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1. CleftGAN: Adapting A Style-Based Generative Adversarial Network To Create Images Depicting Cleft Lip Deformity

Author

Hayajneh, Abdullah, Serpedin, Erchin, Shaqfeh, Mohammad, Glass, Graeme, and Stotland, Mitchell A.

Subjects
Computer Science - Computer Vision and Pattern Recognition, Computer Science - Machine Learning
Abstract

A major obstacle when attempting to train a machine learning system to evaluate facial clefts is the scarcity of large datasets of high-quality, ethics board-approved patient images. In response, we have built a deep learning-based cleft lip generator designed to produce an almost unlimited number of artificial images exhibiting high-fidelity facsimiles of cleft lip with wide variation. We undertook a transfer learning protocol testing different versions of StyleGAN-ADA (a generative adversarial network image generator incorporating adaptive data augmentation (ADA)) as the base model. Training images depicting a variety of cleft deformities were pre-processed to adjust for rotation, scaling, color adjustment and background blurring. The ADA modification of the primary algorithm permitted construction of our new generative model while requiring input of a relatively small number of training images. Adversarial training was carried out using 514 unique frontal photographs of cleft-affected faces to adapt a pre-trained model based on 70,000 normal faces. The Frechet Inception Distance (FID) was used to measure the similarity of the newly generated facial images to the cleft training dataset, while Perceptual Path Length (PPL) and the novel Divergence Index of Severity Histograms (DISH) measures were also used to assess the performance of the image generator that we dub CleftGAN. We found that StyleGAN3 with translation invariance (StyleGAN3-t) performed optimally as a base model. Generated images achieved a low FID reflecting a close similarity to our training input dataset of genuine cleft images. Low PPL and DISH measures reflected a smooth and semantically valid interpolation of images through the transfer learning process and a similar distribution of severity in the training and generated images, respectively.

Published
2023

2. MicroRNA and Protein Cargos of Human Limbal Epithelial Cell-Derived Exosomes and Their Regulatory Roles in Limbal Stromal Cells of Diabetic and Non-Diabetic Corneas.

Author

Verma, Nagendra, Khare, Drirh, Poe, Adam, Amador, Cynthia, Ghiam, Sean, Fealy, Andrew, Ebrahimi, Shaghaiegh, Shadrokh, Odelia, Song, Xue-Ying, Santiskulvong, Chintda, Mastali, Mitra, Parker, Sarah, Stotland, Aleksandr, Van Eyk, Jennifer, Saghizadeh, Mehrnoosh, and Ljubimov, Alexander

Subjects
RNA-seq, cellular crosstalk, diabetic cornea, exosome, extracellular vesicles, limbal epithelial cells, limbal stem cells, mesenchymal stem cells, miRNA, proteomics, Humans, MicroRNAs, Exosomes, Limbus Corneae, Cornea, Diabetes Mellitus, Epithelial Cells, Stromal Cells, Cell Communication
Abstract

Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.

Published
2023

3. Plasma Metabolomics Predicts Chemotherapy Response in Advanced Pancreatic Cancer

Author

Muranaka, Hayato, Hendifar, Andrew, Osipov, Arsen, Moshayedi, Natalie, Placencio-Hickok, Veronica, Tatonetti, Nicholas, Stotland, Aleksandr, Parker, Sarah, Van Eyk, Jennifer, Pandol, Stephen J, Bhowmick, Neil A, and Gong, Jun

Subjects
Medical Biochemistry and Metabolomics, Biomedical and Clinical Sciences, Oncology and Carcinogenesis, Clinical Research, Rare Diseases, Orphan Drug, Pancreatic Cancer, Cancer, Nutrition, Digestive Diseases, Good Health and Well Being, FOLFIRINOX, chemotherapy, gemcitabine/nab-paclitaxel, pancreatic cancer, plasma metabolomics, Oncology and carcinogenesis
Abstract

Pancreatic cancer (PC) is one of the deadliest cancers. Developing biomarkers for chemotherapeutic response prediction is crucial for improving the dismal prognosis of advanced-PC patients (pts). To evaluate the potential of plasma metabolites as predictors of the response to chemotherapy for PC patients, we analyzed plasma metabolites using high-performance liquid chromatography-mass spectrometry from 31 cachectic, advanced-PC subjects enrolled into the PANCAX-1 (NCT02400398) prospective trial to receive a jejunal tube peptide-based diet for 12 weeks and who were planned for palliative chemotherapy. Overall, there were statistically significant differences in the levels of intermediates of multiple metabolic pathways in pts with a partial response (PR)/stable disease (SD) vs. progressive disease (PD) to chemotherapy. When stratified by the chemotherapy regimen, PD after 5-fluorouracil-based chemotherapy (e.g., FOLFIRINOX) was associated with decreased levels of amino acids (AAs). For gemcitabine-based chemotherapy (e.g., gemcitabine/nab-paclitaxel), PD was associated with increased levels of intermediates of glycolysis, the TCA cycle, nucleoside synthesis, and bile acid metabolism. These results demonstrate the feasibility of plasma metabolomics in a prospective cohort of advanced-PC patients for assessing the effect of enteral feeding as their primary source of nutrition. Metabolic signatures unique to FOLFIRINOX or gemcitabine/nab-paclitaxel may be predictive of a patient's response and warrant further study.

Published
2023

4. Unsupervised Anomaly Appraisal of Cleft Faces Using a StyleGAN2-based Model Adaptation Technique

Author

Hayajneh, Abdullah, Shaqfeh, Mohammad, Serpedin, Erchin, and Stotland, Mitchell A.

Subjects
Computer Science - Computer Vision and Pattern Recognition
Abstract

This paper presents a novel machine learning framework to consistently detect, localize and rate congenital cleft lip anomalies in human faces. The goal is to provide a universal, objective measure of facial differences and reconstructive surgical outcomes that matches human judgments. The proposed method employs the StyleGAN2 generative adversarial network with model adaptation to produce normalized transformations of cleft-affected faces in order to allow for subsequent measurement of deformity using a pixel-wise subtraction approach. The complete pipeline of the proposed framework consists of the following steps: image preprocessing, face normalization, color transformation, morphological erosion, heat-map generation and abnormality scoring. Heatmaps that finely discern anatomic anomalies are proposed by exploiting the features of the considered framework. The proposed framework is validated through computer simulations and surveys containing human ratings. The anomaly scores yielded by the proposed computer model correlate closely with the human ratings of facial differences, leading to 0.942 Pearson's r score., Comment: All the face images used in this study were publicly available on the internet

Published
2022

5. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Author

Yepuri, Gautham, Ramirez, Lisa M., Theophall, Gregory G., Reverdatto, Sergei V., Quadri, Nosirudeen, Hasan, Syed Nurul, Bu, Lei, Thiagarajan, Devi, Wilson, Robin, Díez, Raquel López, Gugger, Paul F., Mangar, Kaamashri, Narula, Navneet, Katz, Stuart D., Zhou, Boyan, Li, Huilin, Stotland, Aleksandr B., Gottlieb, Roberta A., Schmidt, Ann Marie, Shekhtman, Alexander, and Ramasamy, Ravichandran

Published
2023
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6. DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress

Author

Gautham Yepuri, Lisa M. Ramirez, Gregory G. Theophall, Sergei V. Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F. Gugger, Kaamashri Mangar, Navneet Narula, Stuart D. Katz, Boyan Zhou, Huilin Li, Aleksandr B. Stotland, Roberta A. Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, and Ravichandran Ramasamy

Subjects
Science
Abstract

Abstract Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

Published
2023
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7. Impact of Surgical Rejuvenation on Visual Processing and Character Attribution of Faces

Author

Thanapoom Boonipat, MD, Nathan S. D. Hebel, BS, Daniel Shapiro, MD, and Mitchell A. Stotland, MD

Subjects
Surgery, RD1-811
Abstract

Background:. This study considers observers’ reflexive responses to the rejuvenated face, and how instinctive responses relate to subjective judgment. We investigated observers’ reflexive perception of faces both pre and post surgical intervention during the early stages of visual processing. Subjective character attribution for all test images was also assessed by the same observers. Method:. Forty frontal facial images of 20 patients portraying the pre- and postoperative high superficial musculoaponeurotic system facelift along with variable concomitant procedures were studied. Nineteen lookzone regions were mapped post hoc onto each image. Forty observers examined the images, whereas an eye-tracking camera recorded their eye movements. Visual fixation data were recorded and analyzed. Observers also rated each image on the basis of five elemental positive character attributes. Results:. A statistically coherent but nonsignificant (P > 0.05) trend was identified with the surgical intervention resulting in greater attention being paid to the central triangle region of the face with reduction in attention to the facial periphery. Facial rejuvenation significantly increased the subjective character ratings of all five positively valenced attributes tested. Average age estimate of the photos decreased significantly from 54 to 48.6 years (true average age of 57.4 years). Conclusions:. We provide data illustrating both reflexive and subjective responses to facial rejuvenation. Observers reported a more favorable impression of the treated faces and evaluated them as being younger than their true age. A trend was detected for increased visual fixation of the central facial region following rejuvenation. Interpretation of these findings and indication for further research is provided.

Published
2023
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8. Poland-Möbius syndrome: a case report implicating a novel mutation of the PLXND1 gene and literature review

Author

Graeme E. Glass, Shiyas Mohammedali, Bran Sivakumar, Mitchell A. Stotland, Faisal Abdulkader, Debra O. Prosser, and Donald R. Love

Subjects
Möbius, Moebius, Poland syndrome, Symbrachydactyly, Pectoralis hypoplasia, Case report, Pediatrics, RJ1-570
Abstract

Abstract Background Möbius (Moebius) and Poland’s syndromes are two rare congenital syndromes characterized by non-progressive bilateral (and often asymmetric) dysfunction of the 6th and 7th cranial nerves and hypoplasia of the pectoral muscles associated with chest wall and upper limb anomalies respectively. Manifest simultaneously as Poland-Möbius (Poland-Moebius) syndrome, debate continues as to whether this is a distinct nosological entity or represents phenotypic variation as part of a spectrum of disorders of rhomboencephalic development. Etiological hypotheses implicate both genetic and environmental factors. The PLXND1 gene codes for a protein expressed in the fetal central nervous system and vascular endothelium and is thus involved in embryonic neurogenesis and vasculogenesis. It is located at chromosome region 3q21-q22, a locus of interest for Möbius syndrome. Case presentation We present the first report of a patient with Poland-Möbius syndrome and a mutation in the PLXND1 gene. A child with Poland-Möbius syndrome and a maternally inherited missense variant (NM_015103.2:ex14:c.2890G > Ap.V964M) in the PLXND1 gene is described. In order to contextualize these findings, the literature was examined to identify other confirmed cases of Poland-Möbius syndrome for which genetic data were available. Fourteen additional cases of Poland-Möbius syndrome with genetic studies are described in the literature. None implicated the PLXND1 gene which has previously been implicated in isolated Möbius syndrome. Conclusions This report provides further evidence in support of a role for PLXND1 mutations in Möbius syndrome and reasserts the nosological link between Möbius and Poland’s syndromes. Level of evidence Level V, Descriptive Study.

Published
2022
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11. MicroRNA and Protein Cargos of Human Limbal Epithelial Cell-Derived Exosomes and Their Regulatory Roles in Limbal Stromal Cells of Diabetic and Non-Diabetic Corneas

Author

Nagendra Verma, Drirh Khare, Adam J. Poe, Cynthia Amador, Sean Ghiam, Andrew Fealy, Shaghaiegh Ebrahimi, Odelia Shadrokh, Xue-Ying Song, Chintda Santiskulvong, Mitra Mastali, Sarah Parker, Aleksandr Stotland, Jennifer E. Van Eyk, Alexander V. Ljubimov, and Mehrnoosh Saghizadeh

Subjects
diabetic cornea, extracellular vesicles, exosome, cellular crosstalk, miRNA, limbal stem cells, Cytology, QH573-671
Abstract

Epithelial and stromal/mesenchymal limbal stem cells contribute to corneal homeostasis and cell renewal. Extracellular vesicles (EVs), including exosomes (Exos), can be paracrine mediators of intercellular communication. Previously, we described cargos and regulatory roles of limbal stromal cell (LSC)-derived Exos in non-diabetic (N) and diabetic (DM) limbal epithelial cells (LECs). Presently, we quantify the miRNA and proteome profiles of human LEC-derived Exos and their regulatory roles in N- and DM-LSC. We revealed some miRNA and protein differences in DM vs. N-LEC-derived Exos’ cargos, including proteins involved in Exo biogenesis and packaging that may affect Exo production and ultimately cellular crosstalk and corneal function. Treatment by N-Exos, but not by DM-Exos, enhanced wound healing in cultured N-LSCs and increased proliferation rates in N and DM LSCs vs. corresponding untreated (control) cells. N-Exos-treated LSCs reduced the keratocyte markers ALDH3A1 and lumican and increased the MSC markers CD73, CD90, and CD105 vs. control LSCs. These being opposite to the changes quantified in wounded LSCs. Overall, N-LEC Exos have a more pronounced effect on LSC wound healing, proliferation, and stem cell marker expression than DM-LEC Exos. This suggests that regulatory miRNA and protein cargo differences in DM- vs. N-LEC-derived Exos could contribute to the disease state.

Published
2023
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12. Parents of Children with Cleft Lip Exhibit Heightened Visual Attention to the Perioral Area

Author

Israa Abuelezz, MSc, Marwa K. Qaraqe, PhD, and Mitchell A. Stotland, MD, MS, FRCSC

Subjects
Surgery, RD1-811
Abstract

Background:. Following high-quality surgical repair, children born with a cleft lip anomaly may still display lasting visual differences. We exposed control adults and parents of affected children to images of children with cleft deformity and compared their visual tracking patterns. The protocol investigated whether parental exposure to secondary cleft deformity heightens or diminishes visual attraction to this type of structural facial variation. Method:. Twenty participants (10 control adults, 10 parents of affected children) assessed 40 colored images of children's faces while their eye movements were tracked. Twenty-four control images and 16 repaired cleft lip images were displayed to observers. Nine bilateral facial aesthetic zones were considered as regions of interest. Percentage of time visually fixating within each region, and statistical differences in fixation duration percentage between the two participant groups and across the bilateral regions of interest were analyzed. Results:. While both groups of observers directed more visual attention to the nasal and oral regions of the cleft images than control images, parents of children with cleft lip spent significantly more time fixating on these areas (25% and 24% of the time, respectively) than did unaffected adults (14.6% and 19.3%; P < 0.001). Conclusions:. These results demonstrate that parents of cleft lip children exhibit heightened attention to this type of facial difference relative to the naive observer. These findings highlight that observer profile can meaningfully influence the perception of a facial deformity. Awareness of this information may enhance communication between surgeon and parents of an affected child by providing added insight into parental perspective.

Published
2023
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15. Impaired renal reserve contributes to preeclampsia via the kynurenine and soluble fms–like tyrosine kinase 1 pathway

Author

Vincent Dupont, Anders H. Berg, Michifumi Yamashita, Chengqun Huang, Ambart E. Covarrubias, Shafat Ali, Aleksandr Stotland, Jennifer E. Van Eyk, Belinda Jim, Ravi Thadhani, and S. Ananth Karumanchi

Subjects
Nephrology, Reproductive biology, Medicine
Abstract

To understand how kidney donation leads to an increased risk of preeclampsia, we studied pregnant outbred mice with prior uninephrectomy and compared them with sham-operated littermates carrying both kidneys. During pregnancy, uninephrectomized (UNx) mice failed to achieve a physiological increase in the glomerular filtration rate and during late gestation developed hypertension, albuminuria, glomerular endothelial damage, and excess placental production of soluble fms–like tyrosine kinase 1 (sFLT1), an antiangiogenic protein implicated in the pathogenesis of preeclampsia. Maternal hypertension in UNx mice was associated with low plasma volumes, an increased rate of fetal resorption, impaired spiral artery remodeling, and placental ischemia. To evaluate potential mechanisms, we studied plasma metabolite changes using mass spectrometry and noted that l-kynurenine, a metabolite of l-tryptophan, was upregulated approximately 3-fold during pregnancy when compared with prepregnant concentrations in the same animals, consistent with prior reports suggesting a protective role for l-kynurenine in placental health. However, UNx mice failed to show upregulation of l-kynurenine during pregnancy; furthermore, when UNx mice were fed l-kynurenine in drinking water throughout pregnancy, their preeclampsia-like state was rescued, including a reversal of placental ischemia and normalization of sFLT1 levels. In aggregate, we provide a mechanistic basis for how impaired renal reserve and the resulting failure to upregulate l-kynurenine during pregnancy can lead to impaired placentation, placental hypoperfusion, an antiangiogenic state, and subsequent preeclampsia.

Published
2022
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16. Toward a Universal Measure of Facial Difference Using Two Novel Machine Learning Models

Author

Abdulrahman Takiddin, MSc, Mohammad Shaqfeh, PhD, Osman Boyaci, MSc, Erchin Serpedin, PhD, and Mitchell A. Stotland, MD, MS, FRCSC

Subjects
Surgery, RD1-811
Abstract

Background:. A sensitive, objective, and universally accepted method of measuring facial deformity does not currently exist. Two distinct machine learning methods are described here that produce numerical scores reflecting the level of deformity of a wide variety of facial conditions. Methods:. The first proposed technique utilizes an object detector based on a cascade function of Haar features. The model was trained using a dataset of 200,000 normal faces, as well as a collection of images devoid of faces. With the model trained to detect normal faces, the face detector confidence score was shown to function as a reliable gauge of facial abnormality. The second technique developed is based on a deep learning architecture of a convolutional autoencoder trained with the same rich dataset of normal faces. Because the convolutional autoencoder regenerates images disposed toward their training dataset (ie, normal faces), we utilized its reconstruction error as an indicator of facial abnormality. Scores generated by both methods were compared with human ratings obtained using a survey of 80 subjects evaluating 60 images depicting a range of facial deformities [rating from 1 (abnormal) to 7 (normal)]. Results:. The machine scores were highly correlated to the average human score, with overall Pearson’s correlation coefficient exceeding 0.96 (P < 0.00001). Both methods were computationally efficient, reporting results within 3 seconds. Conclusions:. These models show promise for adaptation into a clinically accessible handheld tool. It is anticipated that ongoing development of this technology will facilitate multicenter collaboration and comparison of outcomes between conditions, techniques, operators, and institutions.

Published
2022
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18. Thin and superthin free flaps: An innovative approach to pediatric extremity reconstruction.

Author

Glass, Graeme E., Staruch, Robert MT, Sivakumar, Branavan, and Stotland, Mitchell A.

Abstract

Published standards for the management of open extremity fractures have improved limb salvage, fracture union, and deep infection rates, but the aesthetic and functional importance of our flap choices has been overlooked. Thin and superthin free flaps exhibit advantages over traditional free flaps in some situations but have seldom been reported in children. The aim of this paper is to present our experience of thin and superthin free flaps in pediatric extremity reconstruction. Children (≤13 years) who underwent soft tissue reconstruction using a thin and superthin free flap following major extremity trauma are presented. Five patients (5 flaps) met the inclusion criteria. The median age was 9 (range 6–13). There were 3 Gustilo IIIB open fractures and 2 multiplanar degloving injuries. The median mangled extremity severity score (MESS) was 4 (range 2–6). The median time from injury to definitive soft tissue closure was 72 h (range 28–120 h). Four anterolateral thigh (ALT) flaps were raised as thin flaps, and 1 superficial circumflex iliac artery perforator (SCIP) was raised as a superthin flap. There was one re-exploration owing to venous congestion, and a second venous anastomosis was performed to enhance flap drainage. The same ALT flap exhibited necrosis at one margin, which was debrided and grafted before discharge. There were no other flap complications. No flap-related secondary surgeries were required. Thin and superthin free flaps are viable options in pediatric extremity reconstruction. They exhibit excellent aesthetic and functional contouring when a slender fasciocutaneous flap is needed, especially when body habitus renders traditional options unfavorable. [ABSTRACT FROM AUTHOR]

Published
2022
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21. Correcting the scientific record on abortion and mental health outcomes

Author

Littell, Julia H, Abel, Kathryn M, Biggs, M Antonia, Blum, Robert W, Foster, Diana Greene, Haddad, Lisa B, Major, Brenda, Munk-Olsen, Trine, Polis, Chelsea B, Robinson, Gail Erlick, Rocca, Corinne H, Russo, Nancy Felipe, Steinberg, Julia R, Stewart, Donna E, Stotland, Nada Logan, Upadhyay, Ushma D, and van Ditzhuijzen, Jenneke

Published
2024
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23. Reproductive Rights and Women’s Mental Health

Author

Stotland, Nada Logan

Abstract

Reproductive rights, including access to comprehensive reproductive health care, are essential to the well-being of women and society. The Dobbs decision of the US Supreme Court has greatly exacerbated the confusion, the stress, and the loss of services. Psychiatrists need to know and communicate the strong scientific evidence of the advantages of sex education, contraception, abortion, and bodily autonomy and to help patients process their feelings and make informed decisions about their own care.

Published
2023
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25. Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial

Author

Auer, Rebecca C, Ott, Michael, Karanicolas, Paul, Brackstone, Muriel Rebecca, Ashamalla, Shady, Weaver, Joel, Tagalakis, Vicky, Boutros, Marylise, Stotland, Peter, Marulanda, Antonio Caycedo, Moloo, Husein, Jayaraman, Shiva, Patel, Suni, Le Gal, Grégoire, Spadafora, Silvana, MacLellan, Steven, Trottier, Daniel, Jonker, Derek, Asmis, Timothy, Mallick, Ranjeeta, Pecarskie, Amanda, Ramsay, Tim, and Carrier, Marc

Abstract

ObjectiveTo determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer.DesignMulticentre, open label, randomised controlled trial.Settings12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020.Participants614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection.InterventionsRandom assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only.Main outcome measuresPrimary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population.ResultsThe trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1).ConclusionsExtended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups.Trial registrationClinicalTrials.gov NCT01455831.

Published
2022
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26. Response to May and Bethune Comment on 'Transanal total mesorectal excision for abdominoperineal resection is associated with poor oncological outcomes in rectal cancer patients: a word of caution from a multicentric Canadian cohort study'.

Author

Stotland P and Caycedo-Marulanda A

Subjects
Humans, Canada, Treatment Outcome, Male, Female, Cohort Studies, Multicenter Studies as Topic, Perineum surgery, Transanal Endoscopic Surgery methods, Aged, Middle Aged, Rectal Neoplasms surgery, Proctectomy methods, Proctectomy adverse effects
Published
2024
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27. 2023 Canadian Surgery Forum: Sept. 20-23, 2023.

Author

Brière R, Émond M, Benhamed A, Blanchard PG, Drolet S, Habashi R, Golbon B, Shellenberger J, Pasternak J, Merchant S, Shellenberger J, La J, Sawhney M, Brogly S, Cadili L, Horkoff M, Ainslie S, Demetrick J, Chai B, Wiseman K, Hwang H, Alhumoud Z, Salem A, Lau R, Aw K, Nessim C, Gawad N, Alibhai K, Towaij C, Doan D, Raîche I, Valji R, Turner S, Balmes PN, Hwang H, Hameed SM, Tan JGK, Wijesuriya R, Tan JGK, Hew NLC, Wijesuriya R, Lund M, Hawel J, Gregor J, Leslie K, Lenet T, McIsaac D, Hallet J, Jerath A, Lalu M, Nicholls S, Presseau J, Tinmouth A, Verret M, Wherrett C, Fergusson D, Martel G, Sharma S, McKechnie T, Talwar G, Patel J, Heimann L, Doumouras A, Hong D, Eskicioglu C, Wang C, Guo M, Huang L, Sun S, Davis N, Wang J, Skulsky S, Sikora L, Raîche I, Son HJ, Gee D, Gomez D, Jung J, Selvam R, Seguin N, Zhang L, Lacaille-Ranger A, Sikora L, McIsaac D, Moloo H, Follett A, Holly, Organ M, Pace D, Balvardi S, Kaneva P, Semsar-Kazerooni K, Mueller C, Vassiliou M, Al Mahroos M, Fiore JF Jr, Schwartzman K, Feldman L, Guo M, Karimuddin A, Liu GP, Crump T, Sutherland J, Hickey K, Bonisteel EM, Umali J, Dogar I, Warden G, Boone D, Mathieson A, Hogan M, Pace D, Seguin N, Moloo H, Li Y, Best G, Leong R, Wiseman S, Alaoui AA, Hajjar R, Wassef E, Metellus DS, Dagbert F, Loungnarath R, Ratelle R, Schwenter F, Debroux É, Wassef R, Gagnon-Konamna M, Pomp A, Richard CS, Sebajang H, Alaoui AA, Hajjar R, Dagbert F, Loungnarath R, Sebajang H, Ratelle R, Schwenter F, Debroux É, Wassef R, Gagnon-Konamna M, Pomp A, Santos MM, Richard CS, Shi G, Leung R, Lim C, Knowles S, Parmar S, Wang C, Debru E, Mohamed F, Anakin M, Lee Y, Samarasinghe Y, Khamar J, Petrisor B, McKechnie T, Eskicioglu C, Yang I, Mughal HN, Bhugio M, Gok MA, Khan UA, Fernandes AR, Spence R, Porter G, Hoogerboord CM, Neumann K, Pillar M, Guo M, Manhas N, Melck A, Kazi T, McKechnie T, Jessani G, Heimann L, Lee Y, Hong D, Eskicioglu C, McKechnie T, Tessier L, Archer V, Park L, Cohen D, Parpia S, Bhandari M, Dionne J, 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2023
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28. Efficacy and safety of extended duration to perioperative thromboprophylaxis with low molecular weight heparin on disease-free survival after surgical resection of colorectal cancer (PERIOP-01): multicentre, open label, randomised controlled trial.

Author

Auer RC, Ott M, Karanicolas P, Brackstone MR, Ashamalla S, Weaver J, Tagalakis V, Boutros M, Stotland P, Marulanda AC, Moloo H, Jayaraman S, Patel S, Le Gal G, Spadafora S, MacLellan S, Trottier D, Jonker D, Asmis T, Mallick R, Pecarskie A, Ramsay T, and Carrier M

Subjects
Adolescent, Adult, Anticoagulants adverse effects, Disease-Free Survival, Heparin, Low-Molecular-Weight adverse effects, Humans, Neoplasm Recurrence, Local, Ontario, Postoperative Complications prevention & control, Postoperative Hemorrhage, Tinzaparin, Colorectal Neoplasms surgery, Venous Thromboembolism etiology
Abstract

Objective: To determine the efficacy and safety of extended duration perioperative thromboprophylaxis by low molecular weight heparin when assessing disease-free survival in patients undergoing resection for colorectal cancer., Design: Multicentre, open label, randomised controlled trial., Settings: 12 hospitals in Quebec and Ontario, Canada, between 25 October 2011 and 31 December 2020., Participants: 614 adults (age ≥18 years) were eligible with pathologically confirmed invasive adenocarcinoma of the colon or rectum, no evidence of metastatic disease, a haemoglobin concentration of ≥8 g/dL, and were scheduled to undergo surgical resection., Interventions: Random assignment to extended duration thromboprophylaxis using daily subcutaneous tinzaparin at 4500 IU, beginning at decision to operate and continuing for 56 days postoperatively, compared with in-patient postoperative thromboprophylaxis only., Main Outcome Measures: Primary outcome was disease-free survival at three years, defined as survival without locoregional recurrence, distant metastases, second primary (same cancer), second primary (other cancer), or death. Secondary outcomes included venous thromboembolism, postoperative major bleeding complications, and five year overall survival. Analyses were done in the intention-to-treat population., Results: The trial stopped recruitment prematurely after the interim analysis for futility. The primary outcome occurred in 235 (77%) of 307 patients in the extended duration group and in 243 (79%) of 307 patients in the in-hospital thromboprophylaxis group (hazard ratio 1.1, 95% confidence interval 0.90 to 1.33; P=0.4). Postoperative venous thromboembolism occurred in five patients (2%) in the extended duration group and in four patients (1%) in the in-hospital thromboprophylaxis group (P=0.8). Major surgery related bleeding in the first postoperative week was reported in one person (<1%) in the extended duration and in six people (2%) in the in-hospital thromboprophylaxis group (P=0.1). No difference was noted for overall survival at five years in 272 (89%) patients in the extended duration group and 280 (91%) patients in the in-hospital thromboprophylaxis group (hazard ratio 1.12; 95% confidence interval 0.72 to 1.76; P=0.1)., Conclusions: Extended duration to perioperative anticoagulation with tinzaparin did not improve disease-free survival or overall survival in patients with colorectal cancer undergoing surgical resection compared with in-patient postoperative thromboprophylaxis alone. The incidences of venous thromboembolism and postoperative major bleeding were low and similar between groups., Trial Registration: ClinicalTrials.gov NCT01455831., Competing Interests: Competing interests: All authors have completed the ICMJE uniform disclosure form at www.icmje.org/disclosure-of-interest/ and declare: support from the Canadian Institute of Health Research, Ottawa Hospital Academic Medical Organisation, and Leo Pharma, as well as through generous patient donations through the Ottawa Hospital Foundation for the submitted work. MC has received research funding from BMS, Pfizer, and Leo Pharma, and honorariums from Bayer, Pfizer, BMS, Servier, and Leo Pharma. VT received consulting honorariums from Pfizer-BMS and Daiichi-Sankyo and has received research funding from Sanofi. MB received consulting honorariums from Johnson and Johnson. ACM received consulting honorariums from Johnson and Johnson. MO received consulting honorariums from Johnson and Johnson Ethicon. All other authors declare no competing interests., (© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Published
2022
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