Honors & Awards
Best Basic/Translational Abstract, Holman Research Day, Stanford University Department of Surgery (2020)
The Resident Research Award, Stanford Department of Surgery (2020)
NIH Loan Repayment Program (LRP) - Renewal, National Institutes of Health (2019-2020)
NIH NCI F32, National Institutes of Health (2019 - present)
Best Basic/Translational Oral Presentation, Holman Research Day, Stanford University Department of Surgery (2019)
Excellence in Research Award, Surgical Oncology, American College of Surgeons (ACS) Clinical Congress (2019)
The Resident Research Award, Stanford Department of Surgery (2019)
Best Basic/Translational Oral Presentation, Holman Research Day, Stanford University Department of Surgery (2018)
Excellence in Research Award, Surgical Oncology, American College of Surgeons (ACS) Clinical Congress (2018)
Advanced Residency Training at Stanford (ARTS) Program, Stanford University School of Medicine (2017 - present)
NIH Loan Repayment Program (LRP), National Institutes of Health (2017 - 2019)
Resident Research Award, American College of Surgeons (ACS) (2017 - 2019)
Fall Courses Travel Award, Association of Academic Surgery (AAS) (2017)
The Donald R. Cooper, M.D. Award for Excellence in Surgery, Drexel University College of Medicine (2015)
Women’s Health Scholar, Drexel University College of Medicine (2015)
Fulbright Research Scholarship, U.S. Department of State (2010)
FLAS Graduate Fellowship, U.S. Department of Education (2009)
Firestone Medal for Excellence in Undergraduate Research, Stanford University (2008)
Honors, Human Biology, Stanford University (2008)
Current Clinical Interests
- Surgical Oncology
- Wound Healing
Michael Longaker, Longaker Laboratory (7/1/2017)
Global variation in postoperative mortality and complications after cancer surgery: a multicentre, prospective cohort study in 82 countries
2021; 397 (10272): 387–97
80% of individuals with cancer will require a surgical procedure, yet little comparative data exist on early outcomes in low-income and middle-income countries (LMICs). We compared postoperative outcomes in breast, colorectal, and gastric cancer surgery in hospitals worldwide, focusing on the effect of disease stage and complications on postoperative mortality.This was a multicentre, international prospective cohort study of consecutive adult patients undergoing surgery for primary breast, colorectal, or gastric cancer requiring a skin incision done under general or neuraxial anaesthesia. The primary outcome was death or major complication within 30 days of surgery. Multilevel logistic regression determined relationships within three-level nested models of patients within hospitals and countries. Hospital-level infrastructure effects were explored with three-way mediation analyses. This study was registered with ClinicalTrials.gov, NCT03471494.Between April 1, 2018, and Jan 31, 2019, we enrolled 15 958 patients from 428 hospitals in 82 countries (high income 9106 patients, 31 countries; upper-middle income 2721 patients, 23 countries; or lower-middle income 4131 patients, 28 countries). Patients in LMICs presented with more advanced disease compared with patients in high-income countries. 30-day mortality was higher for gastric cancer in low-income or lower-middle-income countries (adjusted odds ratio 3·72, 95% CI 1·70-8·16) and for colorectal cancer in low-income or lower-middle-income countries (4·59, 2·39-8·80) and upper-middle-income countries (2·06, 1·11-3·83). No difference in 30-day mortality was seen in breast cancer. The proportion of patients who died after a major complication was greatest in low-income or lower-middle-income countries (6·15, 3·26-11·59) and upper-middle-income countries (3·89, 2·08-7·29). Postoperative death after complications was partly explained by patient factors (60%) and partly by hospital or country (40%). The absence of consistently available postoperative care facilities was associated with seven to 10 more deaths per 100 major complications in LMICs. Cancer stage alone explained little of the early variation in mortality or postoperative complications.Higher levels of mortality after cancer surgery in LMICs was not fully explained by later presentation of disease. The capacity to rescue patients from surgical complications is a tangible opportunity for meaningful intervention. Early death after cancer surgery might be reduced by policies focusing on strengthening perioperative care systems to detect and intervene in common complications.National Institute for Health Research Global Health Research Unit.
View details for DOI 10.1016/S0140-6736(21)00001-5
View details for Web of Science ID 000614227700026
View details for PubMedID 33485461
View details for PubMedCentralID PMC7846817
- Wounds Inhibit Tumor Growth In Vivo ANNALS OF SURGERY 2021; 273 (1): 173–80
Proceed with Caution: Mouse Deep Digit Flexor Tendon Injury Model.
Plastic and reconstructive surgery. Global open
2021; 9 (1): e3359
The purpose of this study was to determine the feasibility of using mouse models for translational study of flexor tendon repair and reconstruction.Quantitative data detailing the gross anatomy, biomechanical characteristics, and microscopic structure of the deep digit flexor tendon (DDF) of the mouse hindpaw were obtained. Histological characterization of the DDF and the anatomy of the digit in the mouse hindpaw are detailed. Biomechanical testing determined the load-to-failure, stress, elastic modulus, and the site of tendon failure.In gross anatomy, the origins and insertions of the mouse deep digit flexor tendon are similar to those of the human digit, surrounded by a synovial sheath that is only 1- to 2-cells thick. A neurovascular network runs on each side of the digit outside the synovial sheath, but does not clearly penetrate it. The thickness of the DDF is 0.14 ± 0.03 mm and the width is 0.3 ± 0.03 mm. The thickness of the DDF is less than that of 9-0 nylon needle. The mean failure force of the deep flexor tendon was 2.79 ± 0.53N.The gross anatomy of the mouse hindpaw digit is similar to that of the human digit except for key differences seen in the synovial sheath and vascular supply. The dimensions of the mouse DDF make it challenging to create a clinically translatable repair model using currently available surgical techniques. Despite the similarities between the human and mouse anatomy, and the powerful basic science tools available in murine models, mice are an unreliable model for assessing flexor tendon injury and repair.
View details for DOI 10.1097/GOX.0000000000003359
View details for PubMedID 33552814
View details for PubMedCentralID PMC7859083
Prrx1 Fibroblasts Represent a Pro-fibrotic Lineage in the Mouse Ventral Dermis.
2020; 33 (6): 108356
Fibroblast heterogeneity has been shown within the unwounded mouse dorsal dermis, with fibroblast subpopulations being identified according to anatomical location and embryonic lineage. Using lineage tracing, we demonstrate that paired related homeobox 1 (Prrx1)-expressing fibroblasts are responsible for acute and chronic fibroses in the ventral dermis. Single-cell transcriptomics further corroborated the inherent fibrotic characteristics of Prrx1 fibroblasts during wound repair. In summary, we identify and characterize a fibroblast subpopulation in the mouse ventral dermis with intrinsic scar-forming potential.
View details for DOI 10.1016/j.celrep.2020.108356
View details for PubMedID 33176144
Ectoderm-Derived Wnt and Hedgehog Signaling Drive Digit Tip Regeneration
ELSEVIER SCIENCE INC. 2020: S186
View details for Web of Science ID 000582792300339
Detection, Scoring, and Classification of Solid Organ Fibroses with Machine Learning Analysis
ELSEVIER SCIENCE INC. 2020: S222
View details for Web of Science ID 000582792300403
A Surgical Model for Investigating the Role of Creeping Fat in Intestinal Fibrosis
ELSEVIER SCIENCE INC. 2020: S50–S51
View details for Web of Science ID 000582792300070
Wounds Heal by Tissue-Resident Fibroblast Progenitors that Proliferate Polyclonally and Mechanoresponsively
ELSEVIER SCIENCE INC. 2020: S236–S237
View details for Web of Science ID 000582792300433
Peripheral Motor Neuron Activity Influences over Local Sarcoma Progression
ELSEVIER SCIENCE INC. 2020: S230–S231
View details for Web of Science ID 000582792300421
Characterization of Diabetic and Non-Diabetic Foot Ulcers Using Single-Cell RNA-Sequencing.
2020; 11 (9)
Background: Recent advances in high-throughput single-cell sequencing technologies have led to their increasingly widespread adoption for clinical applications. However, challenges associated with tissue viability, cell yield, and delayed time-to-capture have created unique obstacles for data processing. Chronic wounds, in particular, represent some of the most difficult target specimens, due to the significant amount of fibrinous debris, extracellular matrix components, and non-viable cells inherent in tissue routinely obtained from debridement. Methods: Here, we examined the feasibility of single cell RNA sequencing (scRNA-seq) analysis to evaluate human chronic wound samples acquired in the clinic, subjected to prolonged cold ischemia time, and processed without FACS sorting. Wound tissue from human diabetic and non-diabetic plantar foot ulcers were evaluated using an optimized 10X Genomics scRNA-seq platform and analyzed using a modified data pipeline designed for low-yield specimens. Cell subtypes were identified informatically and their distributions and transcriptional programs were compared between diabetic and non-diabetic tissue. Results: 139,000 diabetic and non-diabetic wound cells were delivered for 10X capture after either 90 or 180 min of cold ischemia time. cDNA library concentrations were 858.7 and 364.7 pg/L, respectively, prior to sequencing. Among all barcoded fragments, we found that 83.5% successfully aligned to the human transcriptome and 68% met the minimum cell viability threshold. The average mitochondrial mRNA fraction was 8.5% for diabetic cells and 6.6% for non-diabetic cells, correlating with differences in cold ischemia time. A total of 384 individual cells were of sufficient quality for subsequent analyses; from this cell pool, we identified transcriptionally-distinct cell clusters whose gene expression profiles corresponded to fibroblasts, keratinocytes, neutrophils, monocytes, and endothelial cells. Fibroblast subpopulations with differing fibrotic potentials were identified, and their distributions were found to be altered in diabetic vs. non-diabetic cells. Conclusions: scRNA-seq of clinical wound samples can be achieved using minor modifications to standard processing protocols and data analysis methods. This simple approach can capture widespread transcriptional differences between diabetic and non-diabetic tissue obtained from matched wound locations.
View details for DOI 10.3390/mi11090815
View details for PubMedID 32872278
- Doxycycline Reduces Scar Thickness and Improves Collagen Architecture ANNALS OF SURGERY 2020; 272 (1): 183–93
- Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review PLASTIC AND RECONSTRUCTIVE SURGERY-GLOBAL OPEN 2020; 8 (6)
Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment.
2020; 12 (5)
Pancreatic cancer is the 4th leading cause of cancer deaths in the United States. The pancreatic cancer phenotype is primarily a consequence of oncogenes disturbing the resident pancreas parenchymal cell repair program. Many solid tumor types including pancreatic cancer have severe tumor fibrosis called desmoplasia. Desmoplastic stroma is coopted by the tumor as a support structure and CAFs aid in tumor growth, invasion, and metastases. This stroma is caused by cancer associated fibroblasts (CAFs), which lay down extensive connective tissue in and around the tumor cells. CAFs represent a heterogeneous population of cells that produce various paracrine molecules such as transforming growth factor-beta (TGF-beta) and platelet derived growth factors (PDGFs) that aid tumor growth, local invasion, and development of metastases. The hard, fibrotic shell of desmoplasia serves as a barrier to the infiltration of both chemo- and immunotherapy drugs and host immune cells to the tumor. Although there have been recent improvements in chemotherapy and surgical techniques for management of pancreatic cancer, the majority of patients will die from this disease. Therefore, new treatment strategies are clearly needed. CAFs represent an under-explored potential therapeutic target. This paper discusses what we know about the role of CAFs in pancreatic cancer cell growth, invasion, and metastases. Additionally, we present different strategies that are being and could be explored as anti-CAF treatments for pancreatic cancer.
View details for DOI 10.3390/cancers12051347
View details for PubMedID 32466266
Fibroblast Heterogeneity in and Its Implications for Plastic and Reconstructive Surgery: A Basic Science Review.
Plastic and reconstructive surgery. Global open
2020; 8 (6): e2927
Fibroblasts' integral role in tissue development, maintenance, and disease represents a fast-growing field of basic science research. Although fibroblasts were long thought to be a homogeneous cell population, recent research has illuminated the unforeseen complexity of these cells, giving rise to the rapidly expanding research field of "fibroblast heterogeneity." Fibroblasts play a critical role in states of tissue fibrosis such as skin scarring, which affects hundreds of millions of patients annually and causes severe aesthetic, developmental, and functional morbidity. Beyond scarring, major organ fibrosis is an enormous public health concern responsible for nearly half of all deaths in the United States. Because fibrosis is a conserved response to tissue damage in all organs, the study of fibroblasts throughout the body may help us to understand their role in the conditions most relevant to plastic and reconstructive surgery-for instance, skin scarring (eg, from burns, traumatic lacerations, or surgical incisions), "pathological" scarring (hypertrophic scars, keloids), and capsular contracture. Here, we present a basic science review of fibroblast heterogeneity in wound healing, cancer, organ fibrosis, and human dermal architecture. The field of fibroblast heterogeneity is young, and many of the insights discussed have yet to be translated clinically. However, plastic surgeons stand in a unique position to bridge these discoveries into clinical realities. We hope this information can spur readers to consider both what questions in plastic surgery can be studied from the lens of fibroblast heterogeneity, and how these preclinical insights can be translated to improving care of our patients.
View details for DOI 10.1097/GOX.0000000000002927
View details for PubMedID 32766071
View details for PubMedCentralID PMC7339369
Elucidating the fundamental fibrotic processes driving abdominal adhesion formation.
2020; 11 (1): 4061
Adhesions are fibrotic scars that form between abdominal organs following surgery or infection, and may cause bowel obstruction, chronic pain, or infertility. Our understanding of adhesion biology is limited, which explains the paucity of anti-adhesion treatments. Here we present a systematic analysis of mouse and human adhesion tissues. First, we show that adhesions derive primarily from the visceral peritoneum, consistent with our clinical experience that adhesions form primarily following laparotomy rather than laparoscopy. Second, adhesions are formed by poly-clonal proliferating tissue-resident fibroblasts. Third, using single cell RNA-sequencing, we identify heterogeneity among adhesion fibroblasts, which is more pronounced at early timepoints. Fourth, JUN promotes adhesion formation and results in upregulation of PDGFRA expression. With JUN suppression, adhesion formation is diminished. Our findings support JUN as a therapeutic target to prevent adhesions. An anti-JUN therapy that could be applied intra-operatively to prevent adhesion formation could dramatically improve the lives of surgical patients.
View details for DOI 10.1038/s41467-020-17883-1
View details for PubMedID 32792541
Evaluation of Outcomes Following Surgery for Locally Advanced Pancreatic Neuroendocrine Tumors.
JAMA network open
2020; 3 (11): e2024318
Although outcome of surgical resection of liver metastases from pancreatic neuroendocrine tumors (PNETs) has been extensively studied, little is known about surgery for locally advanced PNETs; it was listed recently by the European neuroendocrine tumor society as a major unmet need.To evaluate the outcome of patients who underwent surgery for locally aggressive PNETs.This retrospective single-center case series reviewed consecutive patients who underwent resection of T3/T4 PNETs at a single academic institution. Data collection occurred from 2003 to 2018. Data analysis was performed in August 2019.Disease-free survival (primary outcome) and overall mortality (secondary outcome) were assessed with Kaplan-Meier analysis. Recurrence risk (secondary outcome, defined as identification of tumor recurrence on imaging) was assessed with Cox proportional hazard models adjusting for covariates.In this case series, 99 patients with locally advanced nondistant metastatic PNET (56 men [57%]) with a mean (SEM) age of 57.0 (1.4) years and a mean (SEM) follow-up of 5.3 (0.1) years underwent surgically aggressive resections. Of those, 4 patients (4%) underwent preoperative neoadjuvant treatment (including peptide receptor radionuclide therapy and chemotherapy); 18 patients (18%) underwent pancreaticoduodenectomy, 68 patients (69%) had distal or subtotal pancreatic resection, 10 patients (10%) had total resection, and 3 patients (3%) had other pancreatic procedures. Additional organ resection was required in 86 patients (87%): spleen (71 patients [71%]), major blood vessel (17 patients [17%]), bowel (2 patients [2%]), stomach (4 patients [4%]), and kidney (2 patients [2%]). Five-year disease-free survival was 61% (61 patients) and 5-year overall survival was 91% (91 patients). Of those living, 75 patients (76%) had an Eastern Cooperative Oncology Group score of less than or equal to 1 at last followup. Lymph node involvement (HR, 7.66; 95% CI, 2.78-21.12; P < .001), additional organ resected (HR, 6.15; 95% CI, 1.61-23.55; P = .008), and male sex (HR, 3.77; 95% CI, 1.68-8.97; P = .003) were associated with increased risk of recurrence. Functional tumors had a lower risk of recurrence (HR, 0.23; CI, 0.06-0.89; P = .03). Required resection of blood vessels was not associated with a significant increase recurrence risk.In this case series, positive lymph node involvement and resection of organs with tumor involvement were associated with an increased recurrence risk. These subgroups may require adjuvant systemic treatment. These findings suggest that patients with locally advanced PNETs who undergo surgical resection have excellent disease-free and overall survival.
View details for DOI 10.1001/jamanetworkopen.2020.24318
View details for PubMedID 33146734
- Breast Surgery Anesthesiologist's Manual of Surgical Procedures Dr. Richard A. Jaffe. 2020; 6
- Management of Pancreatic Islet Cell Tumors Excluding Gastrinoma Current Surgical Therapy John Cameron. 2020; 13
Endogenous Breast Cancer Shows Clonal Proliferation of Cancer Associated Fibroblasts at Primary Tumor and Metastatic Sites
ELSEVIER SCIENCE INC. 2019: S262
View details for Web of Science ID 000492740900510
Role of the Skeletal Stem Cell in Achilles Tendon to Bone Interface Healing
ELSEVIER SCIENCE INC. 2019: S228–S229
View details for Web of Science ID 000492740900438
Effect of Mechanical Loading on Clonality of Injured Flexor Tendons after Repair
ELSEVIER SCIENCE INC. 2019: S221
View details for Web of Science ID 000492740900423
Fibroblast Proliferation in Wound Healing Is Clonal and Focal Adhesion Kinase-Dependent
ELSEVIER SCIENCE INC. 2019: S223
View details for Web of Science ID 000492740900427
Regenerative Skin Healing Through Targeted Modulation of Engrailed1-Negative Fibroblasts
ELSEVIER SCIENCE INC. 2019: S228
View details for Web of Science ID 000492740900437
Cancer-Associated Fibroblasts Persist but Show Decreased Fibroblast Activation Protein Expression after Neoadjuvant Chemotherapy in Human Pancreatic Ductal Adenocarcinoma
ELSEVIER SCIENCE INC. 2019: S257–S258
View details for Web of Science ID 000492740900501
Tumors Co-Opt Fibroblast Wound Healing Capacity
ELSEVIER SCIENCE INC. 2019: S231–S232
View details for Web of Science ID 000492740900444
Wounds Inhibit Tumor Growth In Vivo.
Annals of surgery
OBJECTIVE: The aim of this study was to determine the interaction of full thickness excisional wounds and tumors in vivo.SUMMARY OF BACKGROUND DATA: Tumors have been described as wounds that do not heal due to similarities in stromal composition. On the basis of observations of slowed tumor growth after ulceration, we hypothesized that full thickness excisional wounds would inhibit tumor progression in vivo.METHODS: To determine the interaction of tumors and wounds, we developed a tumor xenograft/allograft (human head and neck squamous cell carcinoma SAS/mouse breast carcinoma 4T1) wound mouse model. We examined tumor growth with varying temporospatial placement of tumors and wounds or ischemic flap. In addition, we developed a tumor/wound parabiosis model to understand the ability of tumors and wounds to recruit circulating progenitor cells.RESULTS: Tumor growth inhibition by full thickness excisional wounds was dose-dependent, maintained by sequential wounding, and relative to distance. This effect was recapitulated by placement of an ischemic flap directly adjacent to a xenograft tumor. Using a parabiosis model, we demonstrated that a healing wound was able to recruit significantly more circulating progenitor cells than a growing tumor. Tumor inhibition by wound was unaffected by presence of an immune response in an immunocompetent model using a mammary carcinoma. Utilizing functional proteomics, we identified 100 proteins differentially expressed in tumors and wounds.CONCLUSION: Full thickness excisional wounds have the ability to inhibit tumor growth in vivo. Further research may provide an exact mechanism for this remarkable finding and new advances in wound healing and tumor biology.
View details for PubMedID 30829705
Management of Ileal Neuroendocrine Tumors with Liver Metastases.
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
Assessment of treating metastatic ileal neuroendocrine tumors (NETs) with complete resection of primary tumor, nodal and liver metastases, plus administration of long-acting somatostatin analogues (SSAs).A prospective database was queried for patients with ileal or pancreatic NETs with pathology-confirmed liver metastases and tumor somatostatin receptors. Patients did not have MEN-1 and had no previous treatment. The impacts of SSA treatment on the primary outcome of survival and secondary outcome of progression-free survival were assessed with Kaplan-Meier analysis. Log rank test was used to compare overall and progression-free survival among groups.Seventeen ileal NET patients and 36 pancreatic NET patients who underwent surgical resection between 2001 and 2018, who had pathology-confirmed liver metastases and confirmed tumor somatostatin receptors, did not have MEN-1, and had no previous treatment were identified. Median follow-up for patients with ileal NETs was 80 months (range 0-197 months) and 32 months (range 1-182 months) for pancreatic NETs. Five-year survival was 93% and 72% for ileal and pancreatic NET, respectively. Progression-free 5-year survival was 70% and 36% for ileal and pancreatic NET, respectively. Overall 5-year survival for pNETs was greater in those patients treated with SSA (79%) compared to those who underwent surgery alone (34%, p < 0.01). The average ECOG score was low for surviving patients with ileal (0.15) and pancreatic NET (0.73) indicating a good quality of life.Resection of primary lymph node and liver metastatic ileal or pancreatic NETs followed with continued SSAs is associated with an excellent progression-free and overall survival and minimal side effects.
View details for DOI 10.1007/s11605-019-04309-7
View details for PubMedID 31346887
Skeletal Stem Cell-Schwann Cell Circuitry in Mandibular Repair.
2019; 28 (11): 2757–66.e5
Regenerative paradigms exhibit nerve dependency, including regeneration of the mouse digit tip and salamander limb. Denervation impairs regeneration and produces morphological aberrancy in these contexts, but the direct effect of innervation on the stem and progenitor cells enacting these processes is unknown. We devised a model to examine nerve dependency of the mouse skeletal stem cell (mSSC), the progenitor responsible for skeletal development and repair. We show that after inferior alveolar denervation, mandibular bone repair is compromised because of functional defects in mSSCs. We present mSSC reliance on paracrine factors secreted by Schwann cells as the underlying mechanism, with partial rescue of the denervated phenotype by Schwann cell transplantation and by Schwann-derived growth factors. This work sheds light on the nerve dependency of mSSCs and has implications for clinical treatment of mandibular defects.
View details for DOI 10.1016/j.celrep.2019.08.021
View details for PubMedID 31509739
Flexor Tendon: Development, Healing, Adhesion Formation, and Contributing Growth Factors.
Plastic and reconstructive surgery
2019; 144 (4): 639e–647e
Management of flexor tendon injuries of the hand remains a major clinical problem. Even with intricate repair, adhesion formation remains a common complication. Significant progress has been made to better understand the mechanisms of healing and adhesion formation. However, there has been slow progress in the clinical prevention and reversal of flexor tendon adhesions. The goal of this article is to discuss recent literature relating to tendon development, tendon healing, and adhesion formation to identify areas in need of further research. Additional research is needed to understand and compare the molecular, cellular, and genetic mechanisms involved in flexor tendon morphogenesis, postoperative healing, and mechanical loading. Such knowledge is critical to determine how to improve repair outcomes and identify new therapeutic strategies to promote tissue regeneration and prevent adhesion formation.
View details for DOI 10.1097/PRS.0000000000006048
View details for PubMedID 31568303
A Clearing Technique to Enhance Endogenous Fluorophores in Skin and Soft Tissue.
2019; 9 (1): 15791
Fluorescent proteins are used extensively in transgenic animal models to label and study specific cell and tissue types. Expression of these proteins can be imaged and analyzed using fluorescent and confocal microscopy. Conventional confocal microscopes cannot penetrate through tissue more than 4-6 μm thick. Tissue clearing procedures overcome this challenge by rendering thick specimens into translucent tissue. However, most tissue clearing techniques do not satisfactorily preserve expression of endogenous fluorophores. Using simple adjustments to the BABB (Benzoic Acid Benzyl Benzoate) clearing methodology, preservation of fluorophore expression can be maintained. Modified BABB tissue clearing is a reliable technique to clear skin and soft tissue specimens for the study of dermal biology, wound healing and fibrotic pathologies.
View details for DOI 10.1038/s41598-019-50359-x
View details for PubMedID 31673001
Wound healing and fibrosis: current stem cell therapies.
2019; 59 (S1): 884–92
Scarring is a result of the wound healing response and causes tissue dysfunction after injury. This process is readily evident in the skin, but also occurs internally across organ systems in the form of fibrosis. Stem cells are crucial to the innate tissue healing response and, as such, present a possible modality to therapeutically promote regenerative healing while minimizing scaring. In this review, the cellular basis of scaring and fibrosis is examined. Current stem cell therapies under exploration for skin wound healing and internal organ fibrosis are discussed. While most therapeutic approaches rely on the direct application of progenitor-type cells to injured tissue to promote healing, novel strategies to manipulate the scarring response are also presented. As our understanding of developmental and stem cell biology continues to increase, therapies to encourage regeneration of healthy functional tissue after damage secondary to injury or disease will continue to expand.
View details for PubMedID 30737822
Doxycycline Reduces Scar Thickness and Improves Collagen Architecture.
Annals of surgery
OBJECTIVE: To investigate the effects of local doxycycline administration on skin scarring.BACKGROUND: Skin scarring represents a major source of morbidity for surgical patients. Doxycycline, a tetracycline antibiotic with off-target effects on the extracellular matrix, has demonstrated antifibrotic effects in multiple organs. However, doxycycline's potential effects on skin scarring have not been explored in vivo.METHODS: Female C57BL/6J mice underwent dorsal wounding following an established splinted excisional skin wounding model. Doxycycline was administered by local injection into the wound base following injury. Wounds were harvested upon complete wound closure (postoperative day 15) for histological examination and biomechanical testing of scar tissue.RESULTS: A one-time dose of 3.90 mM doxycycline (2 mg/mL) within 12 hours of injury was found to significantly reduce scar thickness by 24.8% (P < 0.0001) without compromising tensile strength. The same effect could not be achieved by oral dosing. In doxycycline-treated scar matrices, collagen I content was significantly reduced (P = 0.0317) and fibers were favorably arranged with significantly increased fiber randomness (P = 0.0115). Common culprits of altered wound healing mechanics, including angiogenesis and inflammation, were not impacted by doxycycline treatment. However, engrailed1 profibrotic fibroblasts, responsible for scar extracellular matrix deposition, were significantly reduced with doxycycline treatment (P = 0.0005).CONCLUSIONS: Due to the substantial improvement in skin scarring and well-established clinical safety profile, locally administered doxycycline represents a promising vulnerary agent. As such, we favor rapid translation to human patients as an antiscarring therapy.
View details for PubMedID 30585822
Author Correction: Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.
2018; 9 (1): 4411
In the original version of this Article, the authors inadvertently omitted Elizabeth A. Brett, who contributed to the generation of the histology figures, from the author list.This has now been corrected in both the PDF and HTML versions of the Article.
View details for PubMedID 30341306
- Acta2, Tnc, and Col24a1 Expression Are Associated with Abdominal Adhesion Formation ELSEVIER SCIENCE INC. 2018: E128
- Nerve-Dependent Mandibular Regeneration by Skeletal Stem Cells in Fracture Repair ELSEVIER SCIENCE INC. 2018: S197
- Reduced Scar Thickness Achieved by Topical Doxycycline Is Mediated by Specific Skin Fibroblast Populations and Not Immune Cell Infiltrate ELSEVIER SCIENCE INC. 2018: S210–S211
- Clonal Analysis of Local Fibroblasts in Wound Healing and Tumor Stroma ELSEVIER SCIENCE INC. 2018: S236
Gastrinomas: Medical or Surgical Treatment.
Endocrinology and metabolism clinics of North America
2018; 47 (3): 577–601
This article reviews the role of surgical and medical management in patients with Zollinger-Ellison syndrome (ZES) due to a gastrin-secreting neuroendocrine tumor (gastrinoma). It concentrates on the status at present but also briefly reviews the changes over time in treatment approaches. Generally, surgical and medical therapy are complementary today; however, in some cases, such as patients with ZES and multiple endocrine neoplasia type 1, the treatment approach remains controversial.
View details for PubMedID 30098717
Management of Liver Neuroendocrine Tumors in 2018.
View details for PubMedID 30178021
Fibroblasts and wound healing: an update.
View details for PubMedID 30062921
Genetic dissection of clonal lineage relationships with hydroxytamoxifen liposomes.
2018; 9 (1): 2971
Targeted genetic dissection of tissues to identify precise cell populations has vast biological and therapeutic applications. Here we develop an approach, through thepackaging and delivery of 4-hydroxytamoxifen liposomes (LiTMX), that enables localized induction of CreERT2 recombinase in mice. Our method permits precise, in vivo, tissue-specific clonal analysis with both spatial and temporal control. This technology is effective using mice with both specific and ubiquitous Cre drivers in a variety of tissue types, under conditions of homeostasis and post-injury repair, and is highly efficient for lineage tracing and genetic analysis. This methodology is directly and immediately applicable to the developmental biology, stem cell biology and regenerative medicine, and cancer biology fields.
View details for PubMedID 30061668
Incidence and Prognosis of Primary Gastrinomas in the Hepatobiliary Tract
2018; 153 (3): e175083
View details for PubMedID 29365025
Axillary reverse mapping with indocyanine green or isosulfan blue demonstrate similar crossover rates to radiotracer identified sentinel nodes
JOURNAL OF SURGICAL ONCOLOGY
2018; 117 (3): 336–40
Sentinel lymph node (SLN) resection is imperative for breast cancer staging. Axillary reverse mapping (ARM) can preserve arm draining nodes and lymphatics during surgery. ARM is generally performed with isosulfan blue (ISB), restricting its use for concurrent SLN biopsy. Indocyanine green (ICG) could serve as an alternative to ISB for ARM procedures.SLN mapping and biopsy was performed via periareolar injection of 99 technetium-sulfur colloid (99m TcSc, TSC). ISB and ICG were injected in the upper arm. Blue-stained lymphatics or nodes were visualized in the axilla; ICG was identified using the SPY Elite® system.Twenty-three patients underwent SLN biopsy with or without axillary node dissection and ARM procedures. Twenty of these patients had at least one hot node; 12 patients had SLNs that were only hot, 6 hot/blue/fluorescent, and 2 hot/fluorescent. Overall, crossover of ARM agents with SLNs occurred in 8 cases. Inspection of the axillary cavity after SLN biopsy revealed fluorescent lymphatics and nodes remaining in 14 and 7 patients, respectively. Blue lymphatics and blue nodes were detected in fewer cases.Nearly one-third of patients showed crossover between breast and arm draining nodes, which provides insight as to why some patients develop lymphedema symptoms after SLN biopsy. ICG and ISB identify similar numbers of SLNs. As such ICG could substitute for ISB in ARM procedures.
View details for PubMedID 29228459
Endoscopic Excision of Benign Facial Masses in Children: A Review of Outcomes.
Journal of laparoendoscopic & advanced surgical techniques. Part A
Benign masses of the eyebrow and forehead are common in pediatric patients and can result in facial asymmetry, discomfort, or super-infection. Excision is classically conducted via an incision directly over the mass, which can produce sub-optimal cosmesis. Recently, an endoscopic approach using pediatric brow-lift equipment has been adopted. We reviewed our center's experience with endoscopic removal of benign facial lesions and compared these cases with an equivalent series of open cases.A retrospective chart review was conducted to identify pediatric cases of endoscopic and open removal of benign eyebrow or forehead lesions at our institution from 2009 to 2016. Clinical and cosmetic outcomes were reviewed.A total of 40 endoscopic and 25 open cases of excision of benign facial lesions in children were identified. For the patients who underwent endoscopic excision, the majority (85%) presented with a cyst located at the eyebrow. Histologic examination revealed 36 dermoid cysts (90%), 2 epidermal cysts, and 2 pilomatrixomas. Of the 36 cases with post-operative follow-up, 32 patients (89%) had an uncomplicated recovery with good cosmesis. Two patients had an eyebrow droop that resolved without intervention. One patient had localized numbness overlying the site, but no motor deficits. One patient presented with a recurrent dermoid cyst that required open resection. For the patients who underwent open excision, the majority (52%) had dermoid cysts located at the eyebrow. Of the 22 cases with follow-up, 20 of the patients had an uncomplicated recovery (90%). Comparing the rate of complications, there was no statistically significant difference between the two groups (P = 1.0).Endoscopic excision of benign forehead and eyebrow lesions in pediatric patients is feasible and yields excellent cosmetic results. When compared with open excision, complication rates are similar between both approaches and a facial scar can be avoided with an endoscopic approach.
View details for PubMedID 29446701
The evolving relationship of wound healing and tumor stroma.
2018; 3 (18)
The stroma in solid tumors contains a variety of cellular phenotypes and signaling pathways associated with wound healing, leading to the concept that a tumor behaves as a wound that does not heal. Similarities between tumors and healing wounds include fibroblast recruitment and activation, extracellular matrix (ECM) component deposition, infiltration of immune cells, neovascularization, and cellular lineage plasticity. However, unlike a wound that heals, the edges of a tumor are constantly expanding. Cell migration occurs both inward and outward as the tumor proliferates and invades adjacent tissues, often disregarding organ boundaries. The focus of our review is cancer associated fibroblast (CAF) cellular heterogeneity and plasticity and the acellular matrix components that accompany these cells. We explore how similarities and differences between healing wounds and tumor stroma continue to evolve as research progresses, shedding light on possible therapeutic targets that can result in innovative stromal-based treatments for cancer.
View details for PubMedID 30232274
Wound Healing and Fibrosis: Current Stem Cell Therapies
View details for DOI 10.1111/trf.14836
Management of Chronic Wounds-2018.
2018; 320 (14): 1481–82
View details for PubMedID 30326512
Surgical Site Infections after Inguinal Hernia Repairs Performed in Low and Middle Human Development Index Countries: A Systematic Review.
Inguinal hernias are a common disorder in low- and middle-human development index countries (LMHDICs). Poor access to surgical care and lack of patient awareness often lead to delayed presentations of incarcerated or strangulated hernias and their associated morbidities. There is a scarcity of data on the baseline incidence of surgical site infections (SSIs) after hernia repair procedures in LMHDICs.We performed a systematic review of the literature describing the incidence and management of SSIs after inguinal hernia repair in LMHDICs. We conducted qualitative and quantitative analyses of manuscripts describing patients undergoing hernia repair to establish a baseline SSI rate for this procedure in these settings.Three hundred twenty-three abstracts were identified after applying search criteria, and 31 were suitable for the quantitative analysis. The overall pooled SSI rate was 4.1 infections/100 open hernia repairs (95% confidence interval [CI] 3.0-5.3 infections/100 open repairs), which is consistent with infection rates from high-human development index countries. A separate subgroup analysis of laparoscopic hernia repairs found a weighted pooled SSI rate of 0.4 infections/100 laparoscopic repairs (95% CI 0-2.4 infections/100 laparoscopic repairs).As surgical access continues to expand in LMHDIC settings, it is imperative to monitor surgical outcomes and ensure that care is provided safely. Establishing a baseline SSI rate for inguinal hernia repairs offers a useful benchmark for future studies and surgical programs in these countries.
View details for PubMedID 29048997
Surgical Site Infections after Appendectomy Performed in Low and Middle Human Development-Index Countries: A Systematic Review.
Acute appendicitis is a common surgical emergency worldwide. Early intervention is associated with better outcomes. In low and middle Human Development-Index Countries (LMHDICs), late presentation and poor access to healthcare facilities can contribute to greater illness severity and higher complication rates, such as post-operative surgical site infections (SSIs). The current rate of SSIs post-appendectomy in low- and middle-index settings has yet to be described.We performed a systemic review of the literature describing the incidence and management of SSIs after appendectomy in LMHDICs. We conducted qualitative and quantitative analysis of the data in manuscripts describing patients undergoing appendectomy to establish a baseline SSI rate for this procedure in these settings.Four hundred twenty-three abstracts were initially identified. Of these, 35 studies met the criteria for qualitative and quantitative analysis. The overall weighted, pooled SSI rated were 17.9 infections/100 open appendectomies (95% confidence interval [CI] 10.4-25.3 infections/100 open appendectomies) and 8.8 infections/100 laparoscopic appendectomies (95% CI 4.5-13.2 infections/100 laparoscopic appendectomies). The SSI rates were higher in complicated appendicitis and when pre-operative antibiotic use was not specified.Observed SSI rates after appendectomy in LMHDICs are dramatically higher than rates in high Human Development-Index Countries. This is particularly true in cases of open appendectomy, which remains the most common surgical approach in LMHDICs. These findings highlight the need for SSI prevention in LMHDICs, including prompt access to medical and surgical care, routine pre-operative antibiotic use, and implementation of bundled care packages and checklists.
View details for PubMedID 29058569
Regression of experimental NIS-expressing breast cancer brain metastases in response to radioiodide/gemcitabine dual therapy
2016; 7 (34): 54811-54824
Treating breast cancer brain metastases (BCBMs) is challenging. Na+/I- symporter (NIS) expression in BCBMs would permit their selective targeting with radioiodide (131I-). We show impressive enhancement of tumor response by combining131I- with gemcitabine (GEM), a cytotoxic radiosensitizer. Nude mice mammary fat-pad (MFP) tumors and BCBMs were generated with braintropic MDA-MB-231Br cells transduced with bicistronically-linked NIS and firefly luciferase cDNAs. Response was monitored in vivo via bioluminescent imaging and NIS tumor expression.131I-/GEM therapy inhibited MFP tumor growth more effectively than either agent alone. BCBMs were treated with: high or low-dose GEM (58 or 14.5 mg/Kg×4); 131I- (1mCi or 2×0.5 mCi 7 days apart); and 131I-/GEM therapy. By post-injection day (PID) 25, 82-86% of controls and 78-83% of 131I--treated BCBM grew, whereas 17% low-dose and 36% high-dose GEM regressed. The latter tumors were smaller than the controls with comparable NIS expression (~20% of cells). High and low-dose 131I-/ GEM combinations caused 89% and 57% tumor regression, respectively. High-dose GEM/131I- delayed tumor growth: tumors increased 5-fold in size by PID45 (controls by PID18). Although fewer than 25% of cells expressed NIS, GEM/131I- caused dramatic tumor regression in NIS-transduced BCBMs. This effect was synergistic, and supports the hypothesis that GEM radiosensitizes cells to 131I-.
View details for DOI 10.18632/oncotarget.10238
View details for Web of Science ID 000385435000059
Palliative Surgery for Advanced Cancer: Identifying Evidence-Based Criteria for Patient Selection: Case Report and Review of Literature
JOURNAL OF PALLIATIVE MEDICINE
2016; 19 (1): 22-29
Criteria for selecting patients with advanced cancer for palliative surgery (PS) remains poorly defined. Decision making for PS requires realistic treatment goals with well-defined criteria. Here we discuss a 71-year-old Jehovah's Witness with advanced stage renal cell carcinoma (RCC) who presented with profound anemia due to intractable bleeding from gastric metastasis. After repeated attempts with endoscopic and angiographic management, she underwent surgical palliation. Through this case, we developed 10-item evidence-based criteria for selecting patients for PS.The study objective was to provide a review of pertinent literature for PS and identify evidence-based criteria for patient selection. These criteria were relevant for selecting this patient with metastatic RCC and may prove beneficial for selecting advanced cancer patients for PS.A MEDLINE search revealed 175 publications relevant to PS. Among these, 17 articles defining patient selection criteria (PSC) were reviewed. A frequency-based analysis of each criterion was performed. Another search returned 30 cases of RCC gastric metastases from 25 published reports. Outcome analysis was determined by the Kaplan-Meier actuarial method.Ten criteria were identified: symptom control, prognosis, preoperative performance status, quality of life (QoL), tumor burden amenable to palliation, procedure-related morbidity and mortality, feasibility of nonsurgical therapies, anticipated hospitalization, requirement for additional palliation, and cost. This patient met all inclusion criteria and underwent a successful gastrectomy. Median survival for patients with RCC gastric metastasis was 20 months.This report illustrates an example of implementation of evidence-based criteria for selecting advanced cancer patients for PS. Validation of these criteria is warranted.
View details for DOI 10.1089/jpm.2015.0146
View details for Web of Science ID 000367057700007
View details for PubMedID 26565437
Pancreatic mucinous cystic neoplasm in a transgender patient
WORLD JOURNAL OF SURGICAL ONCOLOGY
Cystic pancreatic lesions are increasingly more frequent detected clinical entities. Mucinous cystic neoplasm (MCN) is a hormone-related pancreatic tumor (HRTP) with a strong predominance in young and middle-aged females.Here, we present the case of a 31-year-old surgically transgendered female-to-male patient with a history of alcoholic pancreatitis, on chronic testosterone therapy. He was found to have a pancreatic MCN and underwent distal pancreatectomy and splenectomy.To our knowledge, this is the first reported case of a transgender patient with a history of hormone replacement therapy (HRT) and pancreatic MCN. We consider possible mechanisms for the pathogenesis to explain this patient's neoplasm.
View details for DOI 10.1186/s12957-015-0620-8
View details for Web of Science ID 000357085900001
View details for PubMedID 26104783
View details for PubMedCentralID PMC4486435
Richter-type Spigelian hernia: A case report and review of the literature.
International journal of surgery case reports
2015; 6C: 160-162
Abdominal wall hernias through the arcuate line termed Spigelian hernias are uncommon. These hernias presenting as a Richter-type, with strangulation of part of the circumference of the bowel wall is very rare.We report a 27-year-old male patient who presented with a Richter-type Spigelian hernia.A MEDLINE literature search of this rare entity yielded six publications presenting Richter-type Spigelian hernias. All of these articles and accompanying references were thoroughly reviewed. There was no gender or anatomical side predominance among the patients. All except our patient presented here were elderly. Pain was the most common symptom and was present in all patients. All patients underwent surgical repair and none reported recurrence of their hernia afterwards.Richter-type Spigelian hernia is rare and has been reported infrequently in the existing literature. Clinical diagnosis is challenging and CT scan is the diagnostic study of choice. Surgical repair is the definitive treatment and involves primary or mesh repair of the defect as appropriate. Necrotic bowel should be resected and we recommend biologic mesh repair in these cases if the defect is large.
View details for DOI 10.1016/j.ijscr.2014.10.088
View details for PubMedID 25544481
View details for PubMedCentralID PMC4334998
Evaluation of three rapid diagnostic tests for the detection of human infections with Plasmodium knowlesi
Plasmodium knowlesi, a malaria parasite of Southeast Asian macaques, infects humans and can cause fatal malaria. It is difficult to diagnose by microscopy because of morphological similarity to Plasmodium malariae. Nested PCR assay is the most accurate method to distinguish P. knowlesi from other Plasmodium species but is not cost effective in resource-poor settings. Rapid diagnostic tests (RDTs) are recommended for settings where malaria is prevalent. In this study, the effectiveness of three RDTs in detecting P. knowlesi from fresh and frozen patient blood samples was evaluated.Forty malaria patients (28 P. knowlesi, ten P. vivax and two P. falciparum) diagnosed by microscopy were recruited in Sarawak, Malaysian Borneo during a 16-month period. Patient blood samples were used to determine parasitaemia by microscopy, confirm the Plasmodium species present by PCR and evaluate three RDTs: OptiMAL-IT, BinaxNOW® Malaria and Paramax-3. The RDTs were also evaluated using frozen blood samples from 41 knowlesi malaria patients.OptiMAL-IT was the most sensitive RDT, with a sensitivity of 71% (20/28; 95% CI = 54-88%) for fresh and 73% (30/41; 95% CI = 59-87%) for frozen knowlesi samples. However, it yielded predominantly falciparum-positive results due to cross-reactivity of the P. falciparum test reagent with P. knowlesi. BinaxNOW® Malaria correctly detected non-P. falciparum malaria in P. knowlesi samples but was the least sensitive, detecting only 29% (8/28; 95% CI = 12-46%) of fresh and 24% (10/41; 95% CI = 11-37%) of frozen samples. The Paramax-3 RDT tested positive for P. vivax with PCR-confirmed P. knowlesi samples with sensitivities of 40% (10/25; 95% CI = 21-59%) with fresh and 32% (13/41; 95% CI = 17-46%) with frozen samples. All RDTs correctly identified P. falciparum- and P. vivax-positive controls with parasitaemias above 2,000 parasites/μl blood.The RDTs detected Plasmodium in P. knowlesi-infected blood samples with poor sensitivity and specificity. Patients with P. knowlesi could be misdiagnosed as P. falciparum with OptiMAL-IT, P. vivax with Paramax-3 and more correctly as non-P. vivax/non-P. falciparum with BinaxNOW® Malaria. There is a need for a sensitive and specific RDT for malaria diagnosis in settings where P. knowlesi infections predominate.
View details for DOI 10.1186/1475-2875-13-60
View details for Web of Science ID 000332774300003
View details for PubMedID 24548805
View details for PubMedCentralID PMC3931291
Ex vivo Evans blue assessment of the blood brain barrier in three breast cancer brain metastasis models.
Breast cancer research and treatment
2014; 144 (1): 93-101
The limited entry of anticancer drugs into the central nervous system represents a special therapeutic challenge for patients with brain metastases and is primarily due to the blood brain barrier (BBB). Albumin-bound Evans blue (EB) dye is too large to cross the BBB but can grossly stain tissue blue when the BBB is disrupted. The course of tumor development and the integrity of the BBB were studied in three preclinical breast cancer brain metastasis (BCBM) models. A luciferase-transduced braintropic clone of MDA-231 cell line was used. Nude mice were subjected to stereotactic intracerebral inoculation, mammary fat pad-derived tumor fragment implantation, or carotid artery injections. EB was injected 30 min prior to euthanasia at various timepoints for each of the BCBM model animals. Serial bioluminescent imaging demonstrated exponential tumor growth in all models. Carotid BCBM appeared as diffuse multifocal cell clusters. EB aided the localization of metastases ex vivo. Tumor implants stained blue at 7 days whereas gross staining was not evident until day 14 in the stereotactic model and day 28 for the carotid model. EB assessment of the integrity of the BBB provides useful information relevant to drug testing in preclinical BCBM models.
View details for DOI 10.1007/s10549-014-2854-5
View details for PubMedID 24510011
Two treatments, one disease: childhood malaria management in Tanga, Tanzania
In the Tanga District of coastal Tanzania, malaria is one of the primary causes of mortality for children under the age of five. While some children are treated with malaria medications in biomedical facilities, as the World Health Organization recommends, others receive home-care or treatment from traditional healers. Recognition of malaria is difficult because symptoms can range from fever with uncomplicated malaria to convulsions with severe malaria. This study explores why caregivers in the Tanga District of Tanzania pursue particular courses of action to deal with malaria in their children.Qualitative data were collected through interviews with three samples: female caregivers of children under five (N = 61), medical practitioners (N = 28), and traditional healers (N = 18) in urban, peri-urban, and rural areas. The female caregiver sample is intentionally stratified to reflect the greater population of the Tanga District in level of education, marital status, gender of household head, religion, and tribal group affiliation. Qualitative data were counted, coded and analysed using NVivo7 software.Results indicate that a variety of factors influence treatment choice, including socio-cultural beliefs about malaria symptoms, associations with spiritual affliction requiring traditional healing, knowledge of malaria, and fear of certain anti-malaria treatment procedures. Most notably, some caregivers identified convulsions as a spiritual condition, unrelated to malaria. While nearly all caregivers reported attending biomedical facilities to treat children with fever (N = 60/61), many caregivers stated that convulsions are best treated by traditional healers (N = 26/61). Qualitative interviews with medical practitioners and traditional healers confirmed this belief.Results offer insight into current trends in malaria management and have implications in healthcare policy, educational campaigns, and the importance of integrating traditional and biomedical approaches.
View details for DOI 10.1186/1475-2875-8-240
View details for Web of Science ID 000272254600001
View details for PubMedID 19860900
View details for PubMedCentralID PMC2779815