Complete mesocolic excision and extended lymphadenectomy: Where should we stand?

Debate regarding the risks and merits of complete mesocolic excision and extended lymphadenectomy is ongoing, particularly for right-sided colon cancers. In this article, we hope to provide a succinct yet encompassing review of the relevant literature. We posit that complete mesocolic excision with D3 dissection is indicated in select patients with colon cancers, particularly those distal to the cecum.

Endoscopy Reports for Rectosigmoid Tumors: Frequently Missing Key Information Needed for Surgical Planning.

INTRODUCTION: Endoscopy reports by gastroenterologists describing rectosigmoid tumors often are missing crucial data for surgical planning, leading to high rates of repeat exams before surgical decision-making. We hypothesize that there will be significant deficiencies in the endoscopic reporting of rectosigmoid lesions leading to high rates of repeat endoscopic examination at our institution. METHODS: Retrospective review from January 2016 to November 2019 included 188 patients with rectosigmoid lesions referred for surgery with an outside endoscopy report. Three criteria were abstracted from these reports or included pictures: (1) distance from the tumor to an anatomical landmark (anal verge, dentate line, sphincter), (2) Tattoo placement (if performed) and location, and (3) tumor relationship to the valves of Houston. Reports were classified exemplary, nearly adequate, or inadequate if 3, 2, and ≤ 1 of these criteria were met, respectively. RESULTS: Distance was reported in 38.8% (n = 73) of reports, with the anal verge being the most commonly reported anatomical landmark (32.4%, n = 61 reports). Tattoo was placed in 34.6% (n = 65), though only 21.8% (n = 41) described the location of the tattoo relative to the tumor. Relationship to the valves of Houston was seen in 29.2% (n = 55) of reports. Only 5.3% (n = 10) of outside endoscopy reports were graded as exemplary, 20.2% (n = 38) nearly adequate, and the remaining 74.5% (n = 140) inadequate. A total of 87.5% (n = 165) of patients required repeat endoscopy with a significantly higher proportion from the inadequate group. CONCLUSIONS: Many referring endoscopy reports contain inadequate information for the surgical planning of rectosigmoid tumor resection. Efforts to improve documentation (particularly about distance and location within the rectum) must be undertaken.

Inking outside the box: systematic review on the utility of tattooing lesions in rectal cancer.

PURPOSE: Endoscopic tattooing in rectal cancer is infrequently utilized for fear of tattoo ink obscuring anatomical planes, increasing the difficulty of surgical excision. Colon cancer tattooing has demonstrated increased lymph node yields and increased accuracy in establishing adequate margins. Rectal cancer tattooing may be especially helpful after neoadjuvant chemoradiation, where complete clinical responses could limit lesion identification and lymph node yields are typically less robust. We seek to review and identify the effects of tattooing in rectal cancer. METHODS: A systematic literature search was performed in PubMed, Embase, and SCOPUS. Studies on endoscopic tattooing with cohorts consisting of at least ≥ 25% of rectal cancer patients were selected. Studies focusing solely on rectal cancer were also reviewed separately. RESULTS: Of 416 studies identified, 10 studies encompassing 2460 patients were evaluated. Seven studies evaluated lymph node yields; five reported beneficial effects of endoscopic tattooing, while two reported no significant difference. Among four studies reporting lesion localization, successful localization rates were between 63 and 100%. Rates of intraoperative endoscopy performed to reevaluate lesion location ranged from 5.7 to 20%. The distal margin was evaluated in two studies, which reported more accurate placement of the distal resection margin after tattooing. When complications of tattooing were documented (7 studies with 889 patients), only five direct complications of endoscopic tattooing were observed (0.6%). CONCLUSIONS: Although the data is heterogenous, it suggests that endoscopic tattooing in rectal cancer may improve lymph node yields and assist in determining accurate distal margins without high rates of complication. Further research must be completed before practice management guidelines can change. TRIAL REGISTRATION: No. CRD42021271784.

Prevalence of mesothelin expression in peritoneal disease from colorectal and appendiceal cancers.

BACKGROUND: Mesothelin is a cell surface glycoprotein overexpressed in 28%-58% of colorectal cancer (CRC). We hypothesized that CRC mesothelin expression contributes to peritoneal spread and that it is selectively overexpressed in those with peritoneal metastasis versus distant metastasis. METHODS: This case-controlled study involved mesothelin immunohistochemistry staining of tumor specimens from patients with metastatic CRC/appendiceal cancers between 2017 and 2019. Staining reactivity was graded from trace to 4+ (low ≤1+; high >1+). Staining patterns were characterized on global (focal/patchy/diffuse) and cellular (apical/cytoplasmic) levels. Immunostaining of normal mesothelial cells served as internal control. RESULTS: Thirty-one patients were identified: 11 peritoneal (study) and 20 distant metastasis (control). The control group did not include appendiceal cancers. The study group had greater proportion of high staining reactivity (55% vs. 5%; odds ratio [OR] = 20.4, 95% confidence interval [CI] 1.96-211.8). The study group had more diffuse (36% vs. 0%; OR = 22.2, 95% CI 1.1-465.3) and cytoplasmic staining patterns (73% vs. 28%; OR = 6.9, 95% CI 1.3-37.2). CONCLUSION: Mesothelin expression is higher in CRC/appendiceal cancers with peritoneal metastasis than those with distant metastasis. Immunohistochemistry staining patterns suggestive of propensity towards peritoneal metastasis include diffuse and cytoplasmic staining. Mesothelin may be a potential target for novel treatments of CRC/appendiceal carcinoma with peritoneal involvement.

Pathologic Outcomes of Short-Course and Long-Course Radiotherapy for Locally Advanced Rectal Cancers Treated With Total Neoadjuvant Therapy.

INTRODUCTION: Total neoadjuvant therapy (TNT) for patients with locally advanced rectal cancer (LARC) is now the standard of care. Randomized trials suggest the use of short-course radiotherapy (SCRT) and long-course radiotherapy (LCRT) are oncologically equivalent. OBJECTIVE: To describe pathologic outcomes after surgical resections of patients receiving SCRT versus LCRT as part of TNT for LARC. PARTICIPANTS: All patients with LARC treated at a single tertiary hospital who underwent proctectomy after completing TNT were included. Patients were excluded if adequate details of TNT were not available in the electronic medical record. RESULTS: A total of 53 patients with LARC were included. Thirty-nine patients (73.5%) received LCRT and 14 (26.4%) received SCRT. Forty-nine patients (92.5%) were clinical stage III (cN1-2) prior to treatment. The average lymph node yield after proctectomy was 20.9 for SCRT and 17.0 for LCRT (P = .075). Of the 49 patients with clinically positive nodes before treatment, 76.9% of those who received SCRT and 72.2% of those who received LCRT achieved pN0 disease after TNT. Additionally, there were no significant differences in rates of pathologic complete response between patients who received SCRT and LCRT, 7.1% and 12.8%, respectively (P = .565). CONCLUSION: Pathologic outcomes of patients with LARC treated with SCRT or LCRT, as part of TNT, may be similar. Further prospective trials are needed to assess long-term clinical outcomes and to determine best treatment protocols.

Gene polymorphisms predict toxicity to neoadjuvant therapy in patients with rectal cancer.

BACKGROUND: Toxicity from neoadjuvant chemoradiation therapy (NT) increases morbidity and limits therapeutic efficacy in patients with rectal cancer. The objective of this study was to determine whether specific polymorphisms in genes associated with rectal cancer response to NT were correlated with NT-related toxicity. METHODS: One hundred thirty-two patients with locally advanced rectal cancer received NT followed by surgery. All patients received 5-fluorouracil (5-FU) and radiation (RT), and 80 patients also received modified infusional 5-FU, folinic acid, and oxaliplatin chemotherapy (mFOLFOX-6). Grade ≥3 adverse events (AEs) that occurred during 5-FU/RT and during combined 5-FU/RT + mFOLFOX-6 were recorded. Pretreatment biopsy specimens and normal rectal tissues were collected from all patients. DNA was extracted and screened for 22 polymorphisms in 17 genes that have been associated with response to NT. Polymorphisms were correlated with treatment-related grade ≥3 AEs. RESULTS: Overall, 27 of 132 patients (20%) had grade ≥3 AEs; 18 patients had a complication associated only with 5-FU/RT, 3 patients experienced toxicity only during mFOLFOX-6, and 6 patients had grade ≥3 AEs associated with both treatments before surgery. Polymorphisms in the genes x-ray repair complementing defective repair in Chinese hamster cells 1 (XRCC1), xeroderma pigmentosum group D (XPD), and tumor protein 53 (TP53) were associated with grade ≥3 AEs during NT (P < .05). Specifically, 2 polymorphisms-an arginine-to-glutamine substitution at codon 399 (Q399R) in XRCC1 and a lysine-to-glutamine substitution at codon 751 (K751Q) in XPD-were associated with increased toxicity to 5-FU/RT (P < .05), and an arginine-to-proline substitution at codon 72 (R72P) in TP53 was associated with increased toxicity to mFOLFOX-6 (P = .008). CONCLUSIONS: Specific polymorphisms in XRCC1, XPD, and TP53 were associated with increased toxicity to NT in patients with rectal cancer. The current results indicated that polymorphism screening may help tailor treatment for patients by selecting therapies with the lowest risk of toxicity, thus increasing patient compliance.

Mutations in specific codons of the KRAS oncogene are associated with variable resistance to neoadjuvant chemoradiation therapy in patients with rectal adenocarcinoma.

BACKGROUND: Mutations in KRAS and TP53 are common in colorectal carcinogenesis and are associated with resistance to therapy. Rectal cancers carrying both mutations are less likely to respond to neoadjuvant chemoradiation therapy (CRT) compared with wild-type tumors. Codon-specific KRAS mutations are associated with variable resistance to targeted therapies, but their association with rectal cancer response to CRT remains unclear. Our objective was to establish a correlation between specific KRAS mutations and rectal cancer response to CRT and to investigate if the correlation was related to a different association between KRAS and TP53 mutations. METHODS: A total of 148 stage II-III rectal cancer patients underwent preoperative CRT followed by surgery. DNA was extracted from pretreatment tumor biopsies and paired normal surgical tissues and KRAS and TP53 genotyping was performed. Specific KRAS mutations were then correlated with tumor response and with concurrent TP53 mutation. RESULTS: A total of 60 patients had KRAS mutation, 12 in codon 13 and 48 in other locations. Also, 80 patients had TP53 mutation; 27 had concurrent KRAS/TP53 mutations. Tumors with any KRAS mutation were less likely to have a pCR compared with wild-type KRAS (p = 0.006). Specifically, no tumors with KRAS codon 13 mutations had a pCR (p = 0.03). Tumors with KRAS codon 13 mutations also had a higher incidence of concurrent TP53 mutation compared with tumors with other KRAS mutations (p = 0.02). CONCLUSIONS: Mutations in different KRAS codons may have different effects on rectal cancer resistance to CRT. This variable resistance may be related to a different frequency of TP53 mutations in KRAS mutant tumors.

Distribution of residual cancer cells in the bowel wall after neoadjuvant chemoradiation in patients with rectal cancer.

BACKGROUND: The standard treatment for locally advanced rectal cancer is preoperative chemoradiation and total mesorectal excision. After surgery, tumors are classified according to the depth of tumor invasion, nodal involvement, and tumor regression grade. However, these staging systems do not provide information about the distribution of residual cancer cells within the bowel wall. OBJECTIVE: This study aimed to determine the distribution of residual cancer cells in each layer of the bowel wall in rectal cancer specimens. DESIGN: This was a secondary analysis of data from a prospective phase II study. SETTING: This study was performed in a multi-institutional setting. PATIENTS: Included were 153 patients with stage II or stage III rectal cancer. INTERVENTIONS: Patients were treated with chemoradiation and surgery. The surgical specimen tumor tissue was analyzed, and the distribution of residual cancer cells in each layer of the bowel wall was determined. MAIN OUTCOME MEASURES: Statistical analysis was used to examine the correlation of residual cancer cells in each layer of the bowel wall with the clinical/pathologic stage and tumor regression grade. RESULTS: Forty-two of 153 (27%) patients had complete response in the bowel wall (ypT0). Of the remaining 111 patients who had residual cancer cells, 5 (3%) were ypTis, 12 (8%) were ypT1, 41 (27%) were ypT2, 50 (33%) were ypT3, and 3 (2%) were ypT4. Of the 94 patients with ypT2-4 tumors, 12 (13%) had cancer cells in the mucosa, and 53 (56%) had cancer cells in the submucosa; 92 (98%) had cancer cells in the muscularis propria. Pretreatment cT correlated with the distribution of residual cancer cells. Tumor regression grade was not associated with the distribution of residual cancer cells after chemoradiation. LIMITATIONS: : Patients received different chemotherapy regimens. CONCLUSIONS: Residual cancer cells in rectal cancer specimens after chemoradiation are preferentially located close to the invasive front. This should be considered when designing strategies to diagnose complete pathologic response and when investigating the mechanisms of tumor resistance to chemoradiation.

Evaluation of lymphadenectomy in patients receiving neoadjuvant radiotherapy for rectal adenocarcinoma.

BACKGROUND: Accurate pathologic staging has been shown to correlate with outcome in rectal cancer. Because the exact number of examined lymph nodes (LNs) may vary with preoperative therapies, our objective was to measure the impact of neoadjuvant radiation on LN number for rectal adenocarcinoma. METHODS: Patients who underwent curative-intent radical surgery for rectal adenocarcinoma in Los Angeles County (LAC) were identified from the Cancer Surveillance Program (CSP) of California (1988-2006). Patients were grouped according to receipt of radiotherapy (neoadjuvant or none), and the number of examined LNs was assessed. RESULTS: Query of CSP identified 2,727 patients meeting eligibility criteria; 70 and 30 % of patients received no radiotherapy or neoadjuvant radiotherapy (NRT), respectively. When comparing LNs, a lower mean number was observed in the neoadjuvant group than the no-radiation group (7 vs. 8.9 LNs, respectively; p < 0.001). When matching the cohorts for age and sex, the neoadjuvant group still had fewer examined LNs (7.1 vs. 9.8, respectively, p < 0.001). In patients who received NRT, no optimal LN number was associated with improved survival. However, on subset analysis of patients with N0 disease, a LN number of ≥8 was associated with best rates of 5 year and overall survival. CONCLUSIONS: Within the LAC population, we observed a lower number of LNs retrieved in patients receiving radical surgery for rectal cancer than guideline recommendation. This number is reduced further in those who received NRT independent of age and sex. Our results highlight the limitations in adhering to minimum LN requirements for rectal cancer when NRT is provided.

Gene expression variations in microsatellite stable and unstable colon cancer cells.

BACKGROUND: Microsatellite instability (MSI) is a marker of chemoresistance, but it is associated with improved survival compared with microsatellite-stable (MSS) colon cancers. We hypothesized that MSI tumors overexpress chemoresistance-associated genes and underexpress DNA damage/repair genes. We used ultra high-throughput sequencing (UHTS) to assess the expression of representative genes in MSI and MSS colon cancer cell lines. METHODS: Solexa UHTS was used to examine gene expression in HCT116 (MSI) and HT29 (MSS) cells, and normal colonic mucosa (NCM). We compared expression of 40 genes involved in chemoresistance, DNA repair, DNA damage, and drug metabolism pathways. RESULTS: We observed gene expression differences between MSI and MSS cell lines in 8 out of 40 genes involved in mismatch repair (MMR), DNA repair, drug metabolism, and chemoresistance. MMR gene expression was lower in MSI cells, which is consistent with the MSI phenotype, whereas DNA repair genes were highly expressed in these cells. Genes associated with chemoresistance and drug metabolism also had increased expression in MSI cells. No difference in expression of DNA damage genes was observed between MSI and MSS cell lines. CONCLUSION: Using UHTS gene expression analysis, we identified differential expression of genes between MSI and MSS cell lines which may account for resistance to chemotherapy in MSI tumors. UHTS expression analysis has the potential to identify genome-wide predictors of response or resistance to chemotherapy.

Prognostic and predictive roles of KRAS mutation in colorectal cancer.

The RAS gene family is among the most studied and best characterized of the known cancer-related genes. Of the three human ras isoforms, KRAS is the most frequently altered gene, with mutations occurring in 17%-25% of all cancers. In particular, approximately 30%-40% of colon cancers harbor a KRAS mutation. KRAS mutations in colon cancers have been associated with poorer survival and increased tumor aggressiveness. Additionally, KRAS mutations in colorectal cancer lead to resistance to select treatment strategies. In this review we examine the history of KRAS, its prognostic value in patients with colorectal cancer, and evidence supporting its predictive value in determining appropriate therapies for patients with colorectal cancer.

Role of SUMO activating enzyme in cancer stem cell maintenance and self-renewal.

Cancer stem cells (CSCs) have key roles in treatment resistance, tumour metastasis and relapse. Using colorectal cancer (CC) cell lines, patient-derived xenograft (PDX) tissues and patient tissues, here we report that CC CSCs, which resist chemoradiation, have higher SUMO activating enzyme (E1) and global SUMOylation levels than non-CSCs. Knockdown of SUMO E1 or SUMO conjugating enzyme (E2) inhibits CC CSC maintenance and self-renewal, while overexpression of SUMO E1 or E2 increases CC cell stemness. We found that SUMOylation regulates CSCs through Oct-1, a transcription factor for aldehyde dehydrogenases (ALDHs). ALDH activity is not only a marker for CSCs but also important in CSC biology. SUMO does not modify Oct-1 directly, but regulates the expression of TRIM21 that enhances Oct-1 ubiquitination and, consequently, reducing Oct-1 stability. In summary, our findings suggest that SUMOylation could be a target to inhibit CSCs and ultimately to reduce treatment resistance, tumour metastasis and relapse.

Alcohol fat clearing increases lymph node yield after surgery for colorectal cancer.

Lymph node (LN) yield is associated with oncologic outcome in patients who undergo surgery for colorectal adenocarcinoma (CRC). Standards to maximize LN yield have been initiated to enhance treatment of patients with CRC. This study evaluates the impact of a simple alcohol-based preparation protocol on LN yield. Surgical specimens from patients with CRC were prepared using either the alcohol protocol or standard formalin fixation and LN yield was compared. In total, 80 consecutive patients (n = 40 formalin, n = 40 alcohol) were examined. Overall, median LN yield increased from 17 to 29 (P < 0.01) with the alcohol fat clearance protocol. For patients with rectal adenocarcinoma who underwent proctectomy after neoadjuvant chemoradiotherapy, LN yield increased from 15 to 23 (P = 0.02). The frequency of need for additional sampling to achieve a minimum 12 LN count was also reduced. Initiation of a standardized alcohol fat-clearing protocol increased LN yield after surgery for CRC. This simple, cost-effective measure may improve the efficiency of LN assessment and accurate staging, which may impact oncologic outcomes.

TP53 and let-7a micro-RNA regulate K-Ras activity in HCT116 colorectal cancer cells.

Recent reports have indicated that KRAS and TP53 mutations predict response to therapy in colorectal cancer. However, little is known about the relationship between these two common genetic alterations. Micro-RNAs (miRNAs), a class of noncoding RNA implicated in cellular processes, have been increasingly linked to KRAS and TP53. We hypothesized that lethal-7a (let-7a) miRNA regulates KRAS through TP53. To investigate the relationship between KRAS, TP53, and let-7a, we used HCT116 KRAS(mut) human colorectal cancer cells with four different genotypic modifications in TP53 (TP53(-/-), TP53(+/-), TP53(mut/+), and TP53(mut/-) ). Using these cells we observed that K-Ras activity was higher in cells with mutant or knocked out TP53 alleles, suggesting that wild-type TP53 may suppress K-Ras activity. Let-7a was present in HCT116 KRAS(mut) cells, though there was no correlation between let-7a level and TP53 genotype status. To explore how let-7a may regulate K-Ras in the different TP53 genotype cells we used let-7a inhibitor and demonstrated increased K-Ras activity across all TP53, thus corroborating prior reports that let-7a regulates K-Ras. To assess potential clinical implications of this regulatory network, we examined the influence of TP53 genotype and let-7a inhibition on colon cancer cell survival following chemoradiation therapy (CRT). We observed that cells with complete loss of wild-type TP53 alleles ((-/-) or (-/mut)) were resistant to CRT following treatment with 5-fluorouracil and radiation. Further increase in K-Ras activity with let-7a inhibition did not impact survival in these cells. In contrast, cells with single or double wild-type TP53 alleles were moderately responsive to CRT and exhibited resistance when let-7a was inhibited. In summary, our results show a complex regulatory system involving TP53, KRAS, and let-7a. Our results may provide clues to understand and target these interactions in colorectal cancer.

Socioeconomic factors impact colon cancer outcomes in diverse patient populations.

PURPOSE: Cancer disparities among racial and ethnic groups are major public health concerns. Our objective was to examine the impact of socioeconomic status (SES) on survival of colon cancer patients within major racial and ethnic groups. METHODS: Patients with colon adenocarcinoma from Los Angeles County (LAC) were assessed. SES was utilized as an indicator of healthcare access and categorized by tertiles (high, middle, and low). Patient characteristics were compared and survival analyses were performed. RESULTS: In our heterogeneous LAC cohort, we confirmed survival disparities. Asians had the best survival followed by Hispanics, whites, and blacks. For each stage of disease, Asians and Hispanics had better outcomes than whites and blacks. Then, we evaluated the impact of SES on survival within each racial and ethnic group. We observed significantly longer survival for high SES patients compared to middle and low SES patients for all racial/ethnic groups. CONCLUSIONS: While disparities across racial/ethnic groups are well-documented, our study is the first to identify socioeconomic disparities in survival for patients within the same group. These novel findings demonstrate the complex role of SES on race and ethnicity and identify the need to improve healthcare access even within select populations.

Surgical complications and pathologic complete response after neoadjuvant chemoradiation in locally advanced rectal cancer.

Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) in patients with rectal cancer is associated with improved prognosis, whereas postoperative surgical complications have been linked with poor oncologic outcomes. Our objective was to examine the association between postoperative complications and pCR. We analyzed 127 patients enrolled in a prospective multicenter study investigating rectal cancer response to CRT. Surgical complications were scored according to the Clavien-Dindo scale (Grade 1 to 4). Among the 127 patients analyzed, 28 (22%) patients had a pCR. In the pCR group, six surgical Grade 3+ complications occurred in five (18%) patients, including anastomotic leak (n = 2), ureteral injury (n = 2), pelvic abscess (n = 1), and pneumonia (n = 1). In the non-pCR group, there were 10 Grade 3+ complications in eight (8%) patients, including severe obstruction (n = 1), postoperative hemorrhage (n = 1), leak (n = 2), pelvic abscess (n = 2), ureteral injury (n = 1), and severe morbidity (stroke, n = 1; acute respiratory distress, n = 1; and cardiac event, n = 1). There was no significant difference in the frequency of total surgical complications between pCR and non-pCR patients; and no association was observed between pCR and major postoperative complications. In conclusion, postoperative complication rates do not differ between pCR and non-pCR groups. The occurrence of major postoperative complications is not associated with response to neoadjuvant CRT.

Molecular diagnosis of response to neoadjuvant chemoradiation therapy in patients with locally advanced rectal cancer.

BACKGROUND: Pathologic complete response (pCR) to neoadjuvant chemoradiation (CRT) is an important prognostic factor in locally advanced rectal cancer. However, it is uncertain if histopathological techniques accurately detect pCR. We tested a novel molecular approach for detecting pCR and compared it with current histopathological approaches. STUDY DESIGN: Pretreatment tumor biopsies and surgical specimens were collected from 96 patients with locally advanced rectal cancer treated with neoadjuvant CRT and surgery. Tumor response was categorized by tumor regression grade. Tumor DNA from pre-CRT tumor biopsies was screened for K-ras and p53 mutations. DNA from paired surgical specimens was then screened for the same mutations using highly sensitive polymerase chain reaction-based techniques. RESULTS: Sixty-eight of 96 (71%) pretreatment biopsies harbored K-ras and/or p53 mutation; 36 (38%) had K-ras mutations, 52 (54%) had p53 mutations, and 20 (21%) carried both mutations. Of 70 patients with tumor regression grades 1 to 3, sixty-six (94%) had a concordant K-ras and p53 mutation profile in pre- and post-treatment tissues. Of 26 patients with tumor regression grade 0 (pCR), 12 had K-ras or p53 mutations in pretreatment biopsies. Of these, 2 (17%) patients had the same K-ras (n = 1) or p53 (n = 1) mutation detected in post-treatment tissue. CONCLUSIONS: Sensitive molecular techniques detect K-ras and p53 mutations in post-CRT surgical specimens in some patients with a pCR. This suggests histopathological techniques might not be completely accurate, and some patients diagnosed with a pCR to CRT might have occult cancers cells in their surgical specimens.