Publications by authors named "Leo Chen"

84 Publications

Impact of new cancer therapies on outpatient treatment delivery for colorectal cancer: A population-based study.

Int J Health Plann Manage 2021 Sep 20. Epub 2021 Sep 20.

Providence Cancer Institute Franz Clinic, Portland Providence Medical Center, Portland, Oregon, USA.

We investigated the impact of new systemic therapies approved in Canada for colorectal cancer on the frequency, intensity and duration of oncology clinic and infusion visits over five treatment phases from diagnosis (P1, P3) to treatment (P2, P4) of primary and metastatic disease, respectively, and during the last 6 months of life (P5). In total, 15,157 adult patients with newly diagnosed colorectal cancer and referred between 2000 and 2012 to any cancer clinic in British Columbia, Canada, were included. Frequency, intensity and duration of medical oncology clinic visits (CVs), oncology infusions (OIs) and oncology prescriptions (OPs) were measured by treatment phase. Mean, total and adjusted total duration for CVs increased for P1-5. CVs increased in P1-5, and in P1-4 when adjusted by treatment length. Adjusted and unadjusted OIs decreased in P1 coinciding with the introduction of an oral treatment option, but increased in P2-5. Mean OI duration increased in P1-5, while total and adjusted total decreased in P1 and increased in P2-5. OPs increased in P2-4, but were unchanged in P1 and P5. Multi-fold increases in resources and time required per patient were also observed, which have significant implications for demand projections in cancer care planning and delivery. In conclusion, patients required more visits in almost all treatment phases, visits on average took longer and patients were in treatment for longer periods of time.
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http://dx.doi.org/10.1002/hpm.3308DOI Listing
September 2021

Are we producing general surgeons who are ready for community or rural practice?

Can J Surg 2021 Sep 1;64(5):E467-E472. Epub 2021 Sep 1.

From the Division of General Surgery, University of British Columbia, Vancouver, BC.

Summary: General surgery remains a broad and unclearly defined specialty in small and medium-sized communities, where general surgeons perform more subspecialty and non-core procedures than their urban counterparts. It is unclear what specific procedures are being performed or whether today's residents are being trained to meet community needs. We surveyed the members of the British Columbia (BC) Surgical Society and found that only 3% of BC's surgeons believe today's graduates are "definitely prepared" for a broad-based community practice. We also identified several non-core procedures performed more frequently by general surgeons in small and medium-sized communities. General surgery residency is narrowing its focus despite the fact that community general surgeons are maintaining a broad-based practice. To meet the needs of smaller communities, residency programs need to address the discrepancies that exist between the emphasis within the current training structure and the practice of our community surgeons.
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http://dx.doi.org/10.1503/cjs.014119DOI Listing
September 2021

Immediate breast reconstruction in locally advanced breast cancer: is it safe?

Breast Cancer Res Treat 2021 Aug 31. Epub 2021 Aug 31.

Division of General Surgery, Department of Surgery, Providence Health Care Breast Centre, Providence Breast Centre & University of British Columbia, Mount Saint Joseph Hospital, 3rd Floor, 3080 Prince Edward Street, Vancouver, BC, V5T 3N4, Canada.

Purpose: Immediate breast reconstruction (IBR) following mastectomy remains controversial for locally advanced breast cancer over concerns regarding recurrence and complications which may delay adjuvant therapies. This study aimed to compare the oncologic outcomes and surgical safety of IBR following mastectomy with mastectomy alone (MA) for locally advanced breast cancer.

Methods: All patients treated at the Providence Breast Center between 2012 and 2017 for biopsy-proven locally advanced breast cancer, AJCC (8th edition) clinical stages (IIB-IIIC), were included. Primary outcomes were overall survival (OS), disease-specific survival (DSS), and disease-free survival (DFS). Secondary outcomes included recurrence rate, adjuvant therapy use, and reoperation.

Results: 267 patients (112 IBR, 155 MA) were included. On average, IBR patients were younger (48.82 years vs 61.42 years, P < 0.001). Median study follow-up was 50.7 months. OS was higher among IBR patients (86.6% vs 73.5%, P < 0.05). However, no significant differences were found in DSS (87.5% vs 84.5%, P = 0.34), DFS (79.5% vs 78.7%, P = 0.55), local recurrence (0% vs 1.9%, P = 0.194), adjuvant therapy use (95.5% vs 91.6%, P = 0.155), or reoperation (1.8% vs 1.3%, P = 0.559).

Conclusion: IBR is a safe option for patients with locally advanced breast cancer and does not negatively impact survival, cancer recurrence rates, and use of adjuvant therapy.
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http://dx.doi.org/10.1007/s10549-021-06366-6DOI Listing
August 2021

Pressurized Hot Water Extraction of Okra Seeds Reveals Antioxidant, Antidiabetic and Vasoprotective Activities.

Plants (Basel) 2021 Aug 10;10(8). Epub 2021 Aug 10.

Science, Math & Technology, Singapore University of Technology & Design, Singapore 487372, Singapore.

(okra) is a commonly consumed vegetable that consists of the seeds and peel component which are rich in polyphenolic compounds. The aim of this study is to utilize pressurized hot water extraction (PHWE) for the extraction of bioactive phytochemicals from different parts of okra. A single step PHWE was performed at various temperatures (60 °C, 80 °C, 100 °C and 120 °C) to determine which extraction temperature exhibits the optimum phytochemical profile, antioxidant and antidiabetic activities. The optimum temperature for PHWE extraction was determined at 80 °C and the biological activities of the different parts of okra (Inner Skin, Outer Skin and Seeds) were characterized using antioxidant (DPPH and ABTS), α-glucosidase and vasoprotective assays. Using PHWE, the different parts of okra displayed distinct phytochemical profiles, which consist of primarily polyphenolic compounds. The okra Seeds were shown to have the most antioxidant capacity and antidiabetic effects compared to other okra parts, likely to be attributed to their higher levels of polyphenolic compounds. Similarly, okra Seeds also reduced vascular inflammation by downregulating TNFα-stimulated and expression. Furthermore, metabolite profiling by LC/MS also provided evidence of the cytoprotective effect of okra Seeds in endothelial cells. Therefore, the use of PHWE may be an alternative approach for the environmentally friendly extraction and evaluation of plant extracts for functional food applications.
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http://dx.doi.org/10.3390/plants10081645DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8399463PMC
August 2021

Accelerated theta burst stimulation for the treatment of depression: A randomised controlled trial.

Brain Stimul 2021 Sep-Oct;14(5):1095-1105. Epub 2021 Jul 29.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Department of Psychiatry, Monash University, Camberwell, Victoria, Australia.

Introduction: Theta burst pattern repetitive transcranial magnetic stimulation (TBS) is increasingly applied to treat depression. TBS's brevity is well-suited to application in accelerated schedules. Sizeable trials of accelerated TBS are lacking; and optimal TBS parameters such as stimulation intensity are not established.

Methods: We conducted a three arm, single blind, randomised, controlled, multi-site trial comparing accelerated bilateral TBS applied at 80 % or 120 % of the resting motor threshold and left unilateral 10 Hz rTMS. 300 patients with treatment-resistant depression (TRD) were recruited. TBS arms applied 20 bilateral prefrontal TBS sessions over 10 days, while the rTMS arm applied 20 daily sessions of 10 Hz rTMS to the left prefrontal cortex over 4 weeks. Primary outcome was depression treatment response at week 4.

Results: The overall treatment response rate was 43.7 % and the remission rate was 28.2 %. There were no significant differences for response (p = 0.180) or remission (p = 0.316) across the three groups. Response rates between accelerated bilateral TBS applied at sub- and supra-threshold intensities were not significantly different (p = 0.319). Linear mixed model analysis showed a significant effect of time (p < 0.01), but not rTMS type (p = 0.680).

Conclusion: This is the largest accelerated bilateral TBS study to date and provides evidence that it is effective and safe in treating TRD. The accelerated application of TBS was not associated with more rapid antidepressant effects. Bilateral sequential TBS did not have superior antidepressant effect to unilateral 10 Hz rTMS. There was no significant difference in antidepressant efficacy between sub- and supra-threshold accelerated bilateral TBS.
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http://dx.doi.org/10.1016/j.brs.2021.07.018DOI Listing
July 2021

The stanford prostate cancer calculator: Development and external validation of online nomograms incorporating PIRADS scores to predict clinically significant prostate cancer.

Urol Oncol 2021 Jul 8. Epub 2021 Jul 8.

Department of Urology, Stanford University School of Medicine, Stanford, CA; Department of Radiology, Stanford University School of Medicine, Stanford, CA.

Background: While multiparametric MRI (mpMRI) has high sensitivity for detection of clinically significant prostate cancer (CSC), false positives and negatives remain common. Calculators that combine mpMRI with clinical variables can improve cancer risk assessment, while providing more accurate predictions for individual patients. We sought to create and externally validate nomograms incorporating Prostate Imaging Reporting and Data System (PIRADS) scores and clinical data to predict the presence of CSC in men of all biopsy backgrounds.

Methods: Data from 2125 men undergoing mpMRI and MR fusion biopsy from 2014 to 2018 at Stanford, Yale, and UAB were prospectively collected. Clinical data included age, race, PSA, biopsy status, PIRADS scores, and prostate volume. A nomogram predicting detection of CSC on targeted or systematic biopsy was created.

Results: Biopsy history, Prostate Specific Antigen (PSA) density, PIRADS score of 4 or 5, Caucasian race, and age were significant independent predictors. Our nomogram-the Stanford Prostate Cancer Calculator (SPCC)-combined these factors in a logistic regression to provide stronger predictive accuracy than PSA density or PIRADS alone. Validation of the SPCC using data from Yale and UAB yielded robust AUC values.

Conclusions: The SPCC combines pre-biopsy mpMRI with clinical data to more accurately predict the probability of CSC in men of all biopsy backgrounds. The SPCC demonstrates strong external generalizability with successful validation in two separate institutions. The calculator is available as a free web-based tool that can direct real-time clinical decision-making.
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http://dx.doi.org/10.1016/j.urolonc.2021.06.004DOI Listing
July 2021

Deep Learning Improves Speed and Accuracy of Prostate Gland Segmentations on Magnetic Resonance Imaging for Targeted Biopsy.

J Urol 2021 09 21;206(3):604-612. Epub 2021 Apr 21.

Department of Urology, Stanford University School of Medicine, Stanford, California.

Purpose: Targeted biopsy improves prostate cancer diagnosis. Accurate prostate segmentation on magnetic resonance imaging (MRI) is critical for accurate biopsy. Manual gland segmentation is tedious and time-consuming. We sought to develop a deep learning model to rapidly and accurately segment the prostate on MRI and to implement it as part of routine magnetic resonance-ultrasound fusion biopsy in the clinic.

Materials And Methods: A total of 905 subjects underwent multiparametric MRI at 29 institutions, followed by magnetic resonance-ultrasound fusion biopsy at 1 institution. A urologic oncology expert segmented the prostate on axial T2-weighted MRI scans. We trained a deep learning model, ProGNet, on 805 cases. We retrospectively tested ProGNet on 100 independent internal and 56 external cases. We prospectively implemented ProGNet as part of the fusion biopsy procedure for 11 patients. We compared ProGNet performance to 2 deep learning networks (U-Net and holistically-nested edge detector) and radiology technicians. The Dice similarity coefficient (DSC) was used to measure overlap with expert segmentations. DSCs were compared using paired t-tests.

Results: ProGNet (DSC=0.92) outperformed U-Net (DSC=0.85, p <0.0001), holistically-nested edge detector (DSC=0.80, p <0.0001), and radiology technicians (DSC=0.89, p <0.0001) in the retrospective internal test set. In the prospective cohort, ProGNet (DSC=0.93) outperformed radiology technicians (DSC=0.90, p <0.0001). ProGNet took just 35 seconds per case (vs 10 minutes for radiology technicians) to yield a clinically utilizable segmentation file.

Conclusions: This is the first study to employ a deep learning model for prostate gland segmentation for targeted biopsy in routine urological clinical practice, while reporting results and releasing the code online. Prospective and retrospective evaluations revealed increased speed and accuracy.
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http://dx.doi.org/10.1097/JU.0000000000001783DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8352566PMC
September 2021

Measurements using mammography and ultrasonography underestimate the size of high-volume ductal carcinoma in situ.

Am J Surg 2021 06 24;221(6):1167-1171. Epub 2021 Mar 24.

Providence Breast Centre, Mount Saint Joseph Hospital, 3080 Prince Edward Street, Vancouver, BC, V5T 3N4, Canada; Department of Surgery, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada. Electronic address:

Background: Surgical decisions for ductal carcinoma in situ (DCIS) are based on lesion sizes. This study aims to determine the accuracy of pre-operative imaging in estimating the size of DCIS.

Methods: This was a retrospective review of clinicopathologic data of patients treated for DCIS with breast conserving surgery (BCS) between 2012 and 2018. Mammographic and sonographic lesion sizes were compared with final pathology sizes.

Results: For the 152 lesions visible on mammography, mean size on imaging was significantly smaller when compared to final pathology (2.3 vs. 3.6 cm, p < 0.001). The mean difference of 1.3 cm was a significant underestimation with a correlation coefficient of 0.367 (p < 0.001). For 48 sonographically visible lesions, the radiologic size was significantly smaller than pathologic size (1.7 vs. 4.1 cm, p < 0.001), but the degree of underestimation was not significantly correlated (p = 0.379).

Conclusion: DCIS size was significantly underestimated by imaging. This must be taken into consideration during surgical planning.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.043DOI Listing
June 2021

Decreasing contralateral prophylactic mastectomy rates in average-risk women with unilateral breast cancer.

Am J Surg 2021 06 24;221(6):1172-1176. Epub 2021 Mar 24.

Providence Breast Centre, Mount Saint Joseph Hospital, 3080 Prince Edward Street, Vancouver, BC V5T 3N4, Canada; Department of Surgery, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada. Electronic address:

Background: Contralateral prophylactic mastectomy (CPM) is not recommended for average-risk women with breast cancer due to lack of evidence for survival benefit, yet recent studies demonstrate increasing CPM rates.

Methods: We identified patients with breast cancer treated with unilateral mastectomy (UM) with or without CPM. Rates of malignancy in CPM specimens and factors in CPM rates were assessed.

Results: From 2013 to 2017, 1353 patients had UM and 355 had CPM. Our institution's occult malignancy detection rate was 5.04%. CPM rates decreased from 31.6% to 17.3% (p < 0.001) over 5 years. Compared to patients receiving UM only, patients receiving CPMs had significantly higher reconstruction rates (p < 0.001), which did not significantly change over time (p = 0.551) and tended to be younger (p < 0.001).

Conclusions: Patients having UM have low risk of contralateral malignancy. CPM is associated with younger age and breast reconstruction, suggesting factors to identify for patient and provider education.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.040DOI Listing
June 2021

Upstage rate of radial scar/complex sclerosing lesion identified on core needle biopsy.

Am J Surg 2021 06 18;221(6):1177-1181. Epub 2021 Mar 18.

Providence Breast Centre, Mount Saint Joseph Hospital, 3080 Prince Edward Street, Vancouver, BC, V5T 3N4, Canada; Department of Surgery, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, Vancouver, BC, V5Z 1M9, Canada. Electronic address:

Background: We assessed the cancer upstage rate of Radial Scars (RS), and Complex Sclerosing Lesions (CSL), and risk-stratified lesions based on radiological and pathological features.

Methods: Characteristics of RS/CSL treated from 2013 to 2018 were examined for features associated with cancer.

Results: 78 RS/CSL were found on core needle biopsy (CNB) and surgically excised. 9 (11.5%) lesions were upstaged. Upstaged patients were older (66 vs 51, p = 0.033). More upstaged lesions were accompanied by a mass on both mammography (87.5% vs. 30.0%, p = 0.005) and ultrasound (100.0% vs. 62.8%, p = 0.043). 20.5% of lesions biopsied under ultrasound guidance with small needles (14-18G) were upstaged, but no lesions biopsied under stereotactic guidance with large needles (9-12 G) with vacuum assistance were upstaged (p = 0.009).

Conclusions: Excision of RS/CSL seen on CNB is warranted, especially if the patient is older, the CNB is performed under ultrasound guidance with small needles, or if a mass is present on imaging.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.029DOI Listing
June 2021

Effect of epidural analgesia on postoperative opioid requirements following elective laparotomies performed at Vancouver General Hospital.

Am J Surg 2021 06 17;221(6):1228-1232. Epub 2021 Mar 17.

Department of Surgery, Faculty of Medicine, University of British Columbia, 2775 Laurel Street, 5th Floor, Vancouver, British Columbia, V5Z 1M9, Canada. Electronic address:

Background: Enhanced recovery pathways aim to reduce postoperative opioid use and opioid-related complications. These pathways often include epidural analgesia (EA). This study examines postoperative opioid use after elective laparotomy with and without EA.

Methods: Retrospective chart review of elective laparotomies performed by General Surgery at a tertiary academic center during 2017 was completed. Primary outcome was postoperative opioid usage. Secondary outcomes were time to mobilization, duration of urinary catheterization and postoperative ileus.

Results: Among 236 patients, 213 (90%) received EA. There was no significant difference in mean total oral morphine equivalent (OME) usage between EA and non-EA groups. Mean OME use on postoperative day three was higher in the EA group (38.0 vs 22.4 mg, p = 0.02). On multivariate analysis, preoperative opioid use was associated with increased postoperative OME consumption (regression coefficient 147.5, p < 0.001).

Conclusions: In this cohort, epidural analgesia did not reduce postoperative opioid consumption.
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http://dx.doi.org/10.1016/j.amjsurg.2021.03.025DOI Listing
June 2021

Automated detection of aggressive and indolent prostate cancer on magnetic resonance imaging.

Med Phys 2021 Jun 3;48(6):2960-2972. Epub 2021 May 3.

Department of Radiology, Stanford University School of Medicine, Stanford, CA, 94305, USA.

Purpose: While multi-parametric magnetic resonance imaging (MRI) shows great promise in assisting with prostate cancer diagnosis and localization, subtle differences in appearance between cancer and normal tissue lead to many false positive and false negative interpretations by radiologists. We sought to automatically detect aggressive cancer (Gleason pattern 4) and indolent cancer (Gleason pattern 3) on a per-pixel basis on MRI to facilitate the targeting of aggressive cancer during biopsy.

Methods: We created the Stanford Prostate Cancer Network (SPCNet), a convolutional neural network model, trained to distinguish between aggressive cancer, indolent cancer, and normal tissue on MRI. Ground truth cancer labels were obtained by registering MRI with whole-mount digital histopathology images from patients who underwent radical prostatectomy. Before registration, these histopathology images were automatically annotated to show Gleason patterns on a per-pixel basis. The model was trained on data from 78 patients who underwent radical prostatectomy and 24 patients without prostate cancer. The model was evaluated on a pixel and lesion level in 322 patients, including six patients with normal MRI and no cancer, 23 patients who underwent radical prostatectomy, and 293 patients who underwent biopsy. Moreover, we assessed the ability of our model to detect clinically significant cancer (lesions with an aggressive component) and compared it to the performance of radiologists.

Results: Our model detected clinically significant lesions with an area under the receiver operator characteristics curve of 0.75 for radical prostatectomy patients and 0.80 for biopsy patients. Moreover, the model detected up to 18% of lesions missed by radiologists, and overall had a sensitivity and specificity that approached that of radiologists in detecting clinically significant cancer.

Conclusions: Our SPCNet model accurately detected aggressive prostate cancer. Its performance approached that of radiologists, and it helped identify lesions otherwise missed by radiologists. Our model has the potential to assist physicians in specifically targeting the aggressive component of prostate cancers during biopsy or focal treatment.
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http://dx.doi.org/10.1002/mp.14855DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8360053PMC
June 2021

Diabetes Attenuates the Contribution of Endogenous Nitric Oxide but Not Nitroxyl to Endothelium Dependent Relaxation of Rat Carotid Arteries.

Front Pharmacol 2020 21;11:585740. Epub 2021 Jan 21.

Drug, Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

Endothelial dysfunction is a major risk factor for several of the vascular complications of diabetes, including ischemic stroke. Nitroxyl (HNO), the one electron reduced and protonated form of nitric oxide (NO•), is resistant to scavenging by superoxide, but the role of HNO in diabetes mellitus associated endothelial dysfunction in the carotid artery remains unknown. To assess how diabetes affects the role of endogenous NO• and HNO in endothelium-dependent relaxation in rat isolated carotid arteries. Male Sprague Dawley rats were fed a high-fat-diet (HFD) for 2 weeks prior to administration of low dose streptozotocin (STZ; 35 mg/kg i. p./day) for 2 days. The HFD was continued for a further 12 weeks. Sham rats were fed standard chow and administered with citrate vehicle. After 14 weeks total, rats were anesthetized and carotid arteries collected to assess responses to the endothelium-dependent vasodilator, acetylcholine (ACh) by myography. The combination of calcium-activated potassium channel blockers, TRAM-34 (1 μmol/L) and apamin (1 μmol/L) was used to assess the contribution of endothelium-dependent hyperpolarization to relaxation. The corresponding contribution of NOS-derived nitrogen oxide species to relaxation was assessed using the combination of the NO• synthase inhibitor, L-NAME (200 μmol/L) and the soluble guanylate cyclase inhibitor ODQ (10 μmol/L). Lastly, L-cysteine (3 mmol/L), a selective HNO scavenger, and hydroxocobalamin (HXC; 100 μmol/L), a NO• scavenger, were used to distinguish between NO• and HNO-mediated relaxation. At study end, diabetic rats exhibited significantly retarded body weight gain and elevated blood glucose levels compared to sham rats. The sensitivity and the maximal relaxation response to ACh was significantly impaired in carotid arteries from diabetic rats, indicating endothelial dysfunction. The vasorelaxation evoked by ACh was abolished by L-NAME plus ODQ, but not affected by the apamin plus TRAM-34 combination, indicating that NOS-derived nitrogen oxide species are the predominant endothelium-derived vasodilators in sham and diabetic rat carotid arteries. The maximum relaxation to ACh was significantly decreased by L-cysteine in both sham and diabetic rats, whereas HXC attenuated ACh-induced relaxation only in sham rats, suggesting that diabetes impaired the contribution of NO•, whereas HNO-mediated vasorelaxation remained intact. Both NO• and HNO contribute to endothelium-dependent relaxation in carotid arteries. In diabetes, NO•-mediated relaxation is impaired, whereas HNO-mediated relaxation was preserved. The potential for preserved HNO activity under pathological conditions that are associated with oxidative stress indicates that HNO donors may represent a viable therapeutic approach to the treatment of vascular dysfunction.
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http://dx.doi.org/10.3389/fphar.2020.585740DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7944142PMC
January 2021

A Functional Taxonomy of Tumor Suppression in Oncogenic KRAS-Driven Lung Cancer.

Cancer Discov 2021 Jul 19;11(7):1754-1773. Epub 2021 Feb 19.

Department of Genetics, Stanford University School of Medicine, Stanford, California.

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer . Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative genetic analyses in autochthonous cancer models..
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http://dx.doi.org/10.1158/2159-8290.CD-20-1325DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8292166PMC
July 2021

Editorial: Inflammation in Cardiovascular Diseases: Role of the Endothelium and Emerging Therapeutics.

Front Pharmacol 2020 17;11:614387. Epub 2020 Nov 17.

Drug, Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, VIC, Australia.

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http://dx.doi.org/10.3389/fphar.2020.614387DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7751751PMC
November 2020

Effect of wound protectors on surgical site infection in patients undergoing whipple procedure.

HPB (Oxford) 2021 Aug 15;23(8):1185-1195. Epub 2020 Dec 15.

University of Calgary, Department of Surgery, Calgary, AB, Canada.

Background: Conflicting data persists for use of wound protectors in pancreatoduodenectomy (PD) to prevent surgical site infection (SSI). We aimed to examine, at a multi-institutional level, the effect of wound protectors on superficial or deep SSI following elective open PD.

Methods: The American College of Surgeons National Surgical Quality Improvement Program pancreatectomy procedure targeted participant use file was queried from 2016 to 2018. Planned open PD procedures were extracted. Univariable, multivariable, and propensity score matched analyses were conducted.

Results: 11,562 patients undergoing PD were evaluated, 27% of which used wound protectors. Wound protectors decreased superficial or deep SSI risk in all patients (5.7% vs. 9.5%, P < 0.001), patients who have (6.6% vs. 12.2%, P < 0.001) and who did not have (4.6% vs. 6.5%, P = 0.011) a biliary stent. Propensity score matched analysis confirms such results (OR = 0.56, 95% CI: 0.46-0.69, P < 0.001 overall, OR = 0.66, 95% CI: 0.46-0.95, P = 0.03 without biliary stent, OR = 0.57, 95% CI: 0.44-0.73, P < 0.001 with biliary stent).

Conclusions: Wound protectors reduce risk of superficial or deep SSI in patients undergoing PD, yet only a quarter of PD were associated with their use. This protective effect is seen whether patients have or have not had preoperative biliary stenting.
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http://dx.doi.org/10.1016/j.hpb.2020.11.1146DOI Listing
August 2021

Artificial intelligence for automatic cerebral ventricle segmentation and volume calculation: a clinical tool for the evaluation of pediatric hydrocephalus.

J Neurosurg Pediatr 2020 Dec 1:1-8. Epub 2020 Dec 1.

3Department of Radiology, Stanford University School of Medicine.

Objective: Imaging evaluation of the cerebral ventricles is important for clinical decision-making in pediatric hydrocephalus. Although quantitative measurements of ventricular size, over time, can facilitate objective comparison, automated tools for calculating ventricular volume are not structured for clinical use. The authors aimed to develop a fully automated deep learning (DL) model for pediatric cerebral ventricle segmentation and volume calculation for widespread clinical implementation across multiple hospitals.

Methods: The study cohort consisted of 200 children with obstructive hydrocephalus from four pediatric hospitals, along with 199 controls. Manual ventricle segmentation and volume calculation values served as "ground truth" data. An encoder-decoder convolutional neural network architecture, in which T2-weighted MR images were used as input, automatically delineated the ventricles and output volumetric measurements. On a held-out test set, segmentation accuracy was assessed using the Dice similarity coefficient (0 to 1) and volume calculation was assessed using linear regression. Model generalizability was evaluated on an external MRI data set from a fifth hospital. The DL model performance was compared against FreeSurfer research segmentation software.

Results: Model segmentation performed with an overall Dice score of 0.901 (0.946 in hydrocephalus, 0.856 in controls). The model generalized to external MR images from a fifth pediatric hospital with a Dice score of 0.926. The model was more accurate than FreeSurfer, with faster operating times (1.48 seconds per scan).

Conclusions: The authors present a DL model for automatic ventricle segmentation and volume calculation that is more accurate and rapid than currently available methods. With near-immediate volumetric output and reliable performance across institutional scanner types, this model can be adapted to the real-time clinical evaluation of hydrocephalus and improve clinician workflow.
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http://dx.doi.org/10.3171/2020.6.PEDS20251DOI Listing
December 2020

Deep Learning for Automated Delineation of Pediatric Cerebral Arteries on Pre-operative Brain Magnetic Resonance Imaging.

Front Surg 2020 26;7:517375. Epub 2020 Oct 26.

Department of Radiology, Stanford University, Stanford, CA, United States.

Surgical resection of brain tumors is often limited by adjacent critical structures such as blood vessels. Current intraoperative navigations systems are limited; most are based on two-dimensional (2D) guidance systems that require manual segmentation of any regions of interest (ROI; eloquent structures to avoid or tumor to resect). They additionally require time- and labor-intensive processing for any reconstruction steps. We aimed to develop a deep learning model for real-time fully automated segmentation of the intracranial vessels on preoperative non-angiogram imaging sequences. We identified 48 pediatric patients (10-months to 22-years old) with high resolution (0.5-1 mm axial thickness) isovolumetric, pre-operative T2 magnetic resonance images (MRIs). Twenty-eight patients had anatomically normal brains, and 20 patients had tumors or other lesions near the skull base. Manually segmented intracranial vessels (internal carotid, middle cerebral, anterior cerebral, posterior cerebral, and basilar arteries) served as ground truth labels. Patients were divided into 80/5/15% training/validation/testing sets. A modified Unet convolutional neural network (CNN) architecture implemented with 5 layers was trained to maximize the Dice coefficient, a measure of the correct overlap between the predicted vessels and ground truth labels. The model was able to delineate the intracranial vessels in a held-out test set of normal and tumor MRIs with an overall Dice coefficient of 0.75. While manual segmentation took 1-2 h per patient, model prediction took, on average, 8.3 s per patient. We present a deep learning model that can rapidly and automatically identify the intracranial vessels on pre-operative MRIs in patients with normal vascular anatomy and in patients with intracranial lesions. The methodology developed can be translated to other critical brain structures. This study will serve as a foundation for automated high-resolution ROI segmentation for three-dimensional (3D) modeling and integration into an augmented reality navigation platform.
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http://dx.doi.org/10.3389/fsurg.2020.517375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7649258PMC
October 2020

Antioxidant and Cytoprotective Effect of Quinoa (.) with Pressurized Hot Water Extraction (PHWE).

Antioxidants (Basel) 2020 Nov 11;9(11). Epub 2020 Nov 11.

Science, Math & Technology, Singapore University of Technology & Design, Singapore 487372, Singapore.

Quinoa is widely noted for its nutritional value. The seed is the main edible part of the plant and exists in at least three different colors: white, red and black. This study utilized a pressurized hot water extraction (PHWE) for the extraction of phytochemicals from quinoa. Chemical fingerprints with LC/UV and LC/MS using a targeted approach and pattern recognition tools were used to evaluate the quinoa extracts. The antioxidant properties for various types of quinoa were evaluated using DPPH assay, ABTS assay and the cytoprotective effect of quinoa extracts were investigated in HMEC-1 cell line. Distinctive chemical profiles obtained from black and red quinoa were well correlated with the antioxidant activities and cytoprotective effects. The combination of PHWE, chemical standardization with LC/UV and LC/MS, pattern recognition tools and biological assay provided an approach for the evaluation and eventual production of quinoa extracts for functional food.
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http://dx.doi.org/10.3390/antiox9111110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7697190PMC
November 2020

Efficacy, efficiency and safety of high-frequency repetitive transcranial magnetic stimulation applied more than once a day in depression: A systematic review.

J Affect Disord 2020 12 11;277:986-996. Epub 2020 Sep 11.

Monash Alfred Psychiatry Research Centre, Monash University, Melbourne VIC 3004, Australia; Epworth Centre for Innovation in Mental Health, Epworth HealthCare, Camberwell VIC 3124, Australia.

Background: Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for depression but a standard course can be time-consuming. Of all rTMS protocols, high-frequency rTMS (HF rTMS) is the most studied and applied in clinical settings. Little is known about applying multiple sessions of HF rTMS per day, in so-called accelerated schedules.

Methods: We systematically searched electronic records up to September 2019 for studies that applied HF rTMS in accelerated schedules to treat depression to review its efficacy, efficiency and safety. Treatment effect sizes of accelerated rTMS versus standard and sham rTMS were calculated from comparison studies and pooled to derive overall treatment effect.

Results: Of 1,361 records screened, 12 met review criteria. Qualitative synthesis suggested accelerated HF rTMS was equally effective as once-daily scheduling in treating depression. It is equivocal if accelerated HF rTMS results in more rapid antidepressant response. Accelerated HF rTMS was well-tolerated. The small number of studies suitable for quantitative analysis led to pooled effect sizes that did not reach statistical significance.

Limitations: There was an overall paucity of studies examining the accelerated application of HF rTMS and even fewer studies comparing accelerated HF rTMS with once-daily or sham rTMS.

Conclusion: Our review found comparable antidepressant efficacy between accelerated and once-daily HF rTMS. Between group differences in therapeutic effect sizes were not clinically meaningful. More studies investigating accelerated rTMS protocols are needed to validate its utility and guide clinical decision making.
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http://dx.doi.org/10.1016/j.jad.2020.09.035DOI Listing
December 2020

Burnout and psychological distress amongst Australian healthcare workers during the COVID-19 pandemic.

Australas Psychiatry 2021 02 12;29(1):26-30. Epub 2020 Oct 12.

Department of Psychiatry, The Alfred Hospital, Melbourne, VIC, Australia.

Objective: To examine psychological distress in healthcare workers (HCWs) during the COVID-19 pandemic in April-May 2020.

Methods: A cross-sectional survey examining demographic, employment and mental health characteristics of HCWs in a large metropolitan hospital in Australia.

Results: HCWs showed significant symptoms of moderate-severe level depression (21%), anxiety (20%) and posttraumatic stress disorder (PTSD; 29%), associated with burnout, prior psychiatric history, profession and resilience.

Conclusion: Despite low levels of COVID contact, moderate to high levels of psychological distress were reported. Continued monitoring and support for HCWs' mental well-being is warranted as the COVID-19 pandemic develops.
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http://dx.doi.org/10.1177/1039856220965045DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554409PMC
February 2021

A versatile system to record cell-cell interactions.

Elife 2020 10 7;9. Epub 2020 Oct 7.

Department of Genetics, Stanford University School of Medicine, Stanford, United States.

Cell-cell interactions influence all aspects of development, homeostasis, and disease. In cancer, interactions between cancer cells and stromal cells play a major role in nearly every step of carcinogenesis. Thus, the ability to record cell-cell interactions would facilitate mechanistic delineation of the role of the cancer microenvironment. Here, we describe GFP-based Touching Nexus (G-baToN) which relies upon nanobody-directed fluorescent protein transfer to enable sensitive and specific labeling of cells after cell-cell interactions. G-baToN is a generalizable system that enables physical contact-based labeling between various human and mouse cell types, including endothelial cell-pericyte, neuron-astrocyte, and diverse cancer-stromal cell pairs. A suite of orthogonal baToN tools enables reciprocal cell-cell labeling, interaction-dependent cargo transfer, and the identification of higher order cell-cell interactions across a wide range of cell types. The ability to track physically interacting cells with these simple and sensitive systems will greatly accelerate our understanding of the outputs of cell-cell interactions in cancer as well as across many biological processes.
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http://dx.doi.org/10.7554/eLife.61080DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7682987PMC
October 2020

Development and Prospective Validation of a Risk Calculator That Predicts a Low Risk Cohort for Atypical Ductal Hyperplasia Upstaging to Malignancy: Evidence for a Watch and Wait Strategy of a High-Risk Lesion.

Ann Surg Oncol 2020 Nov 24;27(12):4622-4627. Epub 2020 Jul 24.

University of British Columbia, Vancouver, Canada.

Background: Guidelines recommend surgical excision of atypical ductal hyperplasia (ADH) due to the concern of undersampling a potential malignancy on core needle biopsy (CNB). The purpose of this study was to determine clinical, radiological and pathological variables associated with ADH upstaging to cancer and to develop a predictive risk calculator capable of identifying women who have a low oncological risk of upstaging.

Methods: A prospectively collected database from a tertiary breast referral center was analyzed for women diagnosed with ADH on CNB between January 2013 to December 2017 who underwent surgical excision. CNB and surgical pathology reports were examined to determine rate of upstaging. The association between clinical, radiological and pathological variables were evaluated using regression analysis to determine predictors of ADH upstaging to cancer. Significant variables (p ≤ 0.05) identified on univariate analysis were assigned a score of "1" and were included in the ADH upstaging risk calculator.

Results: A total of 1986 patients underwent surgery for a high-risk lesion. We identified 318 (16.0%) patients who had ADH identified on their CNB who underwent surgery-of which 290 were included in our study. The upstage rate was 24.8%. Five variables were associated with upstaging and included in our calculator: (1) lesion > 5 mm on ultrasound; (2) lesion > 5 mm on mammogram; (3) one or more "high-risk" lesion(s) on CNB; (4) pathological suspicion for cancer and; (5) incomplete removal of calcifications on CNB. Patients with a score of 0 had a 2% risk of being upstaged to cancer and were deemed low risk with 17.2% of patients falling within this category.

Conclusions: Patients with ADH on CNB can be stratified into a low oncological cohort who have a 2% risk of being upstaged to carcinoma. In the future, these select patients may be counselled and potentially offered observation as an alternative to surgery.
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http://dx.doi.org/10.1245/s10434-020-08881-0DOI Listing
November 2020

The Histone Chaperone FACT Induces Cas9 Multi-turnover Behavior and Modifies Genome Manipulation in Human Cells.

Mol Cell 2020 07 29;79(2):221-233.e5. Epub 2020 Jun 29.

Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, CA 94720, USA; Innovative Genomics Institute, University of California, Berkeley, Berkeley, CA 94720, USA; Department of Biology, ETH Zürich, 8093 Zürich, Switzerland. Electronic address:

Cas9 is a prokaryotic RNA-guided DNA endonuclease that binds substrates tightly in vitro but turns over rapidly when used to manipulate genomes in eukaryotic cells. Little is known about the factors responsible for dislodging Cas9 or how they influence genome engineering. Unbiased detection through proximity labeling of transient protein interactions in cell-free Xenopus laevis egg extract identified the dimeric histone chaperone facilitates chromatin transcription (FACT) as an interactor of substrate-bound Cas9. FACT is both necessary and sufficient to displace dCas9, and FACT immunodepletion converts Cas9's activity from multi-turnover to single turnover. In human cells, FACT depletion extends dCas9 residence times, delays genome editing, and alters the balance between indel formation and homology-directed repair. FACT knockdown also increases epigenetic marking by dCas9-based transcriptional effectors with a concomitant enhancement of transcriptional modulation. FACT thus shapes the intrinsic cellular response to Cas9-based genome manipulation most likely by determining Cas9 residence times.
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http://dx.doi.org/10.1016/j.molcel.2020.06.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398558PMC
July 2020

Registration of presurgical MRI and histopathology images from radical prostatectomy via RAPSODI.

Med Phys 2020 Sep 18;47(9):4177-4188. Epub 2020 Jul 18.

Department of Radiology, School of Medicine, Stanford University, Stanford, CA, 94305, USA.

Purpose: Magnetic resonance imaging (MRI) has great potential to improve prostate cancer diagnosis; however, subtle differences between cancer and confounding conditions render prostate MRI interpretation challenging. The tissue collected from patients who undergo radical prostatectomy provides a unique opportunity to correlate histopathology images of the prostate with preoperative MRI to accurately map the extent of cancer from histopathology images onto MRI. We seek to develop an open-source, easy-to-use platform to align presurgical MRI and histopathology images of resected prostates in patients who underwent radical prostatectomy to create accurate cancer labels on MRI.

Methods: Here, we introduce RAdiology Pathology Spatial Open-Source multi-Dimensional Integration (RAPSODI), the first open-source framework for the registration of radiology and pathology images. RAPSODI relies on three steps. First, it creates a three-dimensional (3D) reconstruction of the histopathology specimen as a digital representation of the tissue before gross sectioning. Second, RAPSODI registers corresponding histopathology and MRI slices. Third, the optimized transforms are applied to the cancer regions outlined on the histopathology images to project those labels onto the preoperative MRI.

Results: We tested RAPSODI in a phantom study where we simulated various conditions, for example, tissue shrinkage during fixation. Our experiments showed that RAPSODI can reliably correct multiple artifacts. We also evaluated RAPSODI in 157 patients from three institutions that underwent radical prostatectomy and have very different pathology processing and scanning. RAPSODI was evaluated in 907 corresponding histpathology-MRI slices and achieved a Dice coefficient of 0.97 ± 0.01 for the prostate, a Hausdorff distance of 1.99 ± 0.70 mm for the prostate boundary, a urethra deviation of 3.09 ± 1.45 mm, and a landmark deviation of 2.80 ± 0.59 mm between registered histopathology images and MRI.

Conclusion: Our robust framework successfully mapped the extent of cancer from histopathology slices onto MRI providing labels from training machine learning methods to detect cancer on MRI.
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http://dx.doi.org/10.1002/mp.14337DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7586964PMC
September 2020

Determining when endoscopic ultrasound changes management for patients with pancreatic cystic neoplasms.

Am J Surg 2021 04 18;221(4):813-818. Epub 2020 Apr 18.

University of British Columbia, 2329, West Mall, Vancouver, BC, V6T 1Z4, Canada. Electronic address:

Introduction: Pancreatic cystic neoplasms (PCNs) are being incidentally detected at an increased rate due to increased CT and MRI usage. EUS is an emerging tool that can differentiate between benign and malignant features of pancreatic cysts. We hoped to identify the specific cross-sectional imaging findings and patient characteristics that warrant EUS referral.

Methods: We conducted a retrospective case-control chart review, evaluating patients, who were diagnosed with pancreatic cysts and underwent EUS between January 1, 2010 and December 31, 2017.

Results: EUS was found to change management when CT imaging found cyst size > 4 cm (OR = 4.07, p < 0.01), cyst size > 3 cm (OR = 3.79, p < 0.001) and associated solid component to the cyst (OR = 5.95, p < 0.01). Additionally, patient characteristics, including age less than 50 years, male sex and 10-pack year smoking history were significantly associated with EUS change in management.

Discussion: Our findings suggest that EUS referral should be coordinated based on the findings of specific HRFs, with support from high risk patient characteristics, rather than the accumulation of multiple HRFs, as suggested by existing guidelines.
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http://dx.doi.org/10.1016/j.amjsurg.2020.03.036DOI Listing
April 2021

Comparison of Treatment, Cost, and Survival in Patients With Metastatic Colorectal Cancer in Western Washington, United States, and British Columbia, Canada.

JCO Oncol Pract 2020 05 16;16(5):e425-e432. Epub 2020 Apr 16.

University of Washington School of Medicine, Seattle, WA.

Purpose: Few studies have directly compared health care utilization, costs, and outcomes between patients treated in the US multipayer health system and Canada's single-payer system. Using cancer registry and claims data, we assessed treatment types, costs, and survival for patients with metastatic colorectal cancer (mCRC) in Western Washington State (WW) and British Columbia (BC).

Materials And Methods: Patients age ≥ 18 years diagnosed with mCRC in 2010 and later were identified from the BC Cancer database and a regional database linking WW SEER to claims from Medicare and two large commercial insurers. Demographics, treatment characteristics, costs of systemic therapy, and survival data were obtained from these databases and compared between the two regions.

Results: A total of 1,592 patients from BC and 901 from WW were included in the study. Median age was similar (BC, 66 years; WW, 63 years), but patients in BC were more likely to be male (57.1% 51.2%; ≤ .01) and to have de novo metastatic disease (61.0% 38.3%; ≤ .01). The use of radiation therapy was similar between regions (BC, 31.2%; WW, 33.9%; = .18), but primary tumor resection was more common in BC (74.1% 66.3%; ≤ .01) as was hepatic metastasectomy (12.4% 2.3%; ≤ .01). Similar percentages of patients received systemic therapy (BC, 68.8%; WW, 67.1%; = .40), but costs were significantly higher for first-line systemic therapy in WW ($6,226 $15,792 per patient per month; ≤ .01). Median overall survival was similar (BC, 16.9 months; WW, 18 months).

Conclusion: Cost of systemic therapy for mCRC was significantly higher for patients in WW than in BC, but this did not translate to a difference in overall survival.
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http://dx.doi.org/10.1200/JOP.19.00719DOI Listing
May 2020

Depressive symptom trajectories associated with standard and accelerated rTMS.

Brain Stimul 2020 May - Jun;13(3):850-857. Epub 2020 Feb 21.

Epworth Centre for Innovation in Mental Health, Epworth Healthcare and Monash University Central Clinical School, Camberwell, Victoria, Australia. Electronic address:

Background: To determine if an accelerated rTMS protocol results in distinct depressive symptom response trajectories, compared to a standard rTMS protocol. We also sought to validate previous analyses that identified distinct depressive symptom response trajectories with rTMS treatment using an external dataset.

Method: Data from two recent clinical trials comparing accelerated rTMS protocol delivered to the left dorsolateral prefrontal cortex (DLPFC) with standard once-daily rTMS protocol were used to identify depressive symptom response trajectories. The accelerated protocol in Trial 1 was conventional 10-Hz rTMS, while Trial 2 employed intermittent theta burst stimulation (iTBS). Participants were adult outpatients (18-70 years old) with bipolar or unipolar depression and moderate-severe depression (Montgomery Asberg Depression Rating Scale score >19) who had failed to respond to adequate courses of two different antidepressants. We used group-based trajectory modeling to identify MADRS response trajectories, and regression techniques adjusting for baseline depressive symptom severity to determine the association between treatment protocol and depressive symptom response trajectory.

Results: Treatment outcomes of 189 participants were analysed. We identified four distinct response trajectories: "nonresponse" (N = 59; 30.7%), "minimal response" (N = 65; 34.1%), "higher symptoms, response" (N = 26; 14.6%), "lower symptoms, response" (N = 39; 20.6%). We failed to find an association between rTMS protocol (accelerated vs standard) with depressive symptom response trajectory even after adjusting for baseline depressive symptom severity.

Conclusion: The accelerated rTMS protocol in this study did not impact depressive symptom response trajectories. This work provides further confirmatory evidence that there are distinct depressive symptom response trajectories with rTMS delivered to the left DLPFC.

Australian New Zealand Clinical Trials Registry: ACTRN12616000443493 and ACTRN12613000044729.
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http://dx.doi.org/10.1016/j.brs.2020.02.021DOI Listing
November 2020

Safe and successful treatment of depression with electroconvulsive therapy in a patient with implanted spinal cord stimulators.

Brain Stimul 2020 Jul - Aug;13(4):955-956. Epub 2020 Apr 10.

Epworth Centre for Innovation in Mental Health, Epworth HealthCare and Department of Psychiatry, Monash University, Camberwell, Victoria, Australia; Epworth Camberwell, Epworth HealthCare, Camberwell, Victoria, Australia.

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http://dx.doi.org/10.1016/j.brs.2020.04.004DOI Listing
April 2020
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