Gastrointestinal Malignancy: Genetic Implications to Clinical Applications.

Advances in molecular genetics have revolutionized our understanding of the pathogenesis, progression, and therapeutic options for treating gastrointestinal (GI) cancers. This chapter provides a comprehensive overview of the molecular landscape of GI cancers, focusing on key genetic alterations implicated in tumorigenesis across various anatomical sites including GIST, colon and rectum, and pancreas. Emphasis is placed on critical oncogenic pathways, such as mutations in tumor suppressor genes, oncogenes, chromosomal instability, microsatellite instability, and epigenetic modifications. The role of molecular biomarkers in predicting prognosis, guiding treatment decisions, and monitoring therapeutic response is discussed, highlighting the integration of genomic profiling into clinical practice. Finally, we address the evolving landscape of precision oncology in GI cancers, considering targeted therapies and immunotherapies.

Altered exocrine function can drive adipose wasting in early pancreatic cancer.

Malignancy is accompanied by changes in the metabolism of both cells and the organism1,2. Pancreatic ductal adenocarcinoma (PDAC) is associated with wasting of peripheral tissues, a metabolic syndrome that lowers quality of life and has been proposed to decrease survival of patients with cancer3,4. Tissue wasting is a multifactorial disease and targeting specific circulating factors to reverse this syndrome has been mostly ineffective in the clinic5,6. Here we show that loss of both adipose and muscle tissue occurs early in the development of pancreatic cancer. Using mouse models of PDAC, we show that tumour growth in the pancreas but not in other sites leads to adipose tissue wasting, suggesting that tumour growth within the pancreatic environment contributes to this wasting phenotype. We find that decreased exocrine pancreatic function is a driver of adipose tissue loss and that replacement of pancreatic enzymes attenuates PDAC-associated wasting of peripheral tissues. Paradoxically, reversal of adipose tissue loss impairs survival in mice with PDAC. When analysing patients with PDAC, we find that depletion of adipose and skeletal muscle tissues at the time of diagnosis is common, but is not associated with worse survival. Taken together, these results provide an explanation for wasting of adipose tissue in early PDAC and suggest that early loss of peripheral tissue associated with pancreatic cancer may not impair survival.

Gender Related Differences in Surgeon Compensation: Survey Results from the American Society of Colon and Rectal Surgeons.

OBJECTIVE: We sought to understand the effect of sex on compensation among colorectal surgeons and to determine which factors contribute to gender-based differences in compensation. SUMMARY OF BACKGROUND DATA: The sex-based wage gap in the medical profession is among the most pronounced wage gaps in the U.S. Data regarding the wage gap among colorectal surgeons and the underlying reasons for this disparity remain unclear. METHODS: The Healthcare Economics Committee of the American Society of Colon and Rectal Surgeons conducted a survey to evaluate surgeon demographics, compensation, and practice characteristics. To evaluate the effect of sex on compensation, we performed multivariable linear regression with backward selection. We used a two-sided P -value with a significance threshold <0.05. RESULTS: The mean difference in normalized total compensation between men and women was $46,250, and when salary was adjusted for FTEs, the difference was $57,000. Women were more likely to perform anorectal surgery, less likely to perform general surgery and less likely to hold positions in leadership. After adjustments, women reported significantly lower compensation (aOR, 0.88; 95% CI, 0.80-0.97). Time spent doing abdominal surgery (aOR, 1.13; 95% CI 1.03-1.23), professor status (aOR, 1.17; 95% CI, 1.03-1.32) and instructor status (aOR, 1.49; 95% 1.28-1.73) were independently associated with compensation. CONCLUSIONS: We found a 12% adjusted sex wage gap among colorectal surgeons. Gender-based differences in leadership positions and allocation of effort may contribute. Further research will be necessary to clarify sources of wage inequalities. Still, our results should prompt expedient actions to support closing the gap.

Cost Effectiveness of Watch and Wait Versus Resection in Rectal Cancer Patients with Complete Clinical Response to Neoadjuvant Chemoradiation.

BACKGROUND: Watch and wait (WW) protocols have gained increasing popularity for patients diagnosed with locally advanced rectal cancer and presumed complete clinical response after neoadjuvant chemoradiation. While studies have demonstrated comparable survival and recurrence rates between WW and radical surgery, the decision to undergo surgery has significant effects on patient quality of life. We sought to conduct a cost-effectiveness analysis comparing WW with abdominoperineal resection (APR) and low anterior resection (LAR) among patients with stage II/III rectal cancer. METHODS: In this comparative-effectiveness study, we built Markov microsimulation models to simulate disease progression, death, costs, and quality-adjusted life-years (QALYs) for WW or APR/LAR. We assessed cost effectiveness using the incremental cost-effectiveness ratio (ICER), with ICERs under $100,000/QALY considered cost effective. Probabilities of disease progression, death, and health utilities were extracted from published, peer-reviewed literature. We assessed costs from the payer perspective. RESULTS: WW dominated both LAR and APR at a willingness to pay (WTP) threshold of $100,000. Our model was most sensitive to rates of distant recurrence and regrowth after WW. Probabilistic sensitivity analysis demonstrated that WW was the dominant strategy over both APR and LAR over 100% of iterations across a range of WTP thresholds from $0-250,000. CONCLUSIONS: Our study suggests WW could reduce overall costs and increase effectiveness compared with either LAR or APR. Additional clinical research is needed to confirm the clinical efficacy and cost effectiveness of WW compared with surgery in rectal cancer.

Current trends in nonoperative management for rectal adenocarcinoma: An unequal playing field?

BACKGROUND AND OBJECTIVES: Increasing evidence suggests patient-oriented benefits of nonoperative management (NOM) for rectal cancer. However, vigilant surveillance requires excellent access to care. We sought to examine patient, socioeconomic, and facility-level factors associated with NOM over time. METHODS: Using the National Cancer Database (2006-2017), we examined patients with Stage II-III rectal adenocarcinoma, who received neoadjuvant chemoradiation and received NOM versus surgery. Factors associated with NOM were assessed using multivariable logistic regression with backward stepwise selection. RESULTS: There were 59,196 surgical and 8520 NOM patients identified. NOM use increased from 12.9% to 15.9% between 2006 and 2017. Patients who were Black (adjusted odds ratio [aOR]: 1.36, 95% confidence interval [CI]: 1.26-1.47), treated at community cancer centers (aOR: 1.22, 95% CI: 1.12-1.30), without insurance (aOR: 1.87, 95% CI: 1.68-2.09), and with less education (aOR: 1.53, 95% CI: 1.42-1.65) exhibited higher odds of NOM. Patients treated at high-volume centers (aOR: 0.79, 95% CI: 0.74-0.84) and those who traveled >25.6 miles for care (aOR: 0.59, 95% CI: 0.55-0.64) had lower odds of NOM. CONCLUSIONS: Vulnerable groups who traditionally have difficulty accessing comprehensive cancer care were more likely to receive NOM, suggesting that healthcare disparities may be driving utilization. More research is needed to understand NOM decision-making in rectal cancer treatment.

A colorimetric chemical tongue detects and distinguishes between multiple analytes.

The rate-limiting step for diagnostics development is the discovery and validation of biomarker analytes. We describe a new analyte-agnostic and label-free approach based on colorimetric reactions involving type I polymerization photoinitiators. We demonstrate that a chemically diverse array of hydrogels embedded with cleaved type I photoinitiators could act as microreactors, undergoing colorimetric reactions with bound analytes. The colorimetric signatures produced were visually distinctive and readable with a flatbed document scanner. Signatures of a broad range of sample types were accurately differentiated by unsupervised clustering without knowledge of any analytes bound to the array. The principles described have the potential to enable scalable and cost-effective analysis of complex samples.

Robotic left-stapled total intracorporeal bowel anastomosis versus stapled partial extracorporeal anastomosis: operative technical description and outcomes.

BACKGROUND: Although there is extensive literature on robotic total intracorporeal anastomosis (TICA) for right colon resection, left total ICA using the da Vinci Xi robotic platform has only been described in short case series previously. In this study, we report on the largest cohort of robotic left total ICA, provide a description of our institution's techniques, and compare outcomes to robotic left partial extracorporeal anastomosis (PECA). METHODS: Patients who underwent robotic left colectomy for any underlying pathology from July 1, 2016 through April 30, 2020 were identified by procedure code. A technical description is provided for two unique techniques performed at our institution. Outcomes included operative time, length of stay, supply cost, post-operative ileus, post-operative morbidity and mortality and need for complete mobilization of the splenic flexure. RESULTS: From a review of our institution's data, 83 robotic TICA cases were identified and 76 robotic PECA cases were identified. Common procedures included low anterior resection, sigmoidectomy, left hemicolectomy, and rectopexy with resection. TICA was associated with significantly shorter intraoperative time compared to PECA. CONCLUSIONS: Our series shows that TICA is a safe and feasible technique that does not increase the risk of adverse outcomes. Using either the anvil-forward or anvil-backward technique, we were able to reliably reproduce this method in a total of 83 patients undergoing left colon resection for either benign or malignant diseases.

Preoperative Serum Vedolizumab Levels Do Not Impact Postoperative Outcomes in Inflammatory Bowel Disease.

BACKGROUND: Vedolizumab has been proposed to lead to fewer postoperative complications because of its gut specificity. Studies, however, suggest an increased risk of surgical site infections, yet the data are conflicting. OBJECTIVE: This study aimed to assess the effect of vedolizumab drug levels on postoperative outcomes in patients undergoing major abdominal surgery for IBD. DESIGN: This was a retrospective study of a prospectively maintained database. SETTING: Patients were operated on by a single surgeon at an academic medical center. PATIENTS: A total of 72 patients with IBD undergoing major abdominal surgery were included. INTERVENTIONS: Patients were exposed preoperatively to vedolizumab. MAIN OUTCOME MEASURES: The primary outcome measured was the postoperative morbidity in patients who had IBD with detectable vs undetectable vedolizumab levels. RESULTS: A total of 72 patients were included in the study. Thirty-eight patients had detectable vedolizumab levels (>1.6 µg/mL), and 34 had undetectable vedolizumab levels. The overall rate of complications was 39%, and ileus was the most common complication. There were no significant differences in clinical variables between the detectable and undetectable vedolizumab level patient groups except for the time between the last dose and surgery (p < 0.01). There were 42 patients in the ulcerative colitis cohort; 48% had an undetectable vedolizumab level and 52% had a detectable vedolizumab level. There were no differences in any postoperative morbidity between ulcerative colitis groups. The Crohn's cohort had 27 patients; 48% had an undetectable vedolizumab levels and 52% had a detectable vedolizumab level. There was a significantly lower incidence of postoperative ileus in patients who had Crohn's disease with detectable vedolizumab levels compared with patients with an undetectable vedolizumab level (p < 0.04). LIMITATIONS: Limitations include a low overall patient population and a high rate of stoma formation. CONCLUSIONS: Serum vedolizumab levels do not influence postoperative morbidity in IBD. Vedolizumab may reduce the incidence of postoperative ileus in patients with Crohn's disease. See Video Abstract at http://links.lww.com/DCR/B574. LOS NIVELES DE VEDOLIZUMAB EN SUERO PREOPERATORIO, NO AFECTAN LOS RESULTADOS POSTOPERATORIOS EN LA ENFERMEDAD INFLAMATORIA INTESTINAL: ANTECEDENTES:Se ha propuesto que el vedolizumab presenta menos complicaciones postoperatorias debido a su especificidad intestinal. Sin embargo, estudios sugieren un mayor riesgo de infecciones en el sitio quirúrgico, aunque los datos son contradictorios.OBJETIVO:Evaluar el efecto en los niveles del fármaco vedolizumab, en resultados postoperatorios de pacientes sometidos a cirugía mayor abdominal, por enfermedad inflamatoria intestinal.DISEÑO:Estudio retrospectivo de una base de datos mantenida prospectivamente.ENTORNO CLÍNICO:Pacientes intervenidos por un solo cirujano en un centro médico académico.PACIENTES:Un total de 72 pacientes con enfermedad inflamatoria intestinal sometidos a cirugía mayor abdominal.INTERVENCIONES:Exposición preoperatoria a vedolizumab.PRINCIPALES MEDIDAS DE VALORACIÓN:Morbilidad postoperatoria en pacientes con enfermedad inflamatoria intestinal, con niveles detectables versus no detectables de vedolizumab.RESULTADOS:Se incluyó en el estudio a un total de 72 pacientes. Treinta y ocho pacientes tuvieron niveles detectables de vedolizumab (> 1,6 mcg / ml) y 34 con niveles no detectables de vedolizumab. La tasa global de complicaciones fue del 39% y el íleo fue la complicación más común. No hubo diferencias significativas en las variables clínicas entre los grupos de pacientes con niveles detectables y no detectables de vedolizumab, excepto por el intervalo de tiempo entre la última dosis y la cirugía (p <.01). La cohorte de colitis ulcerosa tuvo 42 pacientes, el 48% con un nivel no detectable de vedolizumab y el 52% un nivel detectable de vedolizumab. No hubo diferencias en ninguna morbilidad postoperatoria entre los grupos de colitis ulcerosa. La cohorte de Crohn tuvo 27 pacientes, 48% con niveles no detectables de vedolizumab y el 52% con niveles detectables de vedolizumab. Hubo una incidencia significativamente menor de íleo postoperatorio en pacientes de Crohn con niveles detectables de vedolizumab, comparados con los pacientes con un nivel no detectable de vedolizumab (p <0,04).LIMITACIONES:Las limitaciones incluyen una baja población general de pacientes y una alta tasa de formación de estomas.CONCLUSIONES:Los niveles séricos de vedolizumab no influyen en la morbilidad postoperatoria de la enfermedad inflamatoria intestinal. Vedolizumab puede reducir la incidencia de íleo postoperatorio en pacientes de Crohn. Consulte Video Resumen en http://links.lww.com/DCR/B574.

Multiquadrant surgery in the robotic era: a technical description and outcomes for da Vinci Xi robotic subtotal colectomy and total proctocolectomy.

BACKGROUND: Common colorectal procedures that require access to all quadrants of the abdomen are subtotal colectomy (STC) and total proctocolectomy (TPC). These are frequently performed with a surgical robot, but multiquadrant operations have unique challenges during robot-assisted surgery. METHODS: Patients who underwent robotic STC or TPC with the da Vinci Xi surgical robot at our institution from July 1, 2016 through June 30, 2019 were identified by diagnosis and procedure codes. A technical description is provided for the techniques utilized at our institution. Outcomes included operative times (OT), supply cost and length of stay. Associated morbidity and mortality was also analyzed. RESULTS: From a review of our institution's robotic surgery data, 37 cases were identified that utilized the described technique. Of these cases, 21 were robotic STC and 16 were TPC. Total mean OT was 276.86 min (SD ± 119.49). Mean OT was further analyzed by year, which demonstrated an overall decrease in OT from 350.91 min (SD ± 46.38) in 2016 to 221.43 min (SD ± 16.46) in 2018 (p = 0.008). A total of 21 cases were performed prior to 2018. Overall OT for STC was 222.81 min (SD ± 14.54) compared to overall TPC OT 347.81 min (SD ± 34.35). Median length of stay was 5 days [25th and 75th percentiles 4, 6, respectively]. There was no 30-day mortality and only one return to operating room for mesenteric bleeding. There was a low risk of mortality associated with this technique. CONCLUSIONS: The current study provides the largest cohort of patients assessed who have undergone multiquadrant robotic STC or TPC. The study provides a detailed description of the technique utilized at our institution. There was no associated 30-day mortality and a low risk of morbidity. The data suggest that the learning curve for improved operative time is between 15 and 20 cases.

General surgery training in the era of robotic surgery: a qualitative analysis of perceptions from resident and attending surgeons.

BACKGROUND: The use of the surgical robot has increased annually since its introduction, especially in general surgery. Despite the tremendous increase in utilization, there are currently no validated curricula to train residents in robotic surgery, and the effects of robotic surgery on general surgery residency training are not well defined. In this study, we aim to explore the perceptions of resident and attending surgeons toward robotic surgery education in general surgery residency training. METHODS: We performed a qualitative thematic analysis of in-person, one-on-one, semi-structured interviews with general surgery residents and attending surgeons at a large academic health system. Convenient and purposeful sampling was performed in order to ensure diverse demographics, experiences, and opinions were represented. Data were analyzed continuously, and interviews were conducted until thematic saturation was reached, which occurred after 20 residents and seven attendings. RESULTS: All interviewees agreed that dual consoles are necessary to maximize the teaching potential of the robotic platform, and the importance of simulation and simulators in robotic surgery education is paramount. However, further work to ensure proper access to simulation resources for residents is necessary. While most recognize that bedside-assist skills are essential, most think its educational value plateaus quickly. Lastly, residents believe that earlier exposure to robotic surgery is necessary and that almost every case has a portion that is level-appropriate for residents to perform on the robot. CONCLUSIONS: As robotic surgery transitions from novelty to ubiquity, the importance of effective general surgery robotic surgery training during residency is paramount. Through in-depth interviews, this study provides examples of effective educational tools and techniques, highlights the importance of simulation, and explores opinions regarding the role of the resident in robotic surgery education. We hope the insights gained from this study can be used to develop and/or refine robotic surgery curricula.

Challenges in Clinical Trial Implementation: Results from a Survey of the National Accreditation Program of Breast Centers (NAPBC).

BACKGROUND: Although the results of clinical trials often guide best practices, changing clinical practice based on clinical trial results can be challenging. The objective of this study was to examine provider-reported barriers to adopting best clinical practices according to clinical trial data. METHODS: A cross-sectional survey was conducted of providers from the National Accreditation Program for Breast Centers about barriers that prevent the incorporation of trial findings. Descriptive analyses and multivariable analyses were performed to determine provider characteristics that were significantly associated with reported barriers. RESULTS: Overall, 383 institutions participated (63.5% response rate), with a total of 1226 physicians responding to the survey (80% response rate). Providers identified national guidelines and meetings as the most compelling way to receive practice-changing information. They reported the following internal barriers to trial implementation: patient preference (45%), strongly held beliefs by partners/colleagues (37%), and insufficient time to discuss new practices (30%). External barriers preventing trial implementation included a lack of agreement from multidisciplinary tumor boards (32%), fear of reimbursement loss (23%), and resistance from clinical staff (20%). Reported barriers differed by provider specialty, with plastic surgeons and radiation oncologists reporting that strongly held beliefs by partners/colleagues and disagreement from multidisciplinary tumor boards were the most significant factors preventing clinical trial implementation. CONCLUSIONS: Physician beliefs and patient preferences are the most frequently reported barriers to clinical trial implementation. Tactics to better educate providers about how to explain new clinical trial data to their patients and colleagues are needed.

Is There a Role for Ileal Pouch Anal Anastomosis in Crohn's Disease?

Traditionally, surgical interventions for colonic Crohn's disease (CD) have been limited to total abdominal colectomy and ileorectal anastomosis, or total proctocolectomy with end ileostomy if there is rectal involvement. However, improved understandings of the biology of CD, as well as the development of biologic therapies, have enabled more limited resections. Here, we review the indications for, and limitations of, specific procedures aiming to preserve intestinal continuity in colonic CD.

Efficacy of Revision Surgery for the Treatment of Stiffness After Total Knee Arthroplasty: A Systematic Review.

BACKGROUND: Knee stiffness following total knee arthroplasty (TKA) may cause pain and reduced functionality, contributing to unsatisfactory surgical outcomes. Revision surgery remains a possible treatment for refractory postoperative stiffness. However, the efficacy of the procedure has not been systematically evaluated. METHODS: A systematic review of the literature was performed to identify studies that reported on outcomes for patients who underwent revision surgery for postoperative stiffness after TKA. RESULTS: Ten studies (including 485 knees) were reviewed. The most common etiologies of stiffness requiring revision TKA were component malposition, malalignment, overstuffing, aseptic loosening, arthrofibrosis, patella baja, and heterotopic ossification. Of 9 studies reviewing range of motion outcomes after revision TKA, 7 studies documented significant improvement and 2 found trends toward improvement. Seven of 8 studies documenting Knee Society knee scores and 7 of 9 studies documenting functional scores found improvement after revision TKA. All studies reporting on pain found improvement at final follow-up after revision TKA. CONCLUSION: Revision TKA results in increased range of motion, improved functionality, and reduced pain in most patients who require surgery for stiffness. The present literature is inadequate to predict which patients will achieve adequate outcomes from revision TKA based on the specific etiology of their stiffness, although identification of the etiology may help in surgical planning. Surgeons performing revision TKA should counsel patients on the risks and benefits of undergoing revision surgery, with the understanding that outcomes for well-selected patients are generally favorable.

Gastrointestinal Malignancy: Genetic Implications to Clinical Applications.

Alterations in the DNA sequences of genes, or mutations, have traditionally been viewed as the primary factors driving tumor progression, however, epigenetic evidence would suggest that some heritable traits are mediated by changes in DNA expression that are not dependent upon alterations in the primary DNA sequence. Advances in the genetic understanding of cancer have, in some instances, allowed for more precise administration of anti-neoplastic therapy. Targeted therapies, the aim of which are to target specific cellular proteins or processes used by the cancer cells, have been advocated to avoid the adverse side effects attributable to a lack of cell specificity associated with traditional chemotherapy. Here we aim to describe the current state of understanding regarding the genetic related causes of cancers, the targeted therapies aimed at killing them and the inter-relationship between these two.

Advances in Biomarkers: Going Beyond the Carcinoembryonic Antigen.

Using biologically available markers to guide treatment decisions in colorectal cancer care is becoming increasingly common, though our understanding of these biomarkers is in its infancy. In this article, we will discuss how this area is rapidly changing, review important biomarkers being used currently, and explain how the results influence clinical decision-making. We will also briefly discuss the possibility of a liquid biopsy and explore several exciting and new options.

Ghrelin decreases motor deficits after traumatic brain injury.

BACKGROUND: Pharmacologic therapy for traumatic brain injury (TBI) has remained relatively unchanged for decades. Ghrelin, an endogenously produced peptide, has been shown to prevent apoptosis and blood-brain barrier dysfunction after TBI. We hypothesize that ghrelin treatment will prevent neuronal degeneration and improve motor coordination after TBI. MATERIALS AND METHODS: A weight drop model created severe TBI in three groups of BALB/c mice: Sham, TBI, and TBI + ghrelin (20 µg intraperitoneal ghrelin). Brain tissue was examined by hematoxylin and eosin and Fluoro-Jade B (FJB) staining to evaluate histologic signs of injury, cortical volume loss, and neuronal degeneration. Additionally, motor coordination was assessed. RESULTS: Ghrelin treatment prevented volume loss after TBI (19.4 ± 9.8 mm(3)versus 71.4 ± 31.4 mm(3); P < 0.05). Similarly, although TBI increased FJB-positive neuronal degeneration, ghrelin treatment decreased FJB staining in TBI resulting in immunohistologic patterns similar to sham. Compared with sham, TBI animals had a significant increase in foot faults at d 1, 3, and 7 (2.75 ± 0.42; 2.67 ± 0.94; 3.33 ± 0.69 versus 0.0 ± 0.0; 0.17 ± 0.19; 0.0 ± 0.0; P < 0.001). TBI + ghrelin animals had significantly decreased foot faults compared with TBI at d 1, 3, and 7 (0.42 ± 0.63; 0.5 ± 0.43; 1.33 ± 0.58; P versus TBI <0.001; P versus sham = NS). CONCLUSIONS: Ghrelin treatment prevented post-TBI cortical volume loss and neurodegeneration. Furthermore, ghrelin improved post-TBI motor deficits. The mechanisms of these effects are unclear; however, a combination of the anti-apoptotic and inflammatory modulatory effects of ghrelin may play a role. Further studies delineating the mechanism of these observed effects are warranted.

Conversion of Contaminated Post-Consumer Polyethylene Terephthalate into a Thermoset Alkyd Coating Using Biosourced Monomers.

The synthesis of a high-performance oxidative cross-linked thermoset alkyd coating is described that utilizes a novel recycling strategy from contaminated postconsumer waste polyethylene terephthalate (wPET). A single-stage "depolymerization-repolymerization" process has been developed that allows the exploitation of a waste stream from a commercial PET recycling process with 95% efficiency, which, when copolymerized with glycerol and tall oil fatty acid, delivers a sustainable fatty acid-functional polyester suitable for use in thermoset alkyd coatings. Physical drying challenges have been tackled via the development of a convergent polymer formulation strategy from a single source of wPET and the formulation of the resulting fatty acid-functional polymers with commercial alkyd driers, delivering a thermoset alkyd coating suitable for industrial applications.