Combinatorial Inhibition of Complement Factor D and BCL2 for Early-Onset Colorectal Cancer.

BACKGROUND: The tumor immune microenvironment is distinct between early-onset and late-onset colorectal cancer which facilitates tumor progression. We previously identified several genes, including complement factor D, as having increased expression in patients with early-onset colorectal cancer. OBJECTIVE: This study aimed to assess and validate differential expression of immune genes in early and late-onset colorectal cancer. We also aimed to test known drugs targeting genes increased in early-onset colorectal cancer in preclinical mouse models. DESIGN: Retrospective cohort study with analysis performed using tumor RNA from formalin-fixed paraffin-embedded, cell culture and immunohistochemistry to validate gene expression and gene function. In vivo preclinical tumor study to assess drug efficacy. SETTINGS: Oregon Colorectal Cancer Registry was queried to find patients with colorectal cancer. SUBJECTS: Study included 67 patients with early and 54 patients with late-onset colorectal cancer. INTERVENTIONS: Preclinical animal models using the HCT-116 colon cancer cell line were treated with complement factor D inhibitor danicopan and BCL2 inhibitor venetoclax, or with vehicle controls. MAIN OUTCOME MEASURES: Elevated RNA signatures using NanoString data was evaluated from the retrospective cohort. When inhibiting these markers in the mouse preclinical model, tumor volume and weight were the main outcome measures. RESULTS: After updating our sample size from our previously published data, we found that complement factor D and BCL2, genes with known function and small molecule inhibitors, are elevated in patients with early-onset colorectal cancer. When inhibiting these markers with drugs danicopan and venetoclax in a mouse model, we found that the combination of these drugs decreased tumor burden but also resulted in toxicity. LIMITATIONS: This study is limited by small sample size and a subcutaneous tumor model. CONCLUSIONS: Combinatorial inhibition of early-onset associated genes complement factor D and BCL2 slows growth of early-onset colorectal cancer in a mouse preclinical model. See Video Abstract.

Updated Management of Colorectal Cancer Liver Metastases: Scientific Advances Driving Modern Therapeutic Innovations.

Colorectal cancer is the second leading cause of cancer-related deaths in the United States and accounts for an estimated 1 million deaths annually worldwide. The liver is the most common site of metastatic spread from colorectal cancer, significantly driving both morbidity and mortality. Although remarkable advances have been made in recent years in the management for patients with colorectal cancer liver metastases, significant challenges remain in early detection, prevention of progression and recurrence, and in the development of more effective therapeutics. In 2017, our group held a multidisciplinary state-of-the-science symposium to discuss the rapidly evolving clinical and scientific advances in the field of colorectal liver metastases, including novel early detection and prognostic liquid biomarkers, identification of high-risk cohorts, advances in tumor-immune therapy, and different regional and systemic therapeutic strategies. Since that time, there have been scientific discoveries translating into therapeutic innovations addressing the current management challenges. These innovations are currently reshaping the treatment paradigms and spurring further scientific discovery. Herein, we present an updated discussion of both the scientific and clinical advances and future directions in the management of colorectal liver metastases, including adoptive T-cell therapies, novel blood-based biomarkers, and the role of the tumor microbiome. In addition, we provide a comprehensive overview detailing the role of modern multidisciplinary clinical approaches used in the management of patients with colorectal liver metastases, including considerations toward specific molecular tumor profiles identified on next generation sequencing, as well as quality of life implications for these innovative treatments.

Colonic Microbial Abundances Predict Adenoma Formers.

OBJECTIVE: We aimed to examine associations between the oral, fecal, and mucosal microbiome communities and adenoma formation. SUMMARY BACKGROUND DATA: Data are limited regarding the relationships between microbiota and preneoplastic colorectal lesions. METHODS: Individuals undergoing screening colonoscopy were prospectively enrolled and divided into adenoma and nonadenoma formers. Oral, fecal, nonadenoma and adenoma-adjacent mucosa were collected along with clinical and dietary information. 16S rRNA gene libraries were generated using V4 primers. DADA2 processed sequence reads and custom R-scripts quantified microbial diversity. Linear regression identified differential taxonomy and diversity in microbial communities and machine learning identified adenoma former microbial signatures. RESULTS: One hundred four subjects were included, 46% with adenomas. Mucosal and fecal samples were dominated by Firmicutes and Bacteroidetes whereas Firmicutes and Proteobacteria were most abundant in oral communities. Mucosal communities harbored significant microbial diversity that was not observed in fecal or oral communities. Random forest classifiers predicted adenoma formation using fecal, oral, and mucosal amplicon sequence variant (ASV) abundances. The mucosal classifier reliably diagnosed adenoma formation with an area under the curve (AUC) = 0.993 and an out-of-bag (OOB) error of 3.2%. Mucosal classifier accuracy was strongly influenced by five taxa associated with the family Lachnospiraceae, genera Bacteroides and Marvinbryantia, and Blautia obeum. In contrast, classifiers built using fecal and oral samples manifested high OOB error rates (47.3% and 51.1%, respectively) and poor diagnostic abilities (fecal and oral AUC = 0.53). CONCLUSION: Normal mucosa microbial abundances of adenoma formers manifest unique patterns of microbial diversity that may be predictive of adenoma formation.

Transcriptional and Cytotoxic Responses of Human Intestinal Organoids to IFN Types I, II, and III.

The three types of IFN have roles in antimicrobial immunity and inflammation that must be properly balanced to maintain tissue homeostasis. For example, IFNs are elevated in the context of inflammatory bowel disease and may synergize with inflammatory cytokines such as TNF-α to promote tissue damage. Prior studies suggest that in mouse intestinal epithelial cells (IECs), type III IFNs are preferentially produced during viral infections and are less cytotoxic than type I IFN. In this study, we generated human IEC organoid lines from biopsies of ileum, ascending colon, and sigmoid colon of three healthy subjects to establish the baseline responses of normal human IECs to types I, II, and III IFN. We found that all IFN types elicited responses that were qualitatively consistent across intestinal biopsy sites. However, IFN types differed in magnitude of STAT1 phosphorylation and identity of genes in their downstream transcriptional programs. Specifically, there was a core transcriptional module shared by IFN types, but types I and II IFN stimulated unique transcriptional modules beyond this core gene signature. The transcriptional modules of type I and II IFN included proapoptotic genes, and expression of these genes correlated with potentiation of TNF-α cytotoxicity. These data define the response profiles of healthy human IEC organoids across IFN types, and they suggest that cytotoxic effects mediated by TNF-α in inflamed tissues may be amplified by a simultaneous high-magnitude IFN response.

Early Versus Late Recurrence in Rectal Cancer: Does Timing Matter?

BACKGROUND: The definition of early recurrence (ER) in rectal cancer is unclear, and the association of ER with post-recurrence survival (PRS) is poorly described. We therefore sought to identify if time to recurrence (TTR) is associated with PRS. METHODS: We reviewed all curative-intent resections of nonmetastatic rectal cancer from 2003 to 2018 in our institutional registry within an NCI-Designated Comprehensive Cancer Center. Clinicopathologic data at diagnosis and first recurrence were collected and analyzed. ER was pre-specified at < 24 months and late recurrence (LR) at ≥ 24 months. PRS was evaluated by the Kaplan-Meier method and Cox proportional hazards modeling. RESULTS: At a median follow-up of 53 months, 61 out of 548 (11.1%) patients undergoing resection experienced recurrence. Median TTR was 14 months (IQR 10-18) with 45 of 61 patients (74%) classified as ER. There were no significant baseline differences between patients with ER and LR. Most recurrences were isolated to the liver (26%) or lung (31%), and 16% were locoregional. ER was not associated with worse PRS compared to LR (P > 0.99). On multivariable analysis, detection of recurrence via workup for symptoms, CEA > 10 ng/mL at recurrence, and site of recurrence were independently associated with PRS. CONCLUSION: ER is not associated with PRS in patients with resected rectal cancer. Symptomatic recurrences and those accompanied by CEA elevations are associated with worse PRS, while metastatic disease confined to the liver or lung is associated with improved PRS. Attention should be directed away from TTR and instead toward determining therapy for patients with treatable oligometastatic disease.

Circulating Hybrid Cells: A Novel Liquid Biomarker of Treatment Response in Gastrointestinal Cancers.

BACKGROUND: Real-time monitoring of treatment response with a liquid biomarker has potential to inform treatment decisions for patients with rectal adenocarcinoma (RAC), esophageal adenocarcinoma (EAC), and colorectal liver metastasis (CRLM). Circulating hybrid cells (CHCs), which have both immune and tumor cell phenotypes, are detectable in the peripheral blood of patients with gastrointestinal cancers, but their potential as an indicator of treatment response is unexplored. METHODS: Peripheral blood specimens were collected from RAC and EAC patients after neoadjuvant therapy (NAT) or longitudinally during therapy and evaluated for CHC levels by immunostaining. Receiver operating characteristics (ROCs) and the Kaplan-Meier method were used to analyze the CHC level as a predictor of pathologic response to NAT and disease-specific survival (DSS), respectively. RESULTS: Patients with RAC (n = 23) and EAC (n = 34) were sampled on the day of resection, and 11 patients (32%) demonstrated a pathologic complete response (pCR) to NAT. On ROC analysis, CHC levels successfully discriminated pCR from non-pCR with an area under the curve of 0.82 (95% confidence interval [CI], 0.71-0.92; P < 0.001). Additionally, CHC levels in the EAC patients correlated with residual nodal involvement (P = 0.026) and 1-year DSS (P = 0.029). The patients with RAC who were followed longitudinally during NAT (n = 2) and hepatic arterial infusion therapy for CRLM (n = 2) had CHC levels that decreased with therapy response and increased before clinical evidence of disease progression. CONCLUSION: Circulating hybrid cells are a novel blood-based biomarker with potential for monitoring treatment response and disease progression to help guide decisions for further systemic therapy, definitive resection, and post-therapy surveillance. Additional validation studies of CHCs are warranted.

Relevance of circulating hybrid cells as a non-invasive biomarker for myriad solid tumors.

Metastatic progression defines the final stages of tumor evolution and underlies the majority of cancer-related deaths. The heterogeneity in disseminated tumor cell populations capable of seeding and growing in distant organ sites contributes to the development of treatment resistant disease. We recently reported the identification of a novel tumor-derived cell population, circulating hybrid cells (CHCs), harboring attributes from both macrophages and neoplastic cells, including functional characteristics important to metastatic spread. These disseminated hybrids outnumber conventionally defined circulating tumor cells (CTCs) in cancer patients. It is unknown if CHCs represent a generalized cancer mechanism for cell dissemination, or if this population is relevant to the metastatic cascade. Herein, we detect CHCs in the peripheral blood of patients with cancer in myriad disease sites encompassing epithelial and non-epithelial malignancies. Further, we demonstrate that in vivo-derived hybrid cells harbor tumor-initiating capacity in murine cancer models and that CHCs from human breast cancer patients express stem cell antigens, features consistent with the potential to seed and grow at metastatic sites. Finally, we reveal heterogeneity of CHC phenotypes reflect key tumor features, including oncogenic mutations and functional protein expression. Importantly, this novel population of disseminated neoplastic cells opens a new area in cancer biology and renewed opportunity for battling metastatic disease.

A Distinct Innate Immune Signature of Early Onset Colorectal Cancer.

Despite a decrease in the prevalence of colorectal cancer (CRC) over the last 40 y, the prevalence of CRC in people under 50 y old is increasing around the globe. Early onset (≤50 y old) and late onset (≥65 y old) CRC appear to have differences in their clinicopathological and genetic features, but it is unclear if there are differences in the tumor microenvironment. We hypothesized that the immune microenvironment of early onset CRC is distinct from late onset CRC and promotes tumor progression. We used NanoString immune profiling to analyze mRNA expression of immune genes in formalin-fixed paraffin-embedded surgical specimens from patients with early (n = 40) and late onset (n = 39) CRC. We found three genes, SAA1, C7, and CFD, have increased expression in early onset CRC and distinct immune signatures based on the tumor location. After adjusting for clinicopathological features, increased expression of CFD and SAA1 were associated with worse progression-free survival, and increased expression of C7 was associated with worse overall survival. We also performed gain-of-function experiments with CFD and SAA1 in s.c. tumor models and found that CFD is associated with higher tumor volumes, impacted several immune genes, and impacted three genes in mice that were also found to be differentially expressed in early onset CRC (EGR1, PSMB9, and CXCL9). Our data demonstrate that the immune microenvironment, characterized by a distinct innate immune response signature in early onset CRC, is unique, location dependent, and might contribute to worse outcomes.

Are Surgical Guideline Changes in Diverticulitis Care Associated With Decreased Inpatient Healthcare Expenditure?

Objective: To examine possible associations in inpatient healthcare expenditure and guideline changes in the surgical management of diverticulitis, in terms of both cost per discharge and total aggregate costs of care. Background: Medical costs throughout the healthcare system continue to rise due to increased prices for services, increased quantities of high-priced technologies, and an increase in the amount of overall services. Methods: We used a retrospective case-control design using the Healthcare Cost and Utilization Project National Inpatient Sample to evaluate cost per discharge and total aggregate costs of diverticulitis management between 2004 and 2015. The year 2010 was selected as the transition between the pre and postguideline implementation period. Results: The sample consisted of 450,122 unweighted (2,227,765 weighted) inpatient discharges for diverticulitis. Before the implementation period, inpatient costs per discharge increased 1.13% in 2015 dollars (95% confidence intervals [CI] 0.76% to 1.49%) per quarter. In the postimplementation period, the costs per discharge decreased 0.27% (95% CI -0.39% to -0.15%) per quarter. In aggregate, costs of care for diverticulitis increased 0.61% (95% CI 0.28% to 0.95%) per quarter prior to the guideline change, and decreased 0.52% (95% CI -0.87% to -0.17) following the guideline change. Conclusions: This is the first study to investigate any associations between evidence-based guidelines meant to decrease surgical utilization and inpatient healthcare costs. Decreased inpatient costs of diverticulitis management may be associated with guideline changes to reduce surgical intervention for diverticulitis, both in regards to cost per discharge and aggregate costs of care.

Stem Cell Marker Expression in Early Stage Colorectal Cancer is Associated with Recurrent Intestinal Neoplasia.

BACKGROUND: Colorectal cancer (CRC) ranks second in cancer deaths worldwide and presents multiple management challenges, one of which is identifying high risk stage II disease that may benefit from adjuvant therapy. Molecular biomarkers, such as ones that identify stem cell activity, could better stratify high-risk cohorts for additional treatment. METHODS: To identify possible biomarkers of high-risk disease in early-stage CRC, a discovery set (n = 66) of advanced-stage tumors were immunostained with antibodies to stemness proteins (CD166, CD44, CD26, and LGR5) and then digitally analyzed. Using a second validation cohort (n = 54) of primary CRC tumors, we analyzed protein and gene expression of CD166 across disease stages, and extended our analyses to CD166-associated genes (LGR5, ASCL2, BMI1, POSTN, and VIM) by qRT-PCR. RESULTS: Stage III and metastatic CRC tumors highly expressed stem cell-associated proteins, CD166, CD44, and LGR5. When evaluated across stages, CD166 protein expression was elevated in advanced-stage compared to early-stage tumors. Notably, a small subset of stage I and II cancers harbored elevated CD166 protein expression, which correlated with development of recurrent cancer or adenomatous polyps. Gene expression analyses of CD166-associated molecules revealed elevated ASCL2 in primary tumors from patients who recurred. CONCLUSIONS: We identified a protein signature prognostic of aggressive disease in early stage CRC. Stem cell-associated protein and gene expression identified a subset of early-stage tumors associated with cancer recurrence and/or subsequent adenoma formation. Signatures for stemness offer promising fingerprints for stratifying early-stage patients at high risk of recurrence.

Early Postoperative Mortality Among Patients Aged 75 Years or Older With Stage II/III Rectal Cancer.

BACKGROUND: Elderly patients with rectal cancer have been excluded from randomized studies, thus little is known about their early postoperative mortality, which is critical for informed consent and treatment decisions. This study examined early mortality after surgery in elderly patients with locally advanced rectal cancer (LARC). METHODS: Using the National Cancer Database, we identified patients aged ≥75 years, diagnosed with clinical stage II/III rectal cancer who underwent surgery in 2004 through 2015. Descriptive analyses determined proportions and trends and multivariable logistic regression analyses were performed to determine factors associated with early mortality after rectal cancer surgery. RESULTS: Among 11,794 patients with rectal cancer aged ≥75 years, approximately 6% underwent local excision and 94% received radical resection. Overall 30-day, 90-day, and 6-month postoperative mortality rates were 4.2%, 7.8%, and 11.5%, respectively. Six-month mortality varied by age (8.4% in age 75-79 years to 18.3% in age ≥85 years), and comorbidity score (10.1% for comorbidity score 0 to 17.7% for comorbidity score ≥2). Six-month mortality declined from 12.3% in 2004 through 2007 to 10.2% in 2012 through 2015 (Ptrend=.0035). Older age, higher comorbidity score, and lower facility case volume were associated with higher 6-month mortality. Patients treated at NCI-designated centers had 30% lower odds of 6-month mortality compared with those treated at teaching/research centers. CONCLUSIONS: Six-month mortality rates after surgery among patients aged ≥75 years with LARC have declined steadily over the past decade in the United States. Older age, higher comorbidity score, and care at a low-case-volume facility were associated with higher 6-month mortality after surgery. This information is necessary for informed consent and decisions regarding optimal management of elderly patients with LARC.

Benign Anal Disease: Implementation of an Educational Program Across Specialties.

BACKGROUND: Benign anal diseases, including hemorrhoids, fissures, abscesses, fistulas, and anal condylomata, affect 10%-15% of our population. Most patients seen by nonsurgical providers experience delayed treatment. We examined at our institution whether an educational session on anorectal diseases would benefit trainees from medical and surgical specialties. MATERIALS AND METHODS: The study took place at Oregon Health & Science University, a primary institutional practice with 130 resident participants. An exploratory study using a 10-point pretest and posttest regarding these diseases was designed and administered to medical subspecialties, including general surgery (GS), emergency medicine, internal medicine, and family medicine, obstetrics/gynecology, and pediatric residents. Intervention was a 50-min presentation highlighting anatomy, history and physical findings, and disease treatment. The posttest was repeated after 6 mo to evaluate retention and overall satisfaction, and differences were evaluated. RESULTS: With the exception of GS, posttest scores improved. Internal medicine improved most significantly. GS residents scored better on the pretest than other specialties; their posttest scores, however, declined. The survey demonstrated residents with prior education scored better on the pretest. PGY-1 and PGY-2 residents improved most on their posttest. On 6-mo retest, 17.6% of residents responded and posttest performance was 72%. CONCLUSIONS: Nonsurgical residents have limited knowledge about benign anal diseases but demonstrate improvement after educational intervention. Surgery residents performed well, but demonstrate regression to the mean, common in test taking, but may also require a more advanced lecture. Formal institutional, regional, and national educational interventions are needed to improve the understanding of these diseases.

Who Undergoes Cytoreductive Surgery and Perioperative Intraperitoneal Chemotherapy for Appendiceal Cancer? An Analysis of the National Cancer Database.

BACKGROUND: We sought to identify patterns of care for patients with appendiceal cancer and identify clinical factors associated with patient selection for multimodality treatment, including cytoreductive surgery and perioperative intraperitoneal chemotherapy (CRS/PIC). MATERIALS AND METHODS: National Cancer Database (NCDB) data from 2004 to 2014 of all diagnoses of appendiceal cancers were examined. We examined treatment modalities, as well as demographic, tumor-specific, and survival data. A multivariate logistic regression analysis was performed to determine the patient cohort most likely to receive CRS/PIC. Kaplan-Meier was used to estimate survival for all treatment groups. Significance was evaluated at P ≤ 0.05. RESULTS: We analyzed data on 18,055 patients. Nine thousand nine hundred ninety-two (55.3%) were treated with surgery only, 5848 (32.4%) received surgery and systemic chemotherapy, 1393 (7.71%) received CRS/PIC, 520 (2.88%) received chemotherapy alone, and 302 (1.67%) received neither surgery nor chemotherapy. Significant predictors of receiving CRS/PIC included male sex (OR 1.33, 95% CI: 1.11-1.59), white race (OR 2.00, 95% CI 1.40-2.86), non-Hispanic ethnicity (OR 1.92, 95% CI 1.21-3.05), private insurance (OR 1.52, 95% CI 1.26-1.84), and well-differentiated tumors (OR 4.25, CI: 3.39-5.32) (P < 0.05). Treatment with CRS/PIC was associated with a higher 5-year survival for mucinous malignancies, when compared to surgery alone (65.6% versus 62.4%, P < 0.01). Treatment with CRS/PIC was also associated with higher 5-year survival for well-differentiated malignancies, when compared to all other treatment modalities (74.9% versus 65.4%, P < 0.01). CONCLUSIONS: Patients were more likely to undergo CRS/PIC if they were male, white, privately insured, and with well-differentiated tumors. CRS/PIC was associated with improved survival in patients with mucinous and low-grade tumors.

Clinical Research Using the National Inpatient Sample: A Brief Review of Colorectal Studies Utilizing the NIS Database.

The National Inpatient Sample (NIS) is the largest collection of longitudinal hospital care data in the United States and is sponsored by the Agency for Healthcare Research and Quality. The data are collected from state organizations, hospital associations, private organizations, and the federal government. This database has been used in more than 400 disease-focused studies to examine health care utilization, access, charges, quality, and outcomes of care. The database has been maintained since 1988, making it one of the oldest on hospital data. The focus of this review is to explore and discuss the use of NIS database in colorectal surgery research and to formulate a simplified guide of the data captured for future researchers.

Review of Colorectal Studies Using the National Cancer Database.

The National Cancer Database (NCDB) is a large clinical oncology database developed with data collected from Commission on Cancer (CoC)-accredited facilities. The CoC is managed under the American College of Surgeons, and is a multidisciplinary team that maintains standards in cancer care delivery in health care settings. This database has been used in multiple cancer-focused studies and reports on cancer diagnosis, hospital-level, and patient-related demographics. The focus of this review is to explore and discuss the use of NCDB in colorectal surgery research. Furthermore, our aim for this review is to formulate a guide for researchers who are interested in using the NCDB to complete colorectal research.

Assessing the Value of Endoscopy Simulator Modules Designed to Prepare Residents for the Fundamentals of Endoscopic Surgery Examination.

BACKGROUND: The Fundamentals of Endoscopic Surgery examination is required for all general surgery residents. The test modules are not available for practice before the examination; however, similar modules are commercially available. OBJECTIVE: This study aims to determine which modules are most valuable for resident training and preparation for the examination by evaluating which correlates best with experience level. DESIGN: This was a single-institution study. SETTING: A virtual reality endoscopy simulator was utilized. PARTICIPANTS: General surgery residents and faculty endoscopists performed endoscopy simulator modules (Endobasket 2, Endobubble 1 and 2, Mucosal Evaluation 2, and Basic Navigation) designed to prepare residents for the Fundamentals of Endoscopic Surgery examination. Residents were assigned into junior and senior groups based on the completion of a dedicated endoscopy rotation. MAIN OUTCOME MEASURES: The primary outcomes measured were the mean time to completion, mean number of balloons popped, and mean number of wall hits for the 3 groups. RESULTS: A total of 21 junior residents, 11 senior residents, and 3 faculty participated. There were significant differences among groups in the mean time to completion for the Endobasket, Endobubble, and Mucosal Evaluation modules. The modules that correlated best with experience level were Endobubble 2 and Mucosal Evaluation 2. For Endobubble 2, juniors were slower than seniors, who were in turn slower than faculty (junior 118.8 ± 20.55 seconds, senior 100.3 ± 11.78 seconds, faculty 87.67 ± 2.848 seconds; p < 0.01). Juniors popped fewer balloons than seniors, who popped fewer balloons than faculty (junior 9.441 ± 3.838, senior 15.62 ± 4.133, faculty 28.78 ± 1.712; p < 0.001). For Mucosal Evaluation 2, juniors were slower than seniors, who were in turn slower than faculty (junior 468.8 ± 123.5 seconds, senior 368.6 ± 63.42 seconds, faculty 233.1 ± 70.45 seconds; p < 0.01). LIMITATIONS: Study residents have not completed the Fundamentals of Endoscopic Surgery examinations, so correlation with examination performance is not yet possible. CONCLUSIONS: Performance on Endobasket, Endobubble, and Mucosal Evaluation correlated well with experience level, providing benchmarks for each level to attain in preparation for the Fundamentals of Endoscopic Surgery examination. See Video Abstract at http://links.lww.com/DCR/A823.

MiR-486-5p Downregulation Marks an Early Event in Colorectal Carcinogenesis.

BACKGROUND: MicroRNAs are dysregulated in colorectal cancer and subsets correlated with advanced tumor stage and metastasis. Data are lacking on microRNA dysregulation from early to late-stage disease. OBJECTIVE: The purpose of this study was to identify a microRNA signature associated with the primary tumor and metastatic site in stage IV disease and to examine whether the signature is evident in earlier stages. DESIGN: A microRNA profile was generated and then explored in normal colon tissue (n = 5), early stage (stage I and II; n = 10), and late-stage (stage III and IV; n = 14) colorectal primary tumors via polymerase chain reaction to delineate molecular events that may promote colorectal carcinogenesis. SETTING: Genome-wide microRNA expression profiling was performed. PATIENTS: A total of 14 patient-matched stage IV primary colorectal cancer tumors and corresponding liver metastases were included. MAIN OUTCOME MEASURES: MicroRNA array technology was used to identify microRNA expression-predictive metastatic potential in the primary tumor. RESULTS: A distinct 9-member signature group of microRNAs was concurrent in stage IV primary colorectal cancer and their corresponding liver metastases, when compared with surrounding unaffected colon and liver tissue (microRNA-18b, microRNA-93, microRNA-182, microRNA-183, microRNA21, microRNA-486-5p, microRNA-500a, microRNA-552, and microRNA-941). Of the microRNA panel, only microRNA486-5p was differentially expressed in early stage colorectal cancer samples compared with normal tissue (p = 0.001) and additionally differentially expressed between late-stage colorectal cancer samples and normal tissue (p < 0.01). LIMITATIONS: Our microRNA profile was generated in a small subset of patients and will require validation in more samples. CONCLUSIONS: We identified a distinct microRNA signature in primary colon and matched metastatic disease. On additional investigation, 1 microRNA was differentially expressed in both early and late-stage cancer patient samples, and it may herald an early event in colorectal carcinogenesis. This study warrants additional investigation with a larger patient cohort to better understand the effect of microRNAs in carcinogenesis. See Video Abstract at http://links.lww.com/DCR/A723.

Travel distance influences readmissions in colorectal cancer patients-what the primary operative team needs to know.

BACKGROUND: Many colorectal cancer patients receive complex surgical care remotely. We hypothesized that their readmission rates would be adversely affected after accounting for differences in travel distance from primary/index hospital and correlate with mortality. MATERIALS AND METHODS: We identified 48,481 colorectal cancer patients in the Surveillance, Epidemiology and End Results (SEER)-Medicare database. Travel distance was calculated, using Google Maps, and SAS. Multivariate negative binomial regression was used to identify factors associated with readmission rates. Overall survival was analyzed, using Kaplan-Meier and Cox proportional hazard. RESULTS AND CONCLUSIONS: Thirty-day readmissions occurred in 14.9% of the cohort, 27.5% of which were to a nonindex hospital. In the colon and rectal cancer cohorts, readmissions were 14.5% and 16.5%, respectively. Rectal cancer patients had an increase in readmission by 13% (incidence rate ratios [IRR] 1.13; 95% confidence interval [CI] 1.05-1.21). Factors associated with readmission were male gender, advanced disease, length of stay (LOS), discharge disposition, hospital volume, Charlson score, and poverty level (P < 0.05). Greater distance traveled increased the likelihood of readmission but did not affect mortality. Travel distance influences readmission rates but not mortality. Discharge readiness to decrease readmissions is essential for colorectal cancer patients discharged from index hospitals.

Colorectal Cancer Liver Metastasis: Evolving Paradigms and Future Directions.

In patients with colorectal cancer (CRC) that metastasizes to the liver, there are several key goals for improving outcomes including early detection, effective prognostic indicators of treatment response, and accurate identification of patients at high risk for recurrence. Although new therapeutic regimens developed over the past decade have increased survival, there is substantial room for improvement in selecting targeted treatment regimens for the patients who will derive the most benefit. Recently, there have been exciting developments in identifying high-risk patient cohorts, refinements in the understanding of systemic vs localized drug delivery to metastatic niches, liquid biomarker development, and dramatic advances in tumor immune therapy, all of which promise new and innovative approaches to tackling the problem of detecting and treating the metastatic spread of CRC to the liver. Our multidisciplinary group held a state-of-the-science symposium this past year to review advances in this rapidly evolving field. Herein, we present a discussion around the issues facing treatment of patients with CRC liver metastases, including the relationship of discrete gene signatures with prognosis. We also discuss the latest advances to maximize regional and systemic therapies aimed at decreasing intrahepatic recurrence, review recent insights into the tumor microenvironment, and summarize advances in noninvasive multimodal biomarkers for early detection of primary and recurrent disease. As we continue to advance clinically and technologically in the field of colorectal tumor biology, our goal should be continued refinement of predictive and prognostic studies to decrease recurrence after curative resection and minimize treatment toxicity to patients through a tailored multidisciplinary approach to cancer care.