ST6GAL1 is associated with poor response to chemoradiation in rectal cancer.

INTRODUCTION: Colorectal cancer is the third most common cause of cancer death. Rectal cancer makes up a third of all colorectal cases. Treatment for locally advanced rectal cancer includes chemoradiation followed by surgery. We have previously identified ST6GAL1 as a cause of resistance to chemoradiation in vitro and hypothesized that it would be correlated with poor response in human derived models and human tissues. METHODS: Five organoid models were created from primary human rectal cancers and ST6GAL1 was knocked down via lentivirus transduction in one model. ST6GAL1 and Cleaved Caspase-3 (CC3) were assessed after chemoradiation via immunostaining. A tissue microarray (TMA) was created from twenty-six patients who underwent chemoradiation and had pre- and post-treatment specimens of rectal adenocarcinoma available at our institution. Immunohistochemistry was performed for ST6GAL1 and percent positive cancer cell staining was assessed and correlation with pathological grade of response was measured. RESULTS: Organoid models were treated with chemoradiation and both ST6GAL1 mRNA and protein significantly increased after treatment. The organoid model targeted with ST6GAL1 knockdown was found to have increased CC3 after treatment. In the tissue microarray, 42 percent of patient samples had an increase in percent tumor cell staining for ST6GAL1 after treatment. Post-treatment percent staining was associated with a worse grade of treatment response (p = 0.01) and increased staining post-treatment compared to pre-treatment was also associated with a worse response (p = 0.01). CONCLUSION: ST6GAL1 is associated with resistance to treatment in human rectal cancer and knockdown in an organoid model abrogated resistance to apoptosis caused by chemoradiation.

Racial Differences in Aging-Related Deficits Among Older Adults With Colorectal Cancer.

BACKGROUND: Despite the known influences of both race- and aging-related factors in colorectal cancer outcomes and mortality, limited literature is available on the intersection between race and aging-related impairments. OBJECTIVE: To explore racial differences in frailty and geriatric deficit subdomains among patients with colorectal cancer. DESIGN: Retrospective study using data from the Cancer and Aging Resilience Evaluation registry. SETTINGS: A comprehensive cancer center in the Deep South. PATIENTS: Older adults (aged ≥60 years) with colorectal cancer. MAIN OUTCOME MEASURES: Measure of frailty and geriatric assessment subdomains of physical function, functional status, cognitive complaints, psychological function, and health-related quality of life. RESULTS: Black patients lived in areas with a higher social vulnerability index compared to White patients (0.69 vs 0.49; p < 0.01) and had limited social support more often (54.5% vs 34.9%; p = 0.01). After adjustment for age, cancer stage, comorbidities, and social vulnerability index, Black patients were found to have a higher rate of frailty than White patients (adjusted OR 3.77; 95% CI, 1.76-8.18; p = 0.01). In addition, Black patients had more physical limitations (walking 1 block: adjusted OR 1.93; 95% CI, 1.02-3.69; p = 0.04), functional limitations (activities of daily living: adjusted OR 3.21; 95% CI, 1.42-7.24; p = 0.01), and deficits in health-related quality of life (poor global self-reported health: adjusted OR 2.45; 95% CI, 1.23-5.13; p = 0.01). Similar findings were shown after stratification by stage I to III vs IV. LIMITATIONS: Retrospective study at a single institution. CONCLUSIONS: Among older patients with colorectal cancer, Black patients were more likely to be frail than White patients, with deficits observed specifically in physical function, functional status, and health-related quality of life. Geriatric assessment may provide an important tool in addressing racial inequities in colorectal cancer. DIFERENCIAS RACIALES EN LOS DFICITS RELACIONADOS CON EL ENVEJECIMIENTO ENTRE ADULTOS MAYORES CON CNCER COLORRECTAL: ANTECEDENTES: A pesar de las influencias conocidas de los factores relacionados con la raza y el envejecimiento en los resultados y la mortalidad del cáncer colorectal, hay muy poca literatura sobre la intersección entre los impedimentos relacionados con la raza y el envejecimiento.OBJETIVO: El objetivo era explorar las diferencias raciales en los subdominios de fragilidad y déficit geriátrico entre los pacientes con cáncer colorectal.DISEÑO: Estudio retrospectivo utilizando datos del registro Cancer and Aging Resilience Evaluation.AJUSTES: Un centro oncológico integral en el Sur Profundo.PACIENTES: Adultos mayores (≥60 años) con cáncer colorrectal de raza Negra o Blanca.PRINCIPALES MEDIDAS DE RESULTADO: Medida compuesta de fragilidad y subdominios de evaluación geriátrica de función física, estado funcional, quejas cognitivas, función psicológica y calidad de vida relacionada con la salud.RESULTADOS: De los 304 pacientes incluidos, el 21,7% (n = 66) eran negros y la edad media era de 69 años. Los pacientes negros vivían en áreas con un índice de vulnerabilidad social (SVI) más alto en comparación con los pacientes blancos (SVI 0,69 vs 0,49; p < 0,01) y con mayor frecuencia tenían apoyo social limitado (54,5% vs 34,9%; p = 0,01). Después de ajustar por edad, estadio del cáncer, comorbilidades y SVI, los pacientes de raza negra tenían una mayor tasa de fragilidad en comparación con los pacientes de raza blanca (ORa 3,77, IC del 95%: 1,76-8,18; p = 0,01). Además, los pacientes negros tenían más limitaciones físicas (caminar 1 cuadra: ORa 1,93, IC 95% 1,02-3,69; p = 0,04), limitaciones funcionales (actividades de la vida diaria: ORa 3,21, IC 95% 1,42-7,24; p = 0,01 ) y déficits en la calidad de vida relacionada con la salud (mala salud global autoinformada: ORa 2,45, IC 95% 1,23-5,13; p = 0,01). Las quejas cognitivas y las funciones psicológicas no difirieron según la raza (p > 0,05). Se mostraron hallazgos similares después de la estratificación por estadio I-III frente a IV.LIMITACIONES: Estudio retrospectivo en una sola institución.CONCLUSIONES: Entre los pacientes mayores con cáncer colorrectal, los pacientes negros tenían más probabilidades que los pacientes blancos de ser frágiles, observándose déficits específicamente en la función física, el estado funcional y la calidad de vida relacionada con la salud. La evaluación geriátrica puede proporcionar una herramienta importante para abordar las desigualdades raciales en el cáncer colorrectal.

Pearls and Pitfalls for Surgical Investigators in Basic and Translational Research.

Surgeon-scientists are uniquely positioned to contribute to our understanding of the fundamental biology of surgical disease and to bring a unique perspective that leads to innovation in the diagnosis and treatment of many conditions. However, it is broadly recognized that due to the changing landscape of surgery and science, the surgeon-scientists of today face multiple challenges in this pursuit. Today, surgeon-scientists face an increased pressure from their department and hospital to generate clinical revenue, decreased availability of grant funding, greater administrative burden, rising complexity of fundamental research, increased medical school debt, and a growing desire for work-life balance. Given that survival of surgeon-scientists is critical for the progress of not only surgery but medical innovation at large, many surgical societies, notably the Association for Academic Surgery (AAS) and the Society of University Surgeons (SUS) have focused on the issues faced by surgeon-scientists. In this regard, the Basic and Translational Research Committee of the AAS and the Research Committee of the SUS organized a hot topic session at the 2021 Academic Surgical Congress in which experts discussed and addressed many issues concerning the surgeon-scientist pathway. This manuscript provides an overview of the issues discussed at this session.

Using the H-index as a factor in the promotion of surgical faculty.

Introduction: Academic productivity is an important determinant for promotion. However, the measurement of academic productivity is ill-defined. The aim of this study is to demonstrate the academic productivity at the time of promotions at our institution. Methods: We reviewed the data of 33 faculty from Department of Surgery at our institution who were promoted from 2006 to 2021. Gender, academic productivity at hiring, and each promotion were obtained. Academic productivity was assessed by bibliometric indices including total number of publications and citations, and H-index, which were obtained from Web of Science. T-test, Mann-Whitney U test, Fisher's exact test and linear regression analysis were used to assess the association of H-index with length of promotion and gender. P < 0.050 were considered statistically significant. Results: The medians (interquartile ranges) of indexes at hiring, at promotions from assistant professors to associate professors, and from associate professors to full professors were 6.0 (1.5-9.5), 11.0 (9.0-18.0) and 17.0 (9.0-23.0) respectively. A simple linear regression showed significant correlation between the length of promotion to associate professors and their H-indexes at hiring. (F (1, 27) = 10.55, p = 0.003, R2 of 0.281.) There was no statistical significance in the difference of H-indexes at promotions between male and female faculty. Conclusion: At our institution, the median H-indexes at the time of promotions from assistant professor to associate professor and from associate professor to full professor are 11.0 and 17.0. Using the H-index as an objective measure can be a useful tool to junior surgical faculty as reference for applying promotion.

Inhibition of DNA-PK may improve response to neoadjuvant chemoradiotherapy in rectal cancer.

Treatment of locally advanced rectal cancer includes chemoradiation and surgery, but patient response to treatment is variable. Patients who have a complete response have improved outcomes; therefore, there is a critical need to identify mechanisms of resistance to circumvent them. DNA-PK is involved in the repair of DNA double-strand breaks caused by radiation, which we found to be increased in rectal cancer after treatment. We hypothesized that inhibiting this complex with a DNA-PK inhibitor, Peposertib (M3814), would improve treatment response. We assessed pDNA-PK in a rectal cancer cell line and mouse model utilizing western blotting, viability assays, γH2AX staining, and treatment response. The three treatment groups were: standard of care (SOC) (5-fluorouracil (5FU) with radiation), M3814 with radiation, and M3814 with SOC. SOC treatment of rectal cancer cells increased pDNA-PK protein and increased γH2AX foci, but this was abrogated by the addition of M3814. Mice with CT26 tumors treated with M3814 with SOC did not differ in average tumor size but individual tumor response varied. The clinical complete response rate improved significantly with the addition of M3814 but pathological complete response did not. We investigated alterations in DNA repair and found that Kap1 and pATM are increased after M3814 addition suggesting this may mediate resistance. When the DNA-PK inhibitor, M3814, is combined with SOC treatment, response improved in some rectal cancer models but an increase in other repair mechanisms likely diminishes the effect. A clinical trial is ongoing to further explore the role of DNA-PK inhibition in rectal cancer treatment.

Sialyltransferase ST6GAL-1 mediates resistance to chemoradiation in rectal cancer.

Locally advanced rectal cancer is typically treated with chemoradiotherapy followed by surgery. Most patients do not display a complete response to chemoradiotherapy, but resistance mechanisms are poorly understood. ST6GAL-1 is a sialyltransferase that adds the negatively charged sugar, sialic acid (Sia), to cell surface proteins in the Golgi, altering their function. We therefore hypothesized that ST6GAL-1 could mediate resistance to chemoradiation in rectal cancer by inhibiting apoptosis. Patient-derived xenograft and organoid models of rectal cancer and rectal cancer cell lines were assessed for ST6GAL-1 protein with and without chemoradiation treatment. ST6GAL-1 mRNA was assessed in untreated human rectal adenocarcinoma by PCR assays. Samples were further assessed by Western blotting, Caspase-Glo apoptosis assays, and colony formation assays. The presence of functional ST6GAL-1 was assessed via flow cytometry using the Sambucus nigra lectin, which specifically binds cell surface α2,6-linked Sia, and via lectin precipitation. In patient-derived xenograft models of rectal cancer, we found that ST6GAL-1 protein was increased after chemoradiation in a subset of samples. Rectal cancer cell lines demonstrated increased ST6GAL-1 protein and cell surface Sia after chemoradiation. ST6GAL-1 was also increased in rectal cancer organoids after treatment. ST6GAL-1 knockdown in rectal cancer cell lines resulted in increased apoptosis and decreased survival after treatment. We concluded that ST6GAL-1 promotes resistance to chemoradiotherapy by inhibiting apoptosis in rectal cancer cell lines. More research will be needed to further elucidate the importance and mechanism of ST6GAL-1-mediated resistance.

Ileostomy Patients Using Patient Engagement Technology Experience Decreased Length of Stay.

Patients who undergo colorectal surgery, particularly, construction of a new ileostomy, are known to have longer length of stay (LOS) and increased readmissions. With the increased availability of patient engagement technology (PET), we hypothesized that because PET facilitates education before and after surgery, ileostomy patients who used PET would have decreased LOS without increasing readmissions. Variables were obtained from the National Surgical Quality Improvement Program (NSQIP) database for patients undergoing ileostomy construction. Study patients were categorized into three groups: pre-PET (patients prior to PET), non-PET (patients who did not use PET), and PET users (patients who used PET). Univariate analysis of patient and surgical characteristics, LOS, ED visits, and readmissions and multivariable modeling of potential predictors of LOS were performed. There were 106 patients in the pre-PET, 51 in the PET, and 108 in the non-PET and cohorts were similar except pre-op diagnosis. Length of stay was lower for the PET cohort (p = 0.0001), with no significant difference in readmission or ED visits. On multivariable analysis, we identified the PET cohort as an independent predictor of shorter LOS relative to non-PET and pre-PET (p = 0.007 and p = 0.02, respectively). Similarly, patients had significantly shorter LOS who had a diagnosis of neoplasm as compared to IBD (p = 0.03). Hypertension requiring medication (p = 0.001) and Black race relative to White race (p = 0.002) were independent predictors of longer LOS. In this study of ileostomy patients, we have shown that use of PET is an independent predictor of decreased LOS without increased ED visits or readmissions.

NIH Funding of Researchers in Surgery: Decreased Career Development Awards Over Time.

BACKGROUND: Over time, NIH funding has become increasingly competitive. In addition, academic surgeons' research competes with time required for patient care, operating, and administrative work. Due to these competing interests for surgeons, we hypothesize that the percentage of NIH grants awarded to researchers from departments of surgery is decreasing. METHODS: The NIH Research Portfolio Online Reporting Tool was queried for the number and value of new and renewal R01 grants, and career development awards noting which surgery departments received awards from 1998 to -2018. Statistical analysis was performed using univariate and multivariable logistic regression. RESULTS: The number of career development awards granted to researchers from departments of surgery decreased significantly over time (P = 0.007) while new R01's and R01 renewal awards were stable. The number of grants awarded to researchers from all procedural departments were compared to non-procedural departments and again, career development awards decreased significantly (P = 0.005) over time but new R01's and R01 renewals stayed stable. Looking at the difference in average dollar amount received for new R01, renewal R01, or career development awards between department of surgery awardees and non-surgery over time, there was no significant difference. CONCLUSIONS: NIH funding is becoming increasingly competitive and surgeons have many competing interests. Our study found that there has been a significant decrease in career development awards to department of surgery awardees and procedural specialists. The decrease in receipt of these awards is particularly concerning given that they are meant to provide protected time for developing researchers and thus have potential consequences for future research.

Considerations for Thyroidectomy as Treatment for Graves Disease.

Hyperthyroidism is a clinical state that results from abnormally elevated thyroid hormones. Thyroid gland affects many organ systems; therefore, patients usually present with multiple clinical manifestations that involve many organ systems such as the nervous, cardiovascular, muscular, and endocrine system as well as skin manifestations. Hyperthyroidism is most commonly caused by Graves disease, which is caused by autoantibodies to the thyrotropin receptor (TRAb). Other causes of hyperthyroidism include toxic multinodular goiter, toxic single adenoma, and thyroiditis. Diagnosis of hyperthyroidism can be established by measurement of thyroid-stimulating hormone (TSH), which will be suppressed with either elevated free T4 and/or T3 (overt hyperthyroidism) or normal free T3 and T4 (subclinical hyperthyroidism). Hyperthyroidism can be treated with antithyroid drugs (ATDs), radioactive iodine (RAI), or thyroidectomy. ATDs have a higher replacement rate when compared with RAI or thyroidectomy. Recent evidence has shown that thyroidectomy is a very effective, safe treatment modality for hyperthyroidism and can be performed as an outpatient procedure. This review article provides some of the most recent evidence on diagnosing and treating patients with hyperthyroidism.

A Formula for Planning and Predicting Postoperative Mammoplasty Results.

PURPOSE: For women with macromastia, reduction mammoplasty is a safe and effective solution to increasing quality of life through alleviating pain and improving aesthetics. This study developed a way to combine a surgeon's view of breast measurement (volume) with a patient's view of breast measurement (distance between nipple and notch, inframammary fold, or midline) to provide patients with a better understanding of expected surgical outcomes after breast reduction with a medial superior pedicle. PATIENT AND METHODS: An institutional review board approved retrospective chart review was performed on all medial superior pedicle reduction mammoplasties performed by a single surgeon at a university medical center from 2008 to 2016, and a total of 133 patients were identified. Measurements of interest for this study were nipple to sternal notch (N-S), nipple to inframammary fold (N-I), nipple to midline (N-M), and breast diameter (BD). The average bilateral change per measurement was calculated for each patient in centimeters. Change was averaged for left and right breasts for N-S, N-I, N-M, and BD per patient. Grams removed for left and right breasts were also averaged. Each measurement of average change was divided by the gram average and multiplied by 100 to obtain centimeter change per 100 grams. Individual patient measurements per type of measurement were averaged to achieve a final improvement reported in centimeters per 100 g tissue removed per breast. RESULTS: The average change in the N-S distance was calculated to be a decrease of 1.5 ± 0.8 cm/100 g of breast tissue removed. The average change in N-I was calculated to be an overall decrease of 0.7 ± 0.5 cm/100 g. The average change in N-M was calculated to be a decrease of 0.1 ± 0.3 cm/100 g. Finally, the average change in BD was calculated to be 0.0 ± 0.4 cm/100 g. CONCLUSIONS: A surgeon's expression of breast measurements in terms of volume can be difficult for a patient to understand and visualize. This study determined the impact volume has on length of typical breast measurements to increase patients' understanding of expected outcomes. In summary, patients can be told to expect to see a nipple elevation of 1.5 cm per 100 grams of breast tissue removed using this medial superior pedicle technique.