Pre-extensively drug-resistant tuberculosis among pulmonary multidrug-resistant tuberculosis patients in Eastern Nigeria.

Background: Pre-extensively drug-resistant tuberculosis (Pre-XDR-TB), an emerging form of drug-resistant tuberculosis, is challenging efforts at tuberculosis control, leading to treatment failure among multidrug-resistant tuberculosis (MDR-TB) patients and progression to extensively drug-resistant tuberculosis (XDR-TB). We determined the rate of Pre-XDR-TB among multidrug-resistant patients in Southeast, Nigeria. Methods: A prospective laboratory-based study was carried out at the South East Zonal Tuberculosis Reference Laboratory from January 2021 to December 2021. Second-line drug (SLD) resistance was performed on 225 sputum samples of multidrug-resistant patients prior to treatment initiation using GenoType MTBDRsl genotypic drug susceptibility testing (DST) method. Results: The rate of Pre-XDR-TB among 225 MDR-TB cases was 3.1%. Fluoroquinolone-resistant Pre-XDR-TB was observed (100%) in previously treated tuberculosis cases. Only one (0.4%) case showed resistance to both fluoroquinolone (FQ) and one second-line injectable drug (XDR-TB). The extensively drug-resistant case observed was a de-novo resistance. Exactly 0.9% of the multidrug-resistant cases showed resistance to second-line injectables. Conclusion: The prevalence of Pre-XDR-TB among MDR-TB cases was high. There is need for rapid detection of Pre-XDR-TB among MDR-TB cases before treatment initiation.

Surgical versus non-surgical management for patients with malignant bowel obstruction (S1316): a pragmatic comparative effectiveness trial.

BACKGROUND: Malignant small bowel obstruction has a poor prognosis and is associated with multiple related symptoms. The optimal treatment approach is often unclear. We aimed to compare surgical versus non-surgical management with the aim to determine the optimal approach for managing malignant bowel obstruction. METHODS: S1316 was a pragmatic comparative effectiveness trial done within the National Cancer Trials Network at 30 hospital and cancer research centres in the USA, Mexico, Peru, and Colombia. Participants had an intra-abdominal or retroperitoneal primary cancer confirmed via pathological report and malignant bowel disease; were aged 18 years or older with a Zubrod performance status 0-2 within 1 week before admission; had a surgical indication; and treatment equipoise. Participants were randomly assigned (1:1) to surgical or non-surgical treatment using a dynamic balancing algorithm, balancing on primary tumour type. Patients who declined consent for random assignment were offered a prospective observational patient choice pathway. The primary outcome was the number of days alive and out of the hospital (good days) at 91 days. Analyses were based on intention-to-treat linear, logistic, and Cox regression models combining data from both pathways and adjusting for potential confounders. Treatment complications were assessed in all analysed patients in the study. This completed study is registered with ClinicalTrials.gov, NCT02270450. FINDINGS: From May 11, 2015, to April 27, 2020, 221 patients were enrolled (143 [65%] were female and 78 [35%] were male). There were 199 evaluable participants: 49 in the randomised pathway (24 surgery and 25 non-surgery) and 150 in the patient choice pathway (58 surgery and 92 non-surgery). No difference was seen between surgery and non-surgery for the primary outcome of good days: mean 42·6 days (SD 32·2) in the randomised surgery group, 43·9 days (29·5) in the randomised non-surgery group, 54·8 days (27·0) in the patient choice surgery group, and 52·7 days (30·7) in the patient choice non-surgery group (adjusted mean difference 2·9 additional good days in surgical versus non-surgical treatment [95% CI -5·5 to 11·3]; p=0·50). During their initial hospital stay, six participants died, five due to cancer progression (four patients from the randomised pathway, two in each treatment group, and one from the patient choice pathway, in the surgery group) and one due to malignant bowel obstruction treatment complications (patient choice pathway, non-surgery). The most common grade 3-4 malignant bowel obstruction treatment complication was anaemia (three [6%] patients in the randomised pathway, all in the surgical group, and five [3%] patients in the patient choice pathway, four in the surgical group and one in the non-surgical group). INTERPRETATION: In our study, whether patients received a surgical or non-surgical treatment approach did not influence good days during the first 91 days after registration. These findings should inform treatment decisions for patients hospitalised with malignant bowel obstruction. FUNDING: Agency for Healthcare Research and Quality and the National Cancer Institute. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

Comparative whole genome analysis reveals re-emergence of human Wa-like and DS-1-like G3 rotaviruses after Rotarix vaccine introduction in Malawi.

G3 rotaviruses rank among the most common rotavirus strains worldwide in humans and animals. However, despite a robust long-term rotavirus surveillance system from 1997 at Queen Elizabeth Central Hospital in Blantyre, Malawi, these strains were only detected from 1997 to 1999 and then disappeared and re-emerged in 2017, 5 years after the introduction of the Rotarix rotavirus vaccine. Here, we analysed representative twenty-seven whole genome sequences (G3P[4], n = 20; G3P[6], n = 1; and G3P[8], n = 6) randomly selected each month between November 2017 and August 2019 to understand how G3 strains re-emerged in Malawi. We found four genotype constellations that were associated with the emergent G3 strains and co-circulated in Malawi post-Rotarix vaccine introduction: G3P[4] and G3P[6] strains with the DS-1-like genetic backbone genes (G3-P[4]-I2-R2-C2-M2-A2-N2-T2-E2-H2 and G3-P[6]-I2-R2-C2-M2-A2-N2-T2-E2-H2), G3P[8] strains with the Wa-like genetic backbone genes (G3-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1), and reassortant G3P[4] strains consisting of the DS-1-like genetic backbone genes and a Wa-like NSP2 (N1) gene (G3-P[4]-I2-R2-C2-M2-A2-N1-T2-E2-H2). Time-resolved phylogenetic trees demonstrated that the most recent common ancestor for each ribonucleic acid (RNA) segment of the emergent G3 strains was between 1996 and 2012, possibly through introductions from outside the country due to the limited genetic similarity with G3 strains which circulated before their disappearance in the late 1990s. Further genomic analysis revealed that the reassortant DS-1-like G3P[4] strains acquired a Wa-like NSP2 genome segment (N1 genotype) through intergenogroup reassortment; an artiodactyl-like VP3 through intergenogroup interspecies reassortment; and VP6, NSP1, and NSP4 segments through intragenogroup reassortment likely before importation into Malawi. Additionally, the emergent G3 strains contain amino acid substitutions within the antigenic regions of the VP4 proteins which could potentially impact the binding of rotavirus vaccine-induced antibodies. Altogether, our findings show that multiple strains with either Wa-like or DS-1-like genotype constellations have driven the re-emergence of G3 strains. The findings also highlight the role of human mobility and genome reassortment events in the cross-border dissemination and evolution of rotavirus strains in Malawi necessitating the need for long-term genomic surveillance of rotavirus in high disease-burden settings to inform disease prevention and control.

Leadership Diversity in the Association of Program Directors in Surgery: A Report of Progress.

BACKGROUND: Across the last several years, numerous surgical departments and societies have focused on addressing the lack of diversity, equity, and inclusion (DEI) in the field. Since the Association of Program Directors in Surgery (APDS) Diversity and Inclusion Taskforce was created in 2017 (and solidified as a formal committee in 2018, herein referred to as the APDS-DIC), it has sought to address gaps in diversity at various phases of training and development from medical student to surgical leader. OBJECTIVE: In follow-up to a 2018 study that benchmarked leadership demographics of the APDS, this study analyzed how the APDS' efforts have aligned with recommended DEI strategies and whether this produced demographic changes in organizational leadership. METHODS: Fifteen years (2008-2022) of publicly available APDS annual meeting program data and APDS membership lists were analyzed. Leadership positions in the organization were examined by officer, program/vice chair, executive committee, and board of directors. A 2-tailed T-test compared differences in the average proportion of leaders from specific demographic groups before and after the APDS-DIC inception (2008-2016 vs. 2017-2022). RESULTS: APDS has 724 unique faculty and 140 resident members. The majority of both groups identified as White (68% of faculty and 58% of residents). Over 15 years, there have been 307 available leadership positions held by 67 individuals. All presidents and president-elect positions have been held by White surgeons; nearly 80% have been men. The average proportion of female leaders and the average proportion of racial/ethnic minority leaders were both significantly higher after implementation of the APDS-DIC in 2017 (p=0.0009 for gender and p=0.036 for racial/ethnic minorities). CONCLUSIONS: The APDS' commitment to DEI efforts and establishment of the APDS-DIC in 2017 was associated with a significant increase in women and non-White minorities in organizational leadership positions. The specific role of the APDS-DIC in propelling surgeons from underrepresented groups into leadership and promoting key DEI efforts is broadly applicable to other surgical organizations.

The APDS General Surgery Education Quality Improvement Program (EQIP).

BACKGROUND: Although the ACGME has called for outcomes-based evaluation of residency programs, few metrics or benchmarks exist connecting educational processes with resident educational outcomes. To address this deficiency, a national Education Quality Improvement Program (EQIP) for General Surgery training is proposed. METHODS: We describe the initial efforts to create this platform. In addition, a national survey was administered to 330 Program Directors to assess their interest in and concerns about a continuous educational quality improvement project. RESULTS: We demonstrate that through a collaborative process and the support of the Association of Program Directors in Surgery (APDS), we were able to develop the groundwork for a national surgical educational improvement project, now called EQIP. The survey response rate was 45.8% (152 of 332 programs) representing a mix of university (55.3%), university-affiliated (18.4%), independent (24.3%), and military (2.0%) programs. Most respondents (66.2%) had not previously heard of EQIP. Most respondents (69.7%) believe that educational outcomes can be measured. The majority of respondents indicated they believed EQIP could be successful (57%). Only 2.3% thought EQIP would not be successful. Almost all programs (98.7%) expressed a willingness to participate, although 19.1% did not believe that they had adequate resources to participate. CONCLUSION: The APDS EQIP platform holds promise as a useful and achievable method to obtain educational outcomes data. These data can be used as a basis for continuous surgical educational quality improvement. General Surgery Program Directors have expressed enthusiasm for EQIP and are willing to participate in the program examining outcomes of General Surgery training programs, with an ultimate goal of improving overall residency training.

The Role of Implicit Bias in Surgical Resident Evaluations.

BACKGROUND: Implicit bias is a key factor preventing the advancement and retention of women and underrepresented minorities in academic surgery. PURPOSE: We examined the role of implicit bias in the technical component of the residency performance evaluation. The Fundamentals of Laparoscopic Surgery (FLS) score, an objective measure of technical performance, was compared to the subjective technical skills (TS) score given by attending surgeons. PROCEDURES: FLS scores and the average TS scores from chief resident evaluations at a university program were analyzed from 2015 to 2019 (n = 29 residents; female 22%, underrepresented minorities 27%).  The average TS score for each resident was calculated, scores dichotomized above and below the mean for the program and analyzed across gender and racial identity. MAIN FINDINGS: There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). PRINCIPAL CONCLUSIONS: There was statistically significant difference in agreement between the FLS and TS scores of individual female and male trainees, suggesting the presence of implicit bias in our pilot study. Further research with a larger sample size is warranted. OBJECTIVE: To investigate the presence of implicit bias against women and underrepresented minorities in the technical component of the residency performance evaluation. We hypothesized that women and underrepresented racial minorities would have lower subjective technical skills (TS) scores as compared to their objective FLS scores, relative to the mean for the training program. DESIGN: FLS scores and the average TS scores from chief resident performance evaluations were analyzed from 2015-2019. Both FLS and the average TS scores were dichotomized above and below the mean for the program and analyzed across gender and racial identity.  Research was approved by institutional IRB. SETTING: This study was conducted at the University of Arizona General Surgery Residency Program at Banner University Medical Center in Tucson, Arizona. This is a tertiary care university training program. PARTICIPANTS: Educational records of graduated general surgery chief residents from 2015 to 2019 were accessed for the study. We analyzed 37 TS scores from attending performance evaluations and 29 FLS scores reported to the program during the study period (22% female, 27% underrepresented racial minorities). RESULTS: There were no significant differences in FLS or TS scores between male and female trainees or racial identity. The Kappa correlation coefficient between the 2 dichotomized scores was significantly lower for female (-0.50) versus male (0.23) trainees (p < 0.01); it was not significantly different between racial groups (p = 0.34). CONCLUSIONS: There was a statistically significant difference in agreement between the FLS and TS score of individual female and male trainees, suggesting the presence of implicit bias in this pilot study. Further research with a larger sample size is warranted.

Race, Gender, and International Medical Graduates: Leadership Trends in Academic Surgical Societies.

BACKGROUND: Non-White and female surgeons are underrepresented in academic surgery faculty. We hypothesized that the leadership of major U.S. regional and national general surgery societies reflects these same racial and gender disparities. We suspected that attending a medical school or residency program with academic prestige would be more common for surgeons from underrepresented backgrounds. MATERIALS AND METHODS: Race/ethnicity and gender of the 2020-21 executive council members and 2012-21 society presidents of 25 major general surgery societies (7 regional, 18 national) was assessed. Academic prestige was determined by reputational top 25 programs, identified using U.S. News and World Report and Doximity rankings for medical school and residency, respectively. RESULTS: Surgical society executive council members (n = 204) were predominantly White (75.5%) and male (67.2%). The 50 non-White council members were Asian (n = 37), Black (n = 7), and Latinx (n = 6). 14 (6.9%) were international medical graduates (IMGs). 56.4% attended a school or program ranked in the Top 25 (n = 115). Surgical society presidents 2012-21 (n = 242) have been mostly White (87.6%) and male (83.4%). Non-White, male surgical society presidents were Asian (n = 13), Black (n = 9), and Latino (n = 6). Of the 41 female surgery society presidents, 92.7% were White, 7.3% (n = 3) Asian, and none Black or Latina. 13 were IMGs (5.3%). 55.0% of society presidents attended Top 25 (n = 133) schools or programs. The three non-White, female presidents all attended Top 25 schools/programs (100%). Of the 15 unique individuals who were male, non-White presidents, 12 attended top 25 schools or programs (80%). CONCLUSION: Women, non-White surgeons, and IMGs are underrepresented in U.S. surgical society leadership. Increasing racial diversity in U.S. surgical society leadership may require intentionality in mentorship and sponsorship, particularly for surgeons who did not attend prestigious schools or programs.

Early Detection and Remediation of Problem Learners.

There are myriad types of problem learners in surgical residency and most have difficulty in more than 1 competency. Programs that use a standard curriculum of study and assessment are most successful in identifying struggling learners early. Many problem learners lack appropriate systems for study; a multidisciplinary educational team that is separate from the team that evaluates the success of remediation is critical. Struggling residents who require formal remediation benefit from performance improvement plans that clearly outline the issues of concern, describe the steps required for remediation, define success of remediation, and outline consequences for failure to remediate appropriately.

Molecular Pathways Associated with Kallikrein 6 Overexpression in Colorectal Cancer.

Colorectal cancer (CRC) remains one of the leading causes of cancer-related death worldwide. The high mortality of CRC is related to its ability to metastasize to distant organs. The kallikrein-related peptidase Kallikrein 6 (KLK6) is overexpressed in CRC and contributes to cancer cell invasion and metastasis. The goal of this study was to identify KLK6-associated markers for the CRC prognosis and treatment. Tumor Samples from the CRC patients with significantly elevated KLK6 transcript levels were identified in the RNA-Seq data from Cancer Genome Atlas (TCGA) and their expression profiles were evaluated using Gene Ontology (GO), Phenotype and Reactome enrichment, and protein interaction methods. KLK6-high cases had a distinct spectrum of mutations in titin (TTN), APC, K-RAS, and MUC16 genes. Differentially expressed genes (DEGs) found in the KLK6-overexpressing CRCs were associated with cell signaling, extracellular matrix organization, and cell communication regulatory pathways. The top KLK6-interaction partners were found to be the members of kallikrein family (KLK7, KLK8, KLK10), extracellular matrix associated proteins (keratins, integrins, small proline rich repeat, S100A families) and TGF-ß, FOS, and Ser/Thr protein kinase signaling pathways. Expression of selected KLK6-associated genes was validated in a subset of paired normal and tumor CRC patient-derived organoid cultures. The performed analyses identified KLK6 itself and a set of genes, which are co-expressed with KLK6, as potential clinical biomarkers for the management of the CRC disease.

Do General Surgery Residency Program Websites Feature Diversity?

OBJECTIVE: This study assesses ways in which General Surgery residency program websites demonstrate diversity. DESIGN: Literature review and diversity expert opinion informed selection of diversity elements. We limited our evaluation to residency program-specific webpages. We identified 8 program website elements that demonstrate programmatic commitment to diversity: (1) standard nondiscrimination statement; (2) program-specific diversity and inclusion message; (3) community demographics; (4) personalized biographies of faculty, (5) personalized biographies of residents; (6) individual photographs of faculty; (7) individual photographs of residents; and (8) list of additional resources available for trainees. We evaluated the impact of program type (university, independent, or military); city population; region; program director gender and ethnicity; and program size on incorporation of these eight elements. We dichotomized programs that had ≥4 of these elements on their website and determined association with the above factors using chi-square or Fisher's exact test. SETTING: Website review July to December 2019. PARTICIPANTS: All nonmilitary-based general surgery residency program members of the Association of Program Directors in Surgery (APDS) (n = 242/251). RESULTS: General Surgery residency program websites included a mean of 2.7 ± 1.5 elements that showcase diversity. Most program websites (n = 215, 89%) featured ≤4 elements (range 1-4), while 15 (6.2%) had none. When stratified by programs having 4 or more elements on their website, university-based program (p < 0.001) was the only factor associated. Resident photos (n = 147, 61%), resources available to trainees (n = 146, 60%), faculty photos (n = 139, 57%), and community demographics (n = 93, 38%) were the most common of the 8 website elements. CONCLUSIONS: Residency program websites are vital to recruiting applicants. Featuring specific elements on the General Surgery residency website that display a program's commitment to diversity and inclusion may be important in attracting a diverse candidate pool. This research highlights opportunities programs may use to demonstrate more effectively a residency program's commitment to diversity and inclusion.

Ad astra per aspera (Through Hardships to the Stars): Lessons Learned from the First National Virtual APDS Meeting, 2020.

OBJECTIVE: After COVID-19 rendered in-person meetings for national societies impossible in the spring of 2020, the leadership of the Association of Program Directors in Surgery (APDS) innovated via a virtual format in order to hold its national meeting. DESIGN: APDS leadership pre-emptively considered factors that would be important to attendees including cost, value, time, professional commitments, education, sharing of relevant and current information, and networking. SETTING: The meeting was conducted using a variety of virtual formats including a web portal for entry, pre-ecorded poster and oral presentations on the APDS website, interactive panels via a web conferencing platform, and livestreaming. PARTICIPANTS: There were 298 registrants for the national meeting of the APDS, and 59 participants in the New Program Directors Workshop. The registrants and participants comprised medical students, residents, associate program directors, program directors, and others involved in surgical education nationally. RESULTS: There was no significant difference detected for high levels of participant satisfaction between 2019 and 2020 for the following items: overall program rating, topics and content meeting stated objectives, relevant content to educational needs, educational format conducive to learning, and agreement that the program will improve competence, performance, communication skills, patient outcomes, or processes of care/healthcare system performance. CONCLUSIONS: A virtual format for a national society meeting can provide education, engagement, and community, and the lessons learned by the APDS in the process can be used by other societies for utilization and further improvement.

Locally Advanced Rectal Cancer Evaluation by Magnetic Resonance Imaging after Neoadjuvant Therapy on Decision Making: Cancer Center Experience and Literature Review.

PURPOSE: An accurate clinical and radiological staging is the pyramid of treatment decisions in locally advanced rectal cancer (LARC). Guidelines recommended neoadjuvant chemoradiation therapy (CRT) followed by surgical resection for fit patients with LARC. Determining the aggressiveness of intervention while avoiding needless morbidity according to patient risk remains an unmet pre-operative decision-making need. With newer magnetic resonance imaging (MRI) techniques and image acquisition available at our Cancer Center, we seek to retrospectively review the correlation between pre- and post-CRT MRI response to the surgical pathological stage in order to aide multidisciplinary team decision making. METHODS: Our Cancer Center Rectal Cancer Registry between 2011 and 2015 included 57 patients with LARC, 20 completed standard CRT with surgery, and of those 10 had repeated MRI after CRT. RESULTS: Our retrospective case series revealed that 90% of the patients had a downstage tumor response on surgical specimen compared to radiological evaluation after CRT, and furthermore, all patients who were re-staged with MRI prior to surgery correlated with the gold standard pathological stage (p = 0.02). CONCLUSIONS: Post-CRT MRI could potentially aide decision making to further avoid 20% of patients with a complete pathological response from a morbid surgery, whereas 10% of patients with an upstaged disease state may require a more aggressive neoadjuvant or planned surgical intervention. We concluded that future multidisciplinary oncology care treatment decision making would benefit from a repeat MRI after neoadjuvant CRT of LARC.

Intellectual Equipoise and Challenges: Accruing Patients With Advanced Cancer to a Trial Randomizing to Surgical or Nonsurgical Management (SWOG S1316).

BACKGROUND: Prospective, randomized trials are needed to determine optimal treatment approaches for palliative care problems such as malignant bowel obstruction (MBO). Randomization poses unique issues for such studies, especially with divergent treatment approaches and varying levels of equipoise. We report our experience accruing randomized patients to the Prospective Comparative Effectiveness Trial for Malignant Bowel Obstruction (SWOG S1316) study, comparing surgical and nonsurgical management of MBO. METHODS: Patients with MBO who were surgical candidates and had treatment equipoise were accrued and offered randomization to surgical or nonsurgical management. Patients choosing nonrandomization were offered prospective observation. Trial details are listed on www.clinicaltrials.gov (NCT #02270450). An accrual algorithm was developed to enhance enrollment. RESULTS: Accrual is ongoing with 176 patients enrolled. Most (89%) patients chose nonrandomization, opting for nonsurgical management. Of 25 sites that have accrued to this study, 6 enrolled patients on the randomization arm. Approximately 59% (20/34) of the randomization accrual goal has been achieved. Patient-related factors and clinician bias have been the most prevalent reasons for lack of randomization. An algorithm was developed from clinician experience to aid randomization. Using principles in this tool, repeated physician conversations discussing treatment options and goals of care, and a supportive team-approach has helped increase accrual. CONCLUSIONS: Experience gained from the S1316 study can aid future palliative care trials. Although difficult, it is possible to randomize patients to palliative studies by giving clinicians clear recommendations utilizing an algorithm of conversation, allotment of necessary time to discuss the trial, and encouragement to overcome internal bias.

Are We Making an Impact? A Qualitative Program Assessment of the Resident Leadership, Well-being, and Resiliency Program for General Surgery Residents.

OBJECTIVE: After implementing a formal resident well-being and resiliency program in our surgery residency, we performed in-depth qualitative interviews to understand residents' perceptions of: (1) the impact and benefits, (2) the essential elements for success, and (3) the desired changes to the well-being program. DESIGN: The well-being program is structured to address mental, physical, and social aspects of resident well-being through monthly experiential sessions. All General Surgery residents participated in the program; content is delivered during residents' protected educational time. For this study, we conducted individual semistructured interviews: residents were asked for their feedback to understand the value, benefits, and drawbacks of program. SETTING: Accreditation Council for Graduate Medical Education-accredited General Surgery residency program PARTICIPANTS: We used purposeful selection to maximize diversity in recruiting residents who had participated in program for at least 1 year. Recruitment continued until themes were saturated. Eleven residents were interviewed including 2 from each residency year. RESULTS: Residents reported benefits in 3 thematic spheres: (1) Culture/Community, (2) Communication/Emotional Intelligence, and (3) Work-Life Integration Skills. Key structural elements of success for a well-being program included a committed leader, a receptive department culture, occurrence during protected time, and interactive sessions that taught applicable life skills. In discussing opportunities for improvement, residents desired more faculty-level involvement. Some residents were skeptical of the benefit of time spent learning nontechnical skills; some wanted more emphasis placed on accountability to patients and work. CONCLUSIONS: Our qualitative assessment of a novel resident well-being program demonstrates reported benefits that reflect the intent of the program. Residents most benefited from sessions that were interactive, introduced readily applicable skills for their day-to-day lives, and included reinforcement of principles through experiential learning. Engagement of the department leadership is essential to the success of the program, as is ongoing feedback and modification to ensure that program is tailored to the needs of residents.

SFRP4 expression correlates with epithelial mesenchymal transition-linked genes and poor overall survival in colon cancer patients.

BACKGROUND: Colon cancer is among the most commonly diagnosed cancers in the United States with an estimated 97220 new cases expected by the end of 2018. It affects 1.2 million people around the world and is responsible for about 0.6 million deaths every year. Despite decline in overall incidence and mortality over the past 30 years, there continues to be an alarming rise in early-onset colon cancer cases (< 50 years). Patients are often diagnosed at late stages of the disease and tend to have poor survival. We previously showed that the WNT "gatekeeper" gene, secreted frizzled-related protein 4 (SFRP4), is over-expressed in early-onset colon cancer. SFRP4 is speculated to play an essential role in cancer by inhibiting the epithelial mesenchymal transition (EMT). AIM: To investigate the correlation between SFRP4 expression and EMT-linked genes in colon cancer and how it affects patient survival. METHODS: SFRP4 expression relative to that of EMT-linked genes and survival analysis were performed using the University of California Santa Cruz Cancer Browser interface. RESULTS: SFRP4 was found to be co-expressed with the EMT-linked markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP7, MMP9, and COL1A1. SFRP4 expression negatively correlated with the EMT-linked suppressors CLDN4, CLDN7, TJP3, MUC1, and CDH1. The expression of SFRP4 and the EMT-linked markers was higher in mesenchymal-like samples compared to epithelial-like samples which potentially implicates SFRP4-EMT mechanism in colon cancer. Additionally, patients overexpressing SFRP4 presented with poor overall survival (P = 0.0293). CONCLUSION: Considering the implication of SFRP4 in early-onset colon cancer, particularly in the context of EMT, tumor metastasis, and invasion, and the effect of increased expression on colon cancer patient survival, SFRP4 might be a potential biomarker for early-onset colon cancer that could be targeted for diagnosis and/or disease therapy.

Comparison of Covered Laser-cut and Braided Respiratory Stents: From Bench to Pre-Clinical Testing.

Lung cancer patients often suffer from severe airway stenosis, the symptoms of which can be relieved by the implantation of stents. Different respiratory stents are commercially available, but the impact of their mechanical performance on tissue responses is not well understood. Two novel laser-cut and hand-braided nitinol stents, partially covered with polycarbonate urethane, were bench tested and implanted in Rhön sheep for 6 weeks. Bench testing highlighted differences in mechanical behavior: the laser-cut stent showed little foreshortening when crimped to a target diameter of 7.5 mm, whereas the braided stent elongated by more than 50%. Testing also revealed that the laser-cut stent generally exerted higher radial resistive and chronic outward forces than the braided stent, but the latter produced significantly higher radial resistive forces at diameters below 9 mm. No migration was observed for either stent type in vivo. In terms of granulation, most stents exerted a low to medium tissue response with only minimal formation of granulation tissue. We have developed a mechanical and in vivo framework to compare the behavior of different stent designs in a large animal model, providing data, which may be employed to improve current stent designs and to achieve better treatment options for lung cancer patients.

Increasing Incidence of Colon Cancer in the Young: Assessing the Tumor Biology.

BACKGROUND: The overall incidence of colon cancer (CC) is decreasing, but with increasing early-onset colon cancer (EOCC < 50 years old). Our recent study revealed unique overexpression of cartilage oligomeric matrix protein (COMP) in EOCC and its association with aggressiveness. The aim of this study was to assess CC biology, especially in the young, by evaluating the role of COMP in CC carcinogenesis and cancer progression, detecting COMP in serum and its association with disease stage. STUDY DESIGN: Cancer and matching noninvolved tissue blocks from 12 sporadic EOCC and late-onset colon cancer (LOCC) patients of 4 disease stages were obtained from pathology archives. Ribonucleic acid expression profiling of 770 cancer-related genes using nCounter platform was performed. The COMP levels from 16 EOCC and LOCC serum samples were measured by ELISA. Carcinoembryonic antigen levels from these 16 samples were taken at the time of diagnosis. Transwell assay was performed to elucidate the role of COMP in motility and metastases. RESULTS: Expression profiling revealed increased COMP levels in higher disease stage. There was 7-fold higher COMP expression (p ≤ 0.05) in stage III compare to stage I and its coexpression with GAS1, VEGFC, MAP3K8, SFRP1, and PRKACA. Higher COMP expression was seen in stage II compared with stage I (p = 0.07) and its coexpression withTLR2, IL8, RIN1, IRAK3, and CACNA2D2, and COMP was detectable in serum and showed significantly higher levels in EOCC compared with LOCC. Similar correlation was seen with CEA levels, but the difference was not significant. Transwell assay revealed significantly increased motility of HT-29 cells after treatment with recombinant COMP. CONCLUSIONS: These findings suggest different tumor biology between EOCC and LOCC. Cartilage oligomeric matrix protein plays a significant role in CC carcinogenesis and has potential as biomarker for CC, especially aggressive EOCC.

COMP Gene Coexpresses With EMT Genes and Is Associated With Poor Survival in Colon Cancer Patients.

BACKGROUND: About 1.2 million new cases of colon cancer (CC) and 0.6 million deaths are reported every year, establishing CC as an important contributor to worldwide cancer morbidity and mortality. Although the overall incidence and mortality of CC have declined over the past 3 decades, the number of early-onset colon cancer ([EOCC], patients <50 y old) continues to rise alarmingly. These young patients are often diagnosed at a more advanced stage and tend to have poor survival. Our recently published data showed that the cartilage oligomeric matrix protein (COMP) is overexpressed in early-onset colon cancer patients. COMP is also reported in several cancers to coexpress with epithelial-mesenchymal transition (EMT) transcription factors. Given the role of EMT in cancer metastasis and cell invasion, we assessed the correlation between COMP gene expression and EMT gene expression in CC, and COMP's relationship to patient survival. METHODS: mRNA expression of COMP was compared to that of EMT markers using the UCSC Cancer Genomics Browser. Survival analysis was performed using the UCSC Xena Browser for cancer genomics. RESULTS: Expression analysis revealed coexpression of COMP with the EMT markers CDH2, FN1, VIM, TWIST1, TWIST2, SNAI1, SNAI2, ZEB1, ZEB2, POSTN, MMP2, MMP9, and COL1A1. Samples that were more mesenchymal had higher expression levels of COMP and EMT markers, thus suggesting a potential role of COMP in EMT. Patients with increased COMP expression presented with poorer overall survival compared to patients with no change or reduced COMP expression (P = 0.02). CONCLUSIONS: These findings reveal COMP as a potential biomarker for CC especially in more aggressive CC and CC in young patients, with a likely role in EMT during tumor metastasis and invasion, and a contributing factor to patient survival.