Coen L. Klos

The prognostic value of lymph node ratio after neoadjuvant chemoradiation and rectal cancer surgery.

BACKGROUND: Neoadjuvant chemotherapy decreases total lymph nodes harvested and possibly affects lymph node staging after total mesorectal excision in patients with rectal cancer. OBJECTIVE: This study aimed to compare staging by lymph node ratio with staging by absolute number of positive lymph nodes. DESIGN: This study is a retrospective cohort review. SETTING: A tertiary care referral center was the setting for this investigation. PATIENTS: A total of 281 consecutive patients who underwent neoadjuvant chemoradiation and total mesorectal excision after histologically confirmed rectal cancer between January 1, 1998 and December 31, 2008 were included in this study. MAIN OUTCOME MEASURES: Lymph node ratio is the number of positive lymph nodes divided by the total number of lymph nodes within one sample. Risk categories of low (0 to <0.09); medium (0.09 to <0.36); and high (≥0.36) for lymph node ratio were chosen by significance with the use of Cox proportional hazards models. These categories were then used in a reclassification table and compared with positive lymph node stage: low (0 positive nodes), medium (1–3 nodes), and high (>3) by 5-year mortality rates. RESULTS: The majority (87%) of patients were concordant in risk assessment. Thirty patients were downstaged to lower risk lymph node ratio categories without showing actual lower mortality rates. Seven patients were upstaged to a high-risk lymph node ratio category with a supporting higher 5-year mortality rate. When limiting the analysis to those with fewer than 12 nodes, 136 (95%) patients were concordant in risk assessment; all 30 incorrectly downstaged patients were removed, but the 7 correctly upstaged patients remained. CONCLUSIONS: Patients who undergo neoadjuvant chemoradiation before rectal cancer surgery frequently have fewer than 12 lymph nodes harvested despite maintaining vigorous surgical standards. Lymph node ratios may provide excellent prognostic value and are possibly a better independent staging method than absolute positive lymph node counts when less than 12 lymph nodes are harvested after neoadjuvant treatment.

Determining the Need for Radical Surgery in Patients With T1 Rectal Cancer

HYPOTHESIS In the era of modern preoperative staging of patients with rectal cancer, lymph node metastases can be reliably predicted by the histological features of the tumor and preoperative imaging. Local resection can then be safely offered to the patients who are at low risk of having malignant lymph nodes. DESIGN We reviewed the records of 109 consecutive patients with preoperative imaging results suggestive of T1N0 or T2N0 disease who underwent total mesorectal excision. All patients underwent preoperative endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography. Final pathologic investigation identified T3 disease in 27 patients. History, physical examination results, and radiologic and pathologic data were evaluated for predictors of positive nodes in the remaining 82 patients. SETTING Tertiary care referral center. PATIENTS Patients with preoperative imaging suggestive of T1N0 or T2N0 rectal cancer. MAIN OUTCOME MEASURES To evaluate different clinical and pathologic tumor features as predictors of positive lymph nodes in T1 and T2 rectal cancers with negative radiographic nodes. BACKGROUND Local resection of T1 and T2 rectal cancer results in lower morbidity compared with radical resection. However, recurrence rates after local resection are higher, likely owing to unresected nodal metastasis. Reports on predictors of lymph node metastasis remain inconsistent in the literature. Although local resection may be appropriate for some rectal cancers, selection criteria remain unclear. RESULTS Despite indications of negative nodes on radiographic examination, 4 of 35 patients with T1 disease (11%) and 13 of 47 with T2 disease (28%) had positive nodes. On univariate analysis, the only significant predictor was depth of invasion: 24 of 65 patients with negative nodes (37%) vs 13 of 17 patients with positive nodes (76%) had tumors invading the lower third of the submucosa and beyond (P = .02). On logistic regression analysis accounting for depth of invasion (lower third of the submucosa and beyond), size, distance from anal verge, differentiation, and lymphovascular and small-vessel invasion, only depth of invasion remained a significant predictor. CONCLUSIONS In all, 89% of patients with T1 disease (31 of 35) and 72% of those with T2 disease (34 of 47) underwent unnecessary radical resection. Endorectal ultrasonography or magnetic resonance imaging and computed tomography, with or without positron emission tomography, for preoperative staging could not identify these patients reliably. In addition, histologic markers of aggressive disease were not helpful. Thus, local resection for T2 rectal cancer is not justified. Local resection should be offered only to patients with superficial T1 tumors who will adhere to aggressive postoperative surveillance.

The effect of neoadjuvant chemoradiation therapy on the prognostic value of lymph nodes after rectal cancer surgery

BACKGROUND Neoadjuvant therapy may affect the prognostic impact of total lymph node harvests and lymph node positivity after surgery for rectal cancer. METHODS We performed a retrospective review of 390 consecutive patients with histologically confirmed rectal cancer. Postoperative follow-up evaluation and survival were confirmed via medical record review. The impacts of lymph node positivity and total lymph node harvest on survival and recurrence are reflected as proportional hazard ratios (HRs). RESULTS A total of 221 patients underwent neoadjuvant therapy, of whom 75 had positive nodes. Node-positive patients showed a significantly shorter survival time (HR, 2.89; P = .002) and time to local recurrence (HR, 6.36; P = .031) compared with patients without positive nodes. Survival and recurrence were not significantly different between patients with a total harvest of fewer than 12 nodes and patients with a higher lymph node harvest. CONCLUSIONS After neoadjuvant treatment and total mesorectal excision, lymph node positivity is associated with significantly shorter survival and time to local recurrence in rectal cancer patients, whereas absolute total lymph node harvests likely have little impact on prognosis.

Intestinal Epithelial HuR Modulates Distinct Pathways of Proliferation and Apoptosis and Attenuates Small Intestinal and Colonic Tumor Development

HuR is a ubiquitous nucleocytoplasmic RNA-binding protein that exerts pleiotropic effects on cell growth and tumorigenesis. In this study, we explored the impact of conditional, tissue-specific genetic deletion of HuR on intestinal growth and tumorigenesis in mice. Mice lacking intestinal expression of HuR (Hur (IKO) mice) displayed reduced levels of cell proliferation in the small intestine and increased sensitivity to doxorubicin-induced acute intestinal injury, as evidenced by decreased villus height and a compensatory shift in proliferating cells. In the context of Apc(min/+) mice, a transgenic model of intestinal tumorigenesis, intestinal deletion of the HuR gene caused a three-fold decrease in tumor burden characterized by reduced proliferation, increased apoptosis, and decreased expression of transcripts encoding antiapoptotic HuR target RNAs. Similarly, Hur(IKO) mice subjected to an inflammatory colon carcinogenesis protocol [azoxymethane and dextran sodium sulfate (AOM-DSS) administration] exhibited a two-fold decrease in tumor burden. Hur(IKO) mice showed no change in ileal Asbt expression, fecal bile acid excretion, or enterohepatic pool size that might explain the phenotype. Moreover, none of the HuR targets identified in Apc(min/+)Hur(IKO) were altered in AOM-DSS-treated Hur(IKO) mice, the latter of which exhibited increased apoptosis of colonic epithelial cells, where elevation of a unique set of HuR-targeted proapoptotic factors was documented. Taken together, our results promote the concept of epithelial HuR as a contextual modifier of proapoptotic gene expression in intestinal cancers, acting independently of bile acid metabolism to promote cancer. In the small intestine, epithelial HuR promotes expression of prosurvival transcripts that support Wnt-dependent tumorigenesis, whereas in the large intestine epithelial HuR indirectly downregulates certain proapoptotic RNAs to attenuate colitis-associated cancer. Cancer Res; 74(18); 5322-35. ©2014 AACR.

Segmental versus extended resection for sporadic colorectal cancer in young patients.

Guidelines on the management of colon cancer state that extensive colectomy should be “considered” for patients of young age (<50). This study aimed to compare the risk of metachronous cancer, overall recurrence and mortality between segmental and extended colon resections in patients under the age of 50 with sporadic CRC.

Accordion complication grading predicts short-term outcome after right colectomy

BACKGROUND The Accordion severity grading system is a novel system to score the severity of postoperative complications in a standardized fashion. This study aims to demonstrate the validity of the Accordion system in colorectal surgery by correlating severity grades with short-term outcomes after right colectomy for colon cancer. METHODS This is a retrospective cohort review of patients who underwent right colectomy for cancer between January 1, 2002, and January 31, 2007, at a single tertiary care referral center. Complications were categorized according to the Accordion severity grading system: grades 1 (mild), 2 (moderate), 3-5 (severe), and 6 (death). Outcome measures were hospital stay, 30-d readmission rate and 1-y survival. Correlation between Accordion grades and outcome measures is reflected by Spearman rho (ρ). One-year survival was obtained per Kaplan-Meier method and compared by logrank test for trend. Significance was set at P ≤ 0.05. RESULTS Overall, 235 patients underwent right colectomy for cancer of which 122 (51.9%) had complications. In total, 52 (43%) had an Accordion grade 1 complication; 44 (36%) grade 2; four (3%) grade 3; 11 (9%) grade 4; seven (6%) grade 5; and four (3%) grade 6. There was significant correlation between Accordion grades and hospital stay (ρ = 0.495, P < 0.001) and 30-d readmission rate (ρ = 0.335, P < 0.001). There was a significant downward trend in 1-y survival as complication severity by Accordion grade increased (P = 0.02). CONCLUSIONS The Accordion grading system is a useful tool to estimate short-term outcomes after right colectomy for cancer. High-grade Accordion complications are associated with longer hospital stay and increased risk of readmission and mortality.

294 Conditional Intestine-Specific HuR Deletion (HuR-IKO) Modulates Distinct Wnt-Dependent and Independent Pathways of Proliferation and Apoptosis With No Effect on Ileal ASBT Expression or Bile Acid Metabolism

Acute gut mucosal injury occurs commonly during critical pathological conditions, leading to mucosal hemorrhage, epithelial barrier dysfunction, and the translocation of luminal toxic substances and bacteria to the blood stream, but the exact mechanism underlying mucosal injury/repair are still obscure. RNA-binding proteins (RBPs) posttranscriptionally regulate gene expression and are implicated in many aspects of pathophysiology. HuR is among the most prominent sequence-specific RBP and has emerged as a master regulator of the maintenance of the homeostasis of gut mucosa. Our previous studies show that HuR regulates intestinal epithelial cell proliferation and apoptosis, but the exact role of HuR in gut mucosal repair after injury remains unknown. This study tested the hypothesis that HuR plays a role in intestinal mucosal repair after ischemia/reperfusion (I/R)-induced Injury.Methods: Studies were conducted in our recently generating intestinal epithelial tissue-specific HuR knockout (IE-HuR-/-) mice and wild-type littermates. Mucosal injury was induced by exposed to 30min of mesenteric ischemia, followed by 2-h reperfusion. Barrier function was detected by paracellular tracer flux assay using FITC-dextran. Results: The mucosa of the animals subjected to mesenteric I/R displayed signs of remarkable damage. Macroscopically, the intestines of the animals exposed to I/R exhibited swollen and edematous with areas of red streaks in both littermates and IE-HuR-/animals. Microscopic analysis showed that there were severed damages in the small intestinal mucosa as indicated by sloughed cells, denuded villi with dilated capillaries, and frank hemorrhage. Although there were no significant differences in the injury scores between littermates and IE-HuR-/mice when measured immediately after I/R, HuR deletion delayed the process of early mucosal repair after I/Rinduced injury. The mucosal surface remained discontinuous, showing sloughed cells and debris in IE-HuR-/mice (injury score: 3.3 ± 0.12) 6 h after I/R, whereas the mucosa in littermates was almost completely recovered (0.2 ± 0.03). Both littermate and IE-HuR-/mice exhibited significant gut barrier dysfunction after I/R-induced injury, but increased levels of gut permeability in IE-HuR-/mice were much greater than those observed in littermates. The recovery of gut barrier function after I/R was also inhibited by HuR deletion. Moreover, expression of the Wnt co-receptor LRP6 and ARP2 in the intestinal mucosa of HuR-/mice decreased dramatically, which are necessary for normal mucosal repair after injury. Conclusions: These results indicate that 1) HuR is crucial for maintenance of normal gut mucosal epithelial integrity and 2) HuR deletion in intestinal epithelial cells delays mucosal repair and represses the recovery of gut barrier function after I/R-induced mucosal injury.