic urothelial carcinoma (UC). However, evidence for this approach in patients with non-UC of the urinary tract is limited.

Methods: This was a phase II open-label study of durvalumab 1500 mg and tremelimumab 75 mg every 4 weeks for four cycles followed by durvalumab 1500 mg every 4 weeks. Eligible patients had metastatic non-UC with ECOG PS 0-1 regardless of prior therapy (except small cell carcinoma who were pretreated). The primary endpoint was overall response rate per RECIST v1.1. A Simon's minimax two-stage design was employed, with 13 patients planned for stage one. Pre-treatment tumors underwent PD-L1 staining and next-generation sequencing.

Results: Thirteen patients were treated, including seven small cell carcinoma, three squamous cell carcinoma, and three adenocarcinoma. Eleven patients had visceral metastases. No responses were observed; 11 patients had PD and 2 patients had SD. Median PFS was 1.8 months (95% CI, 1.25-not reached [NR]) with a median follow-up of 7.38 months (range, 5.23-21.99 months). Median OS was 6.97 months (95% CI, 4.34-NR). One patient's tumor was PD-L1 positive and all sequenced tumors (n = 8) were microsatellite stable. Grades 3-4 treatment-related adverse events occurred in 38.4% of patients.

Conclusions: In a poor prognosis cohort of patients with non-UC, durvalumab and tremelimumab lacked clinical activity while demonstrating a manageable safety profile.
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http://dx.doi.org/10.1002/cam4.3699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7897955PMC
February 2021

Optimised prophylactic vaccination in metapopulations.

Epidemics 2021 Mar 30;34:100420. Epub 2020 Nov 30.

School of Mathematical Sciences, The University of Adelaide, Adelaide, SA 5005, Australia. Electronic address:

A highly effective method for controlling the spread of an infectious disease is vaccination. However, there are many situations where vaccines are in limited supply. The ability to determine, under this constraint, a vaccination strategy which minimises the number of people that become infected over the course of a potential epidemic is essential. Two questions naturally arise: when is it best to allocate vaccines, and to whom should they be allocated? We address these questions in the context of metapopulation models of disease spread. We discover that in practice it is generally optimal to distribute all vaccines prophylactically, rather than withholding until infection is introduced. For small metapopulations, we provide a method for determining the optimal prophylactic allocation. As the optimal strategy becomes computationally intensive to obtain when the population size increases, we detail an approximation method to determine an approximately optimal vaccination scheme. We find that our approximate strategy is consistently at least as good as three strategies reported in the literature across a wide range of parameter values.
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http://dx.doi.org/10.1016/j.epidem.2020.100420DOI Listing
March 2021

Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients.

Radiother Oncol 2021 Mar 14;156:153-159. Epub 2020 Dec 14.

Department of Medical Physics, St James's University Hospital, Leeds, UK.

Background: Stereotactic Ablative Radiotherapy (SABR) is the standard treatment for early-stage medically inoperable lung cancer. Predictors of radiation pneumonitis (RP) in patients treated with SABR are poorly defined. In this study, we investigate clinical and dosimetric parameters, which can predict symptomatic RP in early-stage lung cancer patients treated with SABR.

Materials And Methods: Patients treated with lung SABR between May 2009 and August 2018, in a single United Kingdom (UK) radiotherapy center were included. The patient's baseline characteristics, treatment details, and toxicity were retrieved from the electronic medical record. Dosimetric data was extracted from Xio and Monaco treatment planning systems. Patients were treated according to the UK SABR consortium guidelines. RP was graded retrospectively using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, based on available clinical and imaging information. Univariate and multivariate binary logistic regression was performed to determine predictive factors for grade ≥ 2 radiation pneumonitis, using Statistical Package for the Social Sciences (SPSS) statistics version 21 software. The goodness of fit was assessed using the Hosmer and Lemeshow test. The optimal diagnostic threshold was tested using the Receiver operating characteristics (ROC) curve. The chi-square test was carried out to test the different risk factors against the likelihood of developing grade ≥ 2 pneumonitis.

Results: A total of 1266 patients included in the analysis. The median age of patients was 75 years. Six hundred sixty-six patients (52.6%) were female. Median follow up was 56 months. Sixty-five percent of patients received 55 Gy in 5 fractions. Forty-three percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and 16.2% had PS of 3. The Median Charlson comorbidity index was 6 (range 2-11). Median Standardized Uptake Value (SUV) max of the tumor was 6.5. Four hundred two patients (31.8%) had confirmed histological diagnosis; other patients were treated based on a radiological diagnosis. The median tumor size was 20 mm (range 4 mm-63 mm). Median Planning Target Volume (PTV) was 30.3 cc. Median values of R100, R50, and D2cm were 1.1, 5.6, 32.8 Gy. The median value of mean lung dose, V20, and V12.5 were 3.9 Gy, 5 %and 9.3% respectively. Eighty-five (6.7%) patients developed symptomatic RP (grade ≥ 2) with only 5(0.4%) developing grade 3 RP. Five percent of patients developed rib fractures but only 28% of these were symptomatic. On univariate analysis lower lobe tumor location, larger tumor size, PTV, mean lung dose, lung V20Gy, and V12.5 Gy were significantly associated with grade ≥ 2 RP. On multivariate analysis, only mean lung dose was associated with grade ≥ 2 pneumonitis. ROC curve analysis showed optimal diagnostic threshold for tumour size, PTV, mean lung dose, V20 and V12.5; are 22.5 mm ((Area Under Curve (AUC)-0.565)), 27.15 cc (AUC-0.58), 3.7 Gy (AUC-0.633), 4.6% (AUC-0.597), 9.5% (AUC-0.616). The incidence of ≥grade 2 RP was significantly high for values higher than the ROC threshold.

Conclusion: SABR treatment resulted in a very low rate of grade 3 pneumonitis. Lower lobe tumor location, larger tumor size, PTV, mean lung dose, V20, and V12.5 were found to be significant predictors of symptomatic radiation pneumonitis.
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http://dx.doi.org/10.1016/j.radonc.2020.12.015DOI Listing
March 2021

Long-term effectiveness and safety of infliximab and golimumab in ankylosing spondylitis patients from a Canadian prospective observational registry.

BMC Rheumatol 2020 Nov 15;4(1):56. Epub 2020 Nov 15.

Janssen Inc., 19 Green Belt Dr., Toronto, ON, M3C 1N9, Canada.

Background: The objectives of this study were to describe the profile of ankylosing spondylitis (AS) patients treated with either infliximab (IFX) or subcutaneous golimumab (GLM) treatment in Canadian routine care setting along with assessing long-term effectiveness and safety.

Methods: AS patients who were eligible for treatment with IFX or subcutaneous GLM as per their respective Canadian product monographs were enrolled into the BioTRAC registry from 2005 to 2017. The study visits occurred at baseline and every 6 months thereafter. Effectiveness was assessed by changes in clinical outcomes and acute phase reactants. Safety was evaluated by assessing the incidence of adverse events (AEs) and drug survival rates.

Results: A total of 389 IFX- and 421 GLM-treated patients were enrolled. A significant decrease in disease duration at baseline was observed in the IFX cohort, from a median of 8.0 in 2005-2008 to 1.0 years in 2009-2015 (p < 0.001). A reduction in baseline BASFI score (p = 0.011) and proportion of patients in ASDAS very high disease activity (p = 0.004) was also observed over time. Meanwhile, in the GLM cohort, most disease parameters remained similar from 2010 to 2017. Treatment with both agents significantly improved all disease parameters over time with similar efficacy between the two agents. The incidence of AEs and SAEs were 136 and 131 events/100 PYs and 10.5 and 8.45 events/100 PYs for IFX- and GLM-treated patients, respectively.

Conclusion: Both IFX and GLM treatment in AS significantly reduced disease activity in most outcome measures in a similar fashion and were well tolerated in Canadian routine care.

Trial Registration: NCT00741793 .
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http://dx.doi.org/10.1186/s41927-020-00158-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666769PMC
November 2020

Prevalence of Insomnia in an Oncology Patient Population: An Irish Tertiary Referral Center Experience.

J Natl Compr Canc Netw 2020 12 2;18(12):1623-1630. Epub 2020 Dec 2.

2Department of Medical Oncology, St. James's Hospital, Dublin, Ireland.

Background: The NCCN Guidelines for Survivorship recommend dedicated sleep assessment. Reported insomnia prevalence in the general Irish population is 6% to 15%. Reported insomnia prevalence internationally among new/recently diagnosed patients with cancer varies from 30.9% to 54.3%. Insomnia prevalence has not been previously quantified in an Irish oncology cohort.

Methods: A 40-item questionnaire was prospectively administered to ambulatory patients with cancer aged ≥18 years. Prespecified criteria to define insomnia syndrome combined those of the International Classification of Sleep Disorders, version 1, and the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). The Hospital Anxiety and Depression Scale-Depression/Anxiety (HADS-D/A) was used to screen for potential confounding variables.

Results: The response rate to the questionnaire was 87% (294/337). The predominant respondent age group was 55 to 64 years (26%; 77/294), 70.7% were female (208/294), and the most common cancer subtypes were breast (37.4%), colorectal (12.9%), and lung (12.2%). A total of 62% (183/294) of patients reported sleep disturbance after diagnosis, 63% (115/183) reported moderate/severe distress related to this disturbance, and 37% (61/183) reported a significant impact on physical function. Although 33% (98/294) met insomnia syndrome criteria, only 34% (33/98) of these patients had a preexisting history of sleep disturbance. Female sex, age <65 years, cancer subtype, alcohol consumption, and HADS-D/A ≥11 were associated with statistically significant higher odds ratios (OR) of insomnia syndrome. Multivariate analysis identified breast cancer (OR, 3.17; P=.01), age <65 years (OR, 1.8; P=.03), and alcohol consumption (OR, 2.3; P=.005) as independent predictors of insomnia syndrome.

Conclusions: Insomnia syndrome prevalence in this cohort is comparable to that reported previously and supports dedicated sleep assessment. This study identifies potentially modifiable risk factors for insomnia and demonstrates additional utility of the HADS score in identifying patients at risk.
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http://dx.doi.org/10.6004/jnccn.2020.7611DOI Listing
December 2020

Multicentre, deep learning, synthetic-CT generation for ano-rectal MR-only radiotherapy treatment planning.

Radiother Oncol 2021 Mar 29;156:23-28. Epub 2020 Nov 29.

Leeds Cancer Centre, Leeds Teaching Hospitals NHS Trust, United Kingdom; Radiotherapy Research Group, Leeds Institute of Medical Research, University of Leeds, United Kingdom.

Background And Purpose: Comprehensive dosimetric analysis is required prior to the clinical implementation of pelvic MR-only sites, other than prostate, due to the limited number of site specific synthetic-CT (sCT) dosimetric assessments in the literature. This study aims to provide a comprehensive assessment of a deep learning-based, conditional generative adversarial network (cGAN) model for a large ano-rectal cancer cohort. The following challenges were investigated; T2-SPACE MR sequences, patient data from multiple centres and the impact of sex and cancer site on sCT quality.

Method: RT treatment position CT and T2-SPACE MR scans, from two centres, were collected for 90 ano-rectal patients. A cGAN model trained using a focal loss function, was trained and tested on 46 and 44 CT-MR ano-rectal datasets, paired using deformable registration, respectively. VMAT plans were created on CT and recalculated on sCT. Dose differences and gamma indices assessed sCT dosimetric accuracy. A linear mixed effect (LME) model assessed the impact of centre, sex and cancer site.

Results: A mean PTV D95% dose difference of 0.1% (range: -0.5% to 0.7%) was found between CT and sCT. All gamma index (1%/1 mm threshold) measurements were >99.0%. The LME model found the impact of modality, cancer site, sex and centre was clinically insignificant (effect ranges: -0.4% and 0.3%). The mean dose difference for all OAR constraints was 0.1%.

Conclusion: Focal loss cGAN models using T2-SPACE MR sequences from multiple centres can produce generalisable, dosimetrically accurate sCTs for ano-rectal cancers.
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http://dx.doi.org/10.1016/j.radonc.2020.11.027DOI Listing
March 2021

Safety and Outcomes of Different Surgical Techniques for Cubital Tunnel Decompression: A Systematic Review and Network Meta-analysis.

JAMA Netw Open 2020 11 2;3(11):e2024352. Epub 2020 Nov 2.

Department of Plastic and Reconstructive Surgery, Leeds Teaching Hospitals Trust, Leeds, United Kingdom.

Importance: Cubital tunnel syndrome is the second most common compressive neuropathy, affecting 6% of the population. Numerous different operations are performed globally to treat it; however, prior conventional (pairwise) meta-analyses have been unable to determine which procedure is associated with the best outcomes and fewest complications.

Objective: To evaluate which operation for cubital tunnel syndrome is associated with the greatest likelihood of symptomatic cure.

Data Sources: PubMed, EMBASE, and CENTRAL were searched from database inception to March 2, 2019, with no restrictions on the setting or design of studies.

Study Selection: Experimental and observational studies directly comparing the outcomes of at least 2 surgical treatments for adults with primary cubital tunnel syndrome were included. Case reports were excluded, and when comparative studies had subgroups with 1 participant, the single-participant subgroup was excluded. The treatments had to be in situ decompression with or without medial epicondylectomy or an anterior subcutaneous, subfascial, intramuscular, or submuscular transposition. The access could be open, minimally invasive, or endoscopic. The comparator could be sham surgery or any operation mentioned earlier.

Data Extraction And Synthesis: Data were extracted by 2 independent reviewers, following the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline and the PRISMA Network Meta-analysis extension statement. Network meta-analysis was used to estimate the relative efficacy and safety associated with interventions using relative risks. Surgical techniques were ranked by their probability of being the best (P score) and interpreted in terms of their clinical impact.

Main Outcomes And Measures: The primary outcome was response to treatment (ie, symptomatic improvement). The secondary outcomes were perioperative complications, reoperation, and recurrence.

Results: A total of 30 studies of 2894 limbs undergoing 8 different operations were included. Across the studies, 56% of participants were men, the mean (SD) age was 48 (8) years, and patients had symptoms for a mean (SD) of 15 (7) months. Overall, 87% (95% CI, 92%-91%) of patients improved with surgery; all forms of in situ decompression were more effective than any type of transposition procedure; for example, open in situ decompression with epicondylectomy was associated with higher success rates than subcutaneous transposition (relative risk, 1.13; 95% CI, 1.01-1.25). Postoperatively, 3% (95% CI, 2%-4%) of patients developed complications, and in situ decompressions were ranked as the least risky, although there was considerable uncertainty in this outcome. Overall, 2% (95% CI, 1%-3%) of patients required reoperation; open in situ decompression was associated with the fewest reoperations; in comparison, submuscular transposition was associated with 5 times the risk of reoperation (relative risk, 5.08; 95% CI, 2.06-12.52). During surveillance, 3% (95% CI, 1%-4%) of patients developed recurrence, and open in situ decompression with epicondylectomy was ranked as the safest operation, although there was uncertainty in the estimates.

Conclusions And Relevance: In this network meta-analysis, open in situ decompression (with or without medial epicondylectomy) appeared to be the safest operation and also was associated with the best outcomes for patients with primary cubital tunnel syndrome. Future research should focus on better defining this disorder and developing core outcome measures.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.24352DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686867PMC
November 2020

Phantosmia as the first presentation of a cavernous sinus - clinoidal meningioma.

Br J Neurosurg 2020 Oct 14:1-7. Epub 2020 Oct 14.

Department of Neurosurgery, Southmead Hospital, Bristol, UK.

Cavernous sinus meningiomas (CSM) are complex skull base lesions that, due to their particular anatomical location, render surgical management difficult. Their symptomatology is versatile, and the clinical outcome is difficult to predict. We present the case of a 57-year old female patient who experienced phantosmia - an abnormal, persistent, olfactory sensation of cigarette smell for 18 months. MRI was performed and revealed a left cavernous sinus meningioma, extending into the left temporal fossa, with olfactory and optic nerve distortion. To our knowledge, this is the first reported case of phantosmia as the initial presentation of a lesion in the cavernous sinus.
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http://dx.doi.org/10.1080/02688697.2020.1834510DOI Listing
October 2020

Low-cost technique for simulating aerosolisation using a manual jet ventilator.

Anaesth Intensive Care 2020 09 6;48(5):415-416. Epub 2020 Oct 6.

Department of Surgical Intensive Care, Singapore General Hospital, Singapore.

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http://dx.doi.org/10.1177/0310057X20953857DOI Listing
September 2020

Multiomic analysis and immunoprofiling reveal distinct subtypes of human angiosarcoma.

J Clin Invest 2020 11;130(11):5833-5846

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

Angiosarcomas are rare, clinically aggressive tumors with limited treatment options and a dismal prognosis. We analyzed angiosarcomas from 68 patients, integrating information from multiomic sequencing, NanoString immuno-oncology profiling, and multiplex immunohistochemistry and immunofluorescence for tumor-infiltrating immune cells. Through whole-genome sequencing (n = 18), 50% of the cutaneous head and neck angiosarcomas exhibited higher tumor mutation burden (TMB) and UV mutational signatures; others were mutationally quiet and non-UV driven. NanoString profiling revealed 3 distinct patient clusters represented by lack (clusters 1 and 2) or enrichment (cluster 3) of immune-related signaling and immune cells. Neutrophils (CD15+), macrophages (CD68+), cytotoxic T cells (CD8+), Tregs (FOXP3+), and PD-L1+ cells were enriched in cluster 3 relative to clusters 2 and 1. Likewise, tumor inflammation signature (TIS) scores were highest in cluster 3 (7.54 vs. 6.71 vs. 5.75, respectively; P < 0.0001). Head and neck angiosarcomas were predominant in clusters 1 and 3, providing the rationale for checkpoint immunotherapy, especially in the latter subgroup with both high TMB and TIS scores. Cluster 2 was enriched for secondary angiosarcomas and exhibited higher expression of DNMT1, BRD3/4, MYC, HRAS, and PDGFRB, in keeping with the upregulation of epigenetic and oncogenic signaling pathways amenable to targeted therapies. Molecular and immunological dissection of angiosarcomas may provide insights into opportunities for precision medicine.
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http://dx.doi.org/10.1172/JCI139080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7598061PMC
November 2020

Looking for Metastasis in Early Breast Cancer: Does Bone Scan Help? A Retrospective Review.

Clin Breast Cancer 2021 Feb 8;21(1):e18-e21. Epub 2020 Jul 8.

Breast and Endocrine Unit, Maroondah Hospital, Eastern Health, Melbourne, Australia.

Background: Routine staging investigations are not recommended for early breast cancer (EBC). Staging scans and further confirmatory tests add to the cost of breast cancer treatment. Despite recommendations from international guidelines, whole body bone scan (BS) is commonly used for staging EBC. We examined our experience with BS as a staging investigation when selectively used in EBC.

Patients And Methods: All EBC patients who underwent treatment through the Eastern Health breast unit during a 50-month period from January 2012 were included in this study. All staging BS results were reviewed to evaluate yield and false-positive rate. The causes of false-positive results were analyzed. The role of BS when performed along with computed tomographic scans of chest, abdomen, and pelvis (CTCAP) was evaluated.

Results: Even with the selective use of BS, we could only achieve a yield of 1% (95% confidence interval, -0.6, 2.7) in EBC. When combined with CTCAP, only one additional metastasis was detected in 194 BSs.

Conclusion: BS plays only a limited role in staging EBC. Patients who have undergone CTCAP will experience minimal benefit by undergoing additional BS.
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http://dx.doi.org/10.1016/j.clbc.2020.07.004DOI Listing
February 2021

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

A Multifunctional Role of Leucine-Rich α-2-Glycoprotein 1 in Cutaneous Wound Healing Under Normal and Diabetic Conditions.

Diabetes 2020 11 4;69(11):2467-2480. Epub 2020 Sep 4.

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

Delayed wound healing is commonly associated with diabetes. It may lead to amputation and death if not treated in a timely fashion. Limited treatments are available partially due to the poor understanding of the complex disease pathophysiology. Here, we investigated the role of leucine-rich α-2-glycoprotein 1 (LRG1) in normal and diabetic wound healing. First, our data showed that LRG1 was significantly increased at the inflammation stage of murine wound healing, and bone marrow-derived cells served as a major source of LRG1. LRG1 deletion causes impaired immune cell infiltration, reepithelialization, and angiogenesis. As a consequence, there is a significant delay in wound closure. On the other hand, LRG1 was markedly induced in diabetic wounds in both humans and mice. LRG1-deficient mice were resistant to diabetes-induced delay in wound repair. We further demonstrated that this could be explained by the mitigation of increased neutrophil extracellular traps (NETs) in diabetic wounds. Mechanistically, LRG1 mediates NETosis in an Akt-dependent manner through TGFβ type I receptor kinase ALK5. Taken together, our studies demonstrated that LRG1 derived from bone marrow cells is required for normal wound healing, revealing a physiological role for this glycoprotein, but that excess LRG1 expression in diabetes is pathogenic and contributes to chronic wound formation.
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http://dx.doi.org/10.2337/db20-0585DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7576570PMC
November 2020

Treatment of gastrointestinal tumor (GIST) of the rectum requiring abdominoperineal resection following neoadjuvant imatinib: a cost-effectiveness analysis.

Clin Sarcoma Res 2020 6;10:13. Epub 2020 Aug 6.

Programme in Health Services and Systems Research, Graduate Medical School, Duke-National University of Singapore, Singapore, Singapore.

Background: Neoadjuvant imatinib for gastrointestinal stromal tumors (GIST) of the rectum can reduce, but may not eliminate, risk of surgical morbidity from permanent bowel diversion. We sought to evaluate the cost-effectiveness of alternative strategies in rectal GIST patients requiring abdominoperineal resection following neoadjuvant imatinib.

Methods: We developed a Markov model using a healthcare payers' perspective to estimate costs in 2017 Singapore dollars (SGD) and quality adjusted life years (QALYs) for upfront abdominoperineal resection (UAPR) versus continued imatinib until progression (CIUP) following 1 year of neoadjuvant imatinib. Transition probabilities and utilities were obtained from published data, and costs were estimated using data from the National Cancer Centre Singapore. Deterministic and probabilistic sensitivity analyses were conducted to probe model uncertainty. Incremental cost-effectiveness ratio below SGD 50,000 per QALY gained was considered cost-effective.

Results: In the base case, UAPR dominates CIUP being both more effective (8.66 QALYS vs 5.43 QALYs) and less expensive (SGD 312,627 vs SGD 339,011). These estimates were most sensitive to 2 variables, utility of abdominoperineal resection and annual recurrence probability post-abdominoperineal resection. However, simultaneously varying the values of these variables to maximally favor CIUP did not render it the more cost effective strategy at willingness to pay (WTP) of SGD 50,000. In probabilistic sensitivity analysis, UAPR had probability of being cost-effective compared with CIUP greater than 95%, reaching 100% at WTP SGD 10,000.

Conclusion: UAPR is more effective and less costly than CIUP for patients with rectal GIST requiring abdominoperineal resection following neoadjuvant imatinib, and is the strategy of choice in this setting.
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http://dx.doi.org/10.1186/s13569-020-00135-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412662PMC
August 2020

Retrospective quality of life study in patients with retroperitoneal sarcoma in an Asian population.

Health Qual Life Outcomes 2020 Aug 6;18(1):270. Epub 2020 Aug 6.

Department of Sarcoma, Peritoneal and Rare Tumours (SPRinT), Division of Surgery and Surgical Oncology, National Cancer Centre Singapore, 11 Hospital Crescent, Singapore, 169610, Singapore.

Background: Retroperitoneal sarcoma represents 15% of sarcomas. The mainstay of treatment is surgery where a majority of patients require multi-visceral resections that may significantly impact their quality of life (QOL) following surgery. Studies in other cancers have shown that QOL may not be significantly impacted after radical or extensive surgery. However, there are limited studies examining the QOL specifically in patients with retroperitoneal sarcoma. In this pilot study, we retrospectively evaluated the QOL of patients with retroperitoneal sarcoma.

Methods: 32 out of 90 patients who underwent surgical intervention for retroperitoneal sarcoma in National Cancer Centre Singapore from January 1999 to August 2018 who were alive and on follow-up were included in this study. EORTC-QLQ-C30 was administered to the patients.

Results: The median age of our patients was 59 years (range, 35-84), and median time from surgery to the implementation of questionnaire was 2.5 years (range, 0.05-9.6). Younger patients had significantly better differences in global health, physical and role functioning scores as compared to older individuals. Female patients reported higher global health, physical, emotional and social functioning scores than males. Patients who were more than 2 years post-surgery exhibited better QOL scores as compared to those who had more recent surgery. Our patients had comparable global health and functioning scores compared to a reference group of outpatient cancer patients at our institution.

Conclusions: Our pilot study investigating the QOL of patients with retroperitoneal sarcoma has shown that patients need to be followed up for at least 2 years following surgery to evaluate their QOL. In general, they achieved better functioning scores when compared with other cancer patients. These findings support the need for larger-scale prospective studies to further evaluate the QOL of these patients.
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http://dx.doi.org/10.1186/s12955-020-01491-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409714PMC
August 2020

Fibroblast Growth Factor Receptor 3 Alteration Status is Associated with Differential Sensitivity to Platinum-based Chemotherapy in Locally Advanced and Metastatic Urothelial Carcinoma.

Eur Urol 2020 12 1;78(6):907-915. Epub 2020 Aug 1.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA. Electronic address:

Background: Alterations in fibroblast growth factor receptor 3 (FGFR3) occur in ∼15% of muscle-invasive bladder cancers (MIBCs) and metastatic urothelial carcinomas (mUCs).

Objective: To determine the association between FGFR3 status and response to platinum-based chemotherapy in patients with MIBC or mUC.

Design, Setting, And Participants: The authors conducted a retrospective review and comparison of patients having (1) MIBC treated with neoadjuvant chemotherapy (NAC), (2) mUC treated with first-line platinum-based chemotherapy (M1 cohort), and (3) MIBC who were from The Cancer Genome Atlas (TCGA).

Intervention: Platinum-based chemotherapy.

Outcome Measurements And Statistical Analysis: Pathologic response, recurrence-free (RFS) or progression-free (PFS) survival, and overall survival (OS) were compared between patients with FGFR3 alteration (FGFR3alt) and those without it (FGFR3wild type [FGFR3wt]) in the three cohorts.

Results And Limitations: Nine of 72 NAC patients (13%) had FGFR3alt, of whom none had pathologic complete response and three had residual non-MIBC (carcinoma in situ, n = 1; pT1, n = 2). FGFR3alt was associated with shorter RFS (hazard ratio, 2.74; p = 0.044) but not OS. Among TCGA patients who underwent adjuvant chemotherapy (n = 74), FGFR3alt patients had shorter RFS as well. Conversely, among chemotherapy-naive TCGA patients, FGFR3alt was associated with longer RFS and OS. In the M1 cohort (FGFR3alt, n = 27; FGFR3wt, n = 81), FGFR3alt was associated with higher rates of pulmonary metastases and nonregional lymphadenopathy. Despite lower response rates among FGFR3alt patients (37% vs 49%; p = 0.056), PFS and OS were not significantly different from FGFR3wt patients.

Conclusions: FGFR3 status is associated with lower responses to platinum-based chemotherapy, which may prompt exploration of nonchemotherapeutic approaches for perioperative management of FGFR3alt urothelial cancers.

Patient Summary: Approximately 15% of bladder cancers harbor mutations in the fibroblast growth factor receptor 3 (FGFR3) gene. Our findings suggest that FGFR3 mutations might be associated with lower responses and shorter time to recurrence among patients with muscle-invasive bladder cancer who received perioperative platinum-based chemotherapy. FGFR3 status does not significantly impact response to chemotherapy among those with metastatic urothelial cancers.
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http://dx.doi.org/10.1016/j.eururo.2020.07.018DOI Listing
December 2020

Letter to the Editor Regarding "Factors Influencing Medical Student Interest in a Career in Neurosurgery".

World Neurosurg 2020 07;139:655

Department of Neurosurgery, North Bristol NHS Trust, Bristol, United Kingdom.

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http://dx.doi.org/10.1016/j.wneu.2020.03.074DOI Listing
July 2020