Pancreatic Cancer Associated Fibroblasts (CAF): Under-Explored Target for Pancreatic Cancer Treatment.
2020; 12 (5)
The Effect of Surgical Trainee Education on Opioid Prescribing: An International Evaluation.
Journal of surgical education
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
Patient-reported health literacy scores are associated with readmissions following surgery.
American journal of surgery
Up to 6% of opioid naive patients who undergo surgery become chronic opioid users. The aim of this study was to determine if formal opioid prescribing education of general surgery residents is associated with decreased opioid prescribing postoperatively.We surveyed surgery residents at 3 general surgery programs in the United States and 1 in Israel. Residents were divided into 2 groups based on whether or not they received formal opioid prescribing education.Of those surveyed, 107 (50%) responded. 45% of residents had formal opioid prescribing education, which included instructional videos, current literature, and hospital guidelines. For the 4 operations analyzed, residents who received no formal teaching prescribed a higher number of opioids (lumpectomy p = 0.001, open inguinal hernia repair p = 0.004, laparoscopic appendectomy p?=?0.007, thyroidectomy p?=?0.002). The largest difference in opioid prescribing was seen in "high prescribers," defined as residents prescribing 15 or more opioid pills. For thyroidectomy, 24.4% of residents without formal education prescribed 20 or more oxycodone 5mg pills compared to 0% of residents with formal education. The Israeli cohort was less likely to receive a pain focused education and was also less likely to prescribe opioids to their patients for all 4 procedures evaluated.Although a minority of general surgery residents are receiving an opioid prescribing education, a formal educational program was associated with significantly decreased opioid prescribing. There is a need for a generalizable educational opioid program for surgery residents.
View details for DOI 10.1016/j.jsurg.2020.04.009
View details for PubMedID 32446768
Elucidating the fundamental fibrotic processes driving abdominal adhesion formation.
2020; 11 (1): 4061
Health literacy (HL) impacts medical care. We hypothesized that patients with low HL would have higher readmission rates following surgery.We conducted a prospective, multi-institutional study from 8/2015-6/2017 within the Veterans Affairs (VA) System including veterans who underwent general, vascular, or thoracic surgery. HL was assessed by Brief Health Literacy Screener and stratified into adequate vs. low. Patients were followed for 30 days post-discharge. Multivariable analyses examined correlations and logistic regression models adjusted for covariates.736 patients were enrolled in the study; 98% (n = 722) completed the HL survey. At discharge, 33.2% of patients had low HL. The overall 30-day readmission rate was 16.3%, with a significant difference by HL (Adequate HL: 13.3% vs. Low HL: 22.5%, p < 0.01). After adjusting for clinical and demographic covariates, patients with low HL were 59% more likely to be readmitted (OR = 1.59, 95% CI = 1.02-2.50).Low HL is common among VA surgery patients and is associated with readmission. Future studies should be focused on interventions to target this vulnerable patient population.
View details for DOI 10.1016/j.amjsurg.2020.06.071
View details for PubMedID 32682501
Evaluation of Outcomes Following Surgery for Locally Advanced Pancreatic Neuroendocrine Tumors.
JAMA network open
2020; 3 (11): e2024318
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
Growth Factor Delivery to a Bovine Defect Using Leukocyte -Rich Platelet-Rich Concentrates on a Hyaluronic Acid Scaffold.
Arthroscopy : the journal of arthroscopic & related surgery : official publication of the Arthroscopy Association of North America and the International Arthroscopy Association
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
A fine balance in tendon healing.
Nature cell biology
Perioperative opioid use and pain-related outcomes in the Veterans Health Administration.
American journal of surgery
PURPOSE: To determine if (1) Human L-PRP or (2) L-PRF delivered on a HA scaffold at a bovine chondral defect, a simulated cartilage tear interface, in vitro would improve tissue formation based on biomechanical, histological, and biochemical measures.METHODS: L-PRF and L-PRP was prepared from 3 healthy volunteer donors which was delivered in conjunction with Hyaluronic acid (HA scaffolds) to defects created in full thickness bovine cartilage plugs harvested from bovine femoral condyle and trochlea. Specimens were cultured in vitro for up to 42 days. Treatment groups included an HA scaffold alone and scaffolds containing L-PRF or L-PRP. Cartilage repair was assessed using biomechanical testing, histology, DNA quantification, and measurement of sulfated glycosaminoglycan (sGAG) and collagen content at 28 and 42 days.RESULTS: L-PRF elicited the greatest degree of defect filling and improvement in other histological measures. L-PRF treated specimens also had the greatest cellularity when compared to L-PRP and control at day 28 (560.4 vs. 191.4 vs. 124.2, p=00.15); at day 48 there remains a difference though not significant between L-PRF vs L-PRP, (761.1 vs 589.3, p=0.219) . L-PRF had greater collagen deposition when compared to L-PRP at day 42 (40.1 vs 16.3, p< 0.0001). L-PRF had significantly higher maximum interfacial strength compared to the control at day 42 (10.92 N vs 0.66 N, p=0.015), but had no significant difference compared to L-PRP (10.92 N vs 6.58, p=0.536). L-PRP facilitated a greater amount of sGAG production at day 42 when compared to L-PRF (15.9 vs. 4.3, p=0.009).CONCLUSIONS: Delivery of leukocyte rich platelet concentrates in conjunction with a HA scaffold may allow for improvements in cartilage healing through different pathways. L-PRF was not superior to L-PRP in its biomechanical strength suggesting that both treatments may be effective in improving biomechanical strength of healing cartilage through different pathways.
View details for DOI 10.1016/j.arthro.2019.12.004
View details for PubMedID 31862290
The influence of hormone replacement therapy on lung cancer incidence and mortality.
The Journal of thoracic and cardiovascular surgery
Understanding variation in perioperative opioid exposure and its effect on patients' outcomes is critical for pain management. This study characterized perioperative exposure to morphine and its association with postoperative pain and 30-day readmissions. We utilized nationwide Veterans Healthcare Administration (VHA) data on four high-volume surgical procedures, 2007-2014. We identified 235,239 Veterans undergoing orthopedic, general, or vascular surgery; 5.4% high trajectories (116.1 OME/Day), 53.2% medium trajectories (39.7 OME/Day), and 41.4% low trajectories (19.1 OME/Day). Modeled estimates suggest that patients in the high OME group had higher risk of a pain-related readmission (OR: 1.59; CI: 1.39, 1.83) compared to the low OME trajectory. Yet when stratified by pain trajectory, patients with high pain and high OME had lower risk of a pain-related readmission compared to patients in the high pain low OME group (OR: 0.76, CI: 0.62, 0.94). In conclusion, patients receiving high perioperative OME are more likely to return to care for pain-related problems. This study highlights opportunities to reduce the amount of prescriptions opioids in the communities.
View details for DOI 10.1016/j.amjsurg.2019.06.022
View details for PubMedID 31280840
Patient expectations for recovery after elective surgery: a common-sense model approach.
Journal of behavioral medicine
Data regarding the effects of hormone replacement therapy (HRT) on non-small cell lung cancer (NSCLC) are mixed. We hypothesized HRT would have a protective benefit with reduced NSCLC incidence among women in a large, prospective cohort.We used data from the multicenter randomized Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial (1993-2001). Participants were women aged 50 to 74 years followed prospectively for up to 13 years for cancer screening. The influence of HRT on the primary outcome of NSCLC incidence and secondary outcomes of all-cause and disease-specific mortality were assessed with Kaplan-Meier analysis and Cox proportional hazard models adjusting for covariates.In the overall cohort of 75,587 women, 1147 women developed NSCLC after a median follow-up of 11.5 years. HRT use was characterized as 49.4% current users, 17.0% former users, and 33.6% never users. Increased age, smoking, comorbidities, and family history were associated with increased risk of NSCLC. On multivariable analysis, current HRT use was associated with reduced risk of NSCLC compared with never users (hazard ratio, 0.80; 95% confidence interval, 0.70-0.93; P = .009). HRT or oral contraception use was not associated with significant differences in all-cause mortality or disease-specific mortality.These data represent among the largest prospective cohorts suggesting HRT use may have a protective effect on the development of NSCLC among women; the physiological basis of this effect merits further study; however, the results may influence discussion surrounding HRT use in women.
View details for DOI 10.1016/j.jtcvs.2019.10.070
View details for PubMedID 31866083
Flexor Tendon: Development, Healing, Adhesion Formation, and Contributing Growth Factors.
Plastic and reconstructive surgery
2019; 144 (4): 639e?647e
Patient perceptions of the causes of preoperative symptoms, expected impact of surgery on symptoms and anticipated timeline of recovery are likely to affect the risk of readmission following elective surgical procedures. However, these perceptions have not been studied. A qualitative study was designed to explore these perceptions, using the common-sense model of self-regulation (CSM) as the conceptual framework. CSM is grounded in illness representations, describing how patients make sense of changes in physical well-being (e.g. symptoms) and develop and assess management plans. It also establishes a broader framework for examining patients' a priori expectations and timelines for outcomes based on comparisons to prior experiences and underlying self-prototypes, or "Self as Anchor". A convenience sample of 14 patients aged 56-81 who underwent elective surgery was recruited. Semi-structured interviews informed by the CSM were completed on the day of discharge. Content analysis with deductive coding was used, and emerging themes were fit to components of the CSM, including the five domains of Illness Representations-identity, cause, timeline, control, and consequences. Two additional themes, outlook (toward the health care system, providers and recovery efforts), and motivation (external or internal for recovering), relate to self-prototypes, expectations for outcomes, and search for coherence. Misattribution of symptoms, unrealistic expectations for outcomes (e.g. expecting complete resolution of symptoms unrelated to the surgical procedure) and timelines for recovery (unrealistically short), and the (baseline) "normal healthy self" as distinct from the (temporarily) "sick self" were recurrent themes. Findings suggest that patient perceptions and the actual recovery process may be misaligned. The results underscore the importance of assessing patients' perceptions and expectations, actively engaging patients in their own healthcare, and providing adequate support during the transition to home.
View details for DOI 10.1007/s10865-019-00097-2
View details for PubMedID 31512105
A Clearing Technique to Enhance Endogenous Fluorophores in Skin and Soft Tissue.
2019; 9 (1): 15791
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
Management of Ileal Neuroendocrine Tumors with Liver Metastases.
Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract
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??m 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
Caring for Caregivers - Resident Physician Health and Wellbeing.
Journal of surgical education
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
Clinical Trigonometry: Right Hepatic Trisegmentectomy After Radiation Trisegmentectomy for Hepatocellular Carcinoma
DIGESTIVE DISEASES AND SCIENCES
2018; 63 (6): 1419?23
Homeless Status, Postdischarge Health Care Utilization, and Readmission After Surgery.
2018; 56 (6): 460?69
There is a national epidemic of physician burnout and serious concerns exist regarding the well-being of future physicians. This project seeks to address resident physician health, by creating a sense of support and community during training, as a method to target one of the many facets of burnout.We created a program that allows residents who fall ill to receive a health package, delivered to work or home, consisting of essential medications, vitamins, nutrition, and hydration. The recipients were asked to answer a short survey regarding their experience.Stanford Health Care, Department of Surgery, Division of General Surgery, Palo Alto California.Eighteen packages have been delivered since the start of the project. One hundred percent of residents agree that this program fulfills an otherwise unmet need in residency. Similarly, all felt that the supplies they received helped them recover faster. The majority (83%) of the packages were requested by colleagues of the ill residents.We present an innovative project aimed at improving resident physician health, fostering a feeling of support, and helping to reduce resident burnout. This is the first report of a program of this kind and we hope that it incentivizes a broader discussion and implementation of similar initiatives in other residency programs across the country.
View details for DOI 10.1016/j.jsurg.2019.08.007
View details for PubMedID 31494061
Tendinopathy: Investigating the Intersection of Clinical and Animal Research to Identify Progress and Hurdles in the Field.
2016; 4 (10)
The Choice Between Total Hip Arthroplasty and Arthrodesis in Adolescent Patients: A Survey of Orthopedic Surgeons
JOURNAL OF ARTHROPLASTY
2016; 31 (1): 70-75
Homeless Veterans are vulnerable to poor care transitions, yet little research has examined their risk of readmission following inpatient surgery. This study investigates the predictors of surgical readmission among homeless relative to housed Veteran patients.Inpatient general, vascular, and orthopedic surgeries occurring in the Veterans Health Administration from 2008 to 2014 were identified. Administrative International Classification of Diseases, Ninth Revision, Clinical Modification codes and Veterans Health Administration clinic stops were used to identify homeless patients. Bivariate analyses examined characteristics and predictors of readmission among homeless patients. Multivariate logistic models were used to estimate the association between homeless experience and housed patients with readmission following surgery.Our study included 232,373 surgeries: 43% orthopedic, 39% general, and 18% vascular with 5068 performed on homeless patients. Homeless individuals were younger (56 vs. 64?y, P<0.01), more likely to have a psychiatric comorbidities (51.3% vs. 19.4%, P<0.01) and less likely to have other medical comorbidities such as hypertension (57.1% vs. 70.8%, P<0.01). Homeless individuals were more likely to be readmitted [odds ratio (OR), 1.43; confidence interval (CI), 1.30-1.56; P<0.001]. Discharge destination other than community (OR, 0.57; CI, 0.44-0.74; P<0.001), recent alcohol abuse (OR, 1.45; CI, 1.15-1.84; P<0.01), and elevated American Society Anesthesiologists classification (OR, 1.86; CI, 1.30-2.68; P<0.01) were significant risk factors associated with readmissions within the homeless cohort.Readmissions are higher in homeless individuals discharged to the community after surgery. Judicious use of postoperative nursing or residential rehabilitation programs may be effective in reducing readmission and improving care transitions among these vulnerable Veterans. Relative costs and benefits of alternatives to community discharge merit investigation.
View details for PubMedID 29746348
Variations in chondrogenesis of human bone marrow-derived mesenchymal stem cells in fibrin/alginate blended hydrogels
2012; 8 (10): 3754-3764
For adolescent patients with end-stage hip disease, the choice between total hip arthroplasty (THA) and arthrodesis is complex; the clinical evidence is not definitive, and there are difficult trade-offs between clear short-term benefits from THA and uncertain long-term risks. We surveyed nearly 700 members of the Pediatric Orthopedic Society of North America and the American Association of Hip and Knee Surgeons. Respondents chose between a recommendation of THA or arthrodesis in four clinical vignettes. A clear majority of surgeons recommended THA in two of the vignettes, however opinion was somewhat divided in one vignette (overweight adolescent) and deeply divided in another (adolescent destined for manual labor job). Across all vignettes, recommendations varied systematically according to surgeons' age and their attitudes regarding tradeoffs between life stages.
View details for DOI 10.1016/j.arth.2015.07.020
View details for Web of Science ID 000366677000014
View details for PubMedID 26298281
Fibrin and alginate hydrogels have been widely used to support chondrogenesis of bone marrow-derived mesenchymal stem cells (BM-MSCs) for articular cartilage and fibrocartilage tissue engineering, with each material offering distinct advantages and disadvantages. Attempting to produce a gel scaffold exhibiting beneficial characteristics of both materials, we fabricated fibrin/alginate blended hydrogels at various blend ratios and evaluated the gel morphology, mechanical properties and their support for BM-MSC chondrogenesis. Results show that when the fibrin/alginate ratio decreased, the fibrin architecture transitioned from uniform to interconnected fibrous and finally to disconnected islands against an alginate background, with opposing trends in the alginate architecture. Fibrin maintained gel extensibility and promoted cell proliferation, while alginate improved the gel biostability and better supported glycosaminoglycan and collagen II production and chondrogenic gene expression. Blended gels had physical and biological characteristics intermediate between fibrin and alginate. Of the blends examined, FA 40:8 (40 mg ml(-1) fibrinogen blended with 8 mg ml(-1) alginate) was found to be the most appropriate group for future studies on tension-driven BM-MSC fibrochondrogenesis. As BM-MSC differentiation appeared to vary between fibrin and alginate regions of blended scaffolds, this study also highlighted the potential to develop spatially heterogeneous tissues through manipulating the heterogeneity of scaffold composition.
View details for DOI 10.1016/j.actbio.2012.06.028
View details for Web of Science ID 000309301400022
View details for PubMedID 22750738
View details for PubMedCentralID PMC3429695