Endonuclease VIII-like 1 deficiency potentiates nigrostriatal dopaminergic neuron degeneration in a male mouse model of Parkinson's disease.

Parkinson's disease (PD) is a common movement disorder caused by a characteristic loss of dopaminergic neurons in the substantia nigra and degeneration of dopamine terminals in the dorsal striatum. Previous studies have suggested that oxidative stress-induced DNA damage may be involved in PD pathogenesis, as steady-state levels of several types of oxidized nucleobases were shown to be elevated in PD brain tissues. These DNA lesions are normally removed from the genome by base excision repair, which is initiated by DNA glycosylase enzymes such as endonuclease VIII-like 1 (Neil1). In this study, we show that Neil1 plays an important role in limiting oxidative stress-induced degeneration of dopaminergic neurons. In particular, Neil1-deficient male mice exhibited enhanced sensitivity to nigrostriatal degeneration after 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration, and Neil1-deficient animals had higher levels of γH2AX-marked DNA damage than wild-type (WT) controls, regardless of treatment status. Moreover, MPTP-treated Neil1-/- male mice had slightly elevated expression of genes related to the nuclear factor erythroid 2-related factor 2 (Nrf2)-dependent antioxidant pathway. Treatment with the Nrf2 activator, monomethyl fumarate, reduced PD-like behaviors and pathology in Neil1-/- male mice, suggesting that Neil1 is an important defense molecule in an oxidative cellular environment. Taken together, these results suggest that Neil1 DNA glycosylase may play an important role in limiting oxidative stress-mediated PD pathogenesis.

Impact of cumulative operative time on postoperative complication risk in simultaneous resections of colorectal liver metastases and primary tumors.

BACKGROUND: Simultaneous resection of colorectal liver metastases (CLM) and primary colorectal cancers (CRC) is nuanced without firm rules for selection. This study aimed to identify factors associated with morbidity after simultaneous resection. METHODS: Using a prospective database, patients undergoing simultaneous CLM-CRC resection from 1/1/2017-7/1/2020 were analyzed. Regression modeling estimated impact of colorectal resection type, Kawaguchi-Gayet (KG) hepatectomy complexity, and perioperative factors on 90-day complications. RESULTS: Overall, 120 patients underwent simultaneous CLM-CRC resection. Grade≥2 complications occurred in 38.3% (n = 46); these patients experienced longer length of stay (median LOS 7.5 vs. 4, p < 0.001) and increased readmission (39% vs. 1.4%, p < 0.001) compared to patients with zero or Grade 1 complications. Median OR time was 298 min. Patients within highest operative time quartile (>506 min) had higher grade≥2 complications (57%vs. 23%, p = 0.04) and greater than 4-fold increased odds of grade≥2 morbidity (OR 4.3, 95% CI (Confidence Interval) 1.41-13.1, p = 0.01). After adjusting for Pringle time, KG complexity and colorectal resection type, increasing operative time was associated with grade≥2 complications, especially for resections in highest quartile of operative time (OR 7.28, 95% CI 1.73-30.6, p = 0.007). CONCLUSION: In patients undergoing simultaneous CLM-CRC resection, prolonged operative time is independently associated with grade≥2 complications. Awareness of cumulative operative time may inform intraoperative decision-making by surgical teams.

What is the Risk for Peritoneal Metastases and Survival Afterwards in T4 Colon Cancers?

BACKGROUND: Patients with T4 colon adenocarcinomas have an increased risk of peritoneal metastases (PM) but the histopathologic risk factors for its development are not well-described. OBJECTIVE: The purpose of this study was to determine factors associated with PM, time to recurrence, and survival after recurrence among patients with T4 colon cancer. PATIENTS AND METHODS: Patients with pathologic T4 colon cancer who underwent curative resection from 2005 to 2017 were identified from a prospectively maintained institutional database and classified by recurrence pattern: (a) none - 68.8%; (b) peritoneal only - 7.9%; (c) peritoneal and extraperitoneal - 9.9%; and (d) extraperitoneal only - 13.2%. Associations between PM development and patient, primary tumor, and treatment factors were assessed. RESULTS: Overall, 151 patients were analyzed, with a median follow-up of 66.2 months; 27 patients (18%) developed PM (Groups B and C) and 20 (13%) patients recurred at non-peritoneal sites only (Group D). Median time to developing metastases was shorter for Groups B and C compared with Group D (B and C: 13.7 months; D: 46.7 months; p = 0.022). Tumor deposits (TDs) and nodal stage were associated with PM (p < 0.05), and TDs (p = 0.048) and LVI (p = 0.015) were associated with additional extraperitoneal recurrence. Eleven (41%) patients with PM underwent salvage surgery, and median survival after recurrence was associated with the ability to undergo cytoreduction (risk ratio 0.20, confidence interval 0.06-0.70). CONCLUSION: PM risk after resection of T4 colon cancer is independently associated with factors related to lymphatic spread, such as N stage and TDs. Well-selected patients can undergo cytoreduction with long-term survival. These findings support frequent postoperative surveillance and aggressive early intervention, including cytoreduction.

Development of an Online Curriculum for Surgeons on the Use of Pelvic Magnetic Resonance Imaging in Rectal Cancer and Results of a Pilot Study.

BACKGROUND: High-resolution pelvic magnetic resonance imaging (MRI) is a critical tool in the management of patients with rectal cancer. An on-line curriculum was developed for surgical trainees on the interpretation of pelvic MRI in rectal cancer for clinical staging and surgical planning. METHODS: The online curriculum was developed using the six-step approach to curriculum development for medical education. The curriculum incorporated case-based learning, annotated videos, and narrated presentations on key aspects of pelvic MRI in rectal cancer. A pilot study was conducted to assess curriculum effectiveness among Complex General Surgical Oncology (CGSO) fellows using pre- and post-intervention assessments. RESULTS: Of 15 eligible fellows, nine completed the pilot study (60%). The fellows' median confidence score after completing the online curriculum (40, IQR: 33-46) was significantly higher than their baseline median confidence score (23, IQR: 14-30), P = 0.0039. The total practical assessment score significantly increased from a pre-median score of 9 (IQR: 8-11) to a post-median score of 14 (IQR: 13-14), P = 0.0078. A subgroup analysis revealed a significant change in the knowledge assessment with a median score of 7 compared to a baseline median score of 4, Z = 2.64, P = 0.0078. However, the skills assessment showed no significant change. CONCLUSIONS: The case-based online curriculum had a positive impact on CGSO fellows' knowledge and confidence in the utilization of pelvic MRI for patients with rectal cancer. This unique on-line curriculum demonstrates a mechanism to enhance shared educational collaboration across CGSO fellowships and other surgical training programs.

CEA as a blood-based biomarker in anal cancer.

BACKGROUND: The clinical utility of a blood-based biomarker in squamous cell carcinoma of the anus (SCCA) is unknown. We analyzed carcinoembryonic antigen (CEA), a commonly employed assay for patients with colorectal adenocarcinoma, as a serum biomarker for patients with biopsy-proven SCCA. MATERIALS AND METHODS: Medical records from 219 patients with biopsy-proven SCCA at the University of Texas MD Anderson Cancer Center were reviewed under an IRB-approved protocol from 2013 to 2020 to assess for correlations between CEA levels and corresponding clinical and pathologic characteristics. RESULTS: The mean CEA among subgroups by clinical status at the time of presentation to our institution was highest among those patients with metastatic SCCA to visceral organs (M-V, 20.7 ng/mL), however this finding was not statistically significant by ANOVA (p = .74). By clinical subgroup, the percentage of patients with an abnormally elevated CEA was highest in those patients with metastatic disease to lymph nodes (M-L, 41.2%) followed by recurrent/unresectable SCCA (36.8%), and metastatic SCCA to visceral organs (M-V, 35.2%), and was statistically significant between groups (Fisher's exact test p = .02). Using RECIST criteria for tumor progression and disease response, the mean change in CEA for patients with progression was an increase in 19 ng/mL, compared to a change of -7.3 ng/mL in those with disease response (p = .004). We likewise assessed whether CEA levels were associated with survival outcomes for all patients with metastatic SCCA, and found no correlation between CEA and likelihood for survival in a ROC analysis (multivariate, age-adjusted analysis for CEA cutoff of 8, HR = 1.01, 95% CI 0.52-1.96). CONCLUSIONS: Despite interesting patterns of abnormally high CEA in SCCA patients with advanced disease, and correlation of increased CEA with disease progression (and conversely decreased CEA with disease response), CEA is not associated with survival outcomes in SCCA, and is not a clinically relevant biomarker in this disease.

Tumor Sidedness, Recurrence, and Survival After Curative Resection of Localized Colon Cancer.

BACKGROUND: Right-sided primary tumor location is associated with worse prognosis in metastatic colon cancer, but the effect of sidedness on recurrence and prognosis for non-metastatic disease is less understood. The purpose of this study was to examine the relationship between sidedness, recurrence, and survival among patients with localized colon cancer. PATIENTS AND METHODS: Consecutive patients who underwent curative resection of colon cancer (2006-2013) were identified from a prospective database and retrospectively analyzed. Risk for recurrence, overall survival, and survival after recurrence (SAR) were compared between left- and right-sided tumors using the log-rank test, and multivariable Cox proportional hazards regression. RESULTS: We evaluated 673 patients (347 right-sided). There was no difference in overall recurrence rates (adjusted hazard ratio [HR], 0.92; 95% confidence interval [CI], 0.54-1.55; P = .75) or overall survival (HR, 1.22; 95% CI, 0.75-1.97; P = .42) between right- and left-sided primary tumors. However, right-sided tumors were more likely to develop multi-focal and poor prognostic site recurrence (P = .04). Among the 71 patients who developed recurrence, those with right-sided tumors had significantly lower SAR (HR, 3.88; 95% CI, 1.42-10.62; P = .008). CONCLUSIONS: Among patients with colon cancer who underwent curative resection, tumor sidedness was not associated with recurrence risk. However, among patients who developed recurrence, right-sidedness was associated with unique recurrence patterns and inferior SAR. For patients presenting with localized disease, treatment stratification should not be based on tumor sidedness alone.

Genomic and Transcriptomic Characterisation of Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer.

Standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (NACRT), followed by surgical resection. However, >70% of patients do not achieve a complete pathological response and have higher rates of relapse and death. There are no validated pre- or on-treatment factors that predict response to NACRT besides tumour stage and size. We characterised the response of 33 LARC patients to NACRT, collected tumour samples from patients prior to, during and after NACRT, and performed whole exome, transcriptome and high-depth targeted sequencing. The pre-treatment LARC genome was not predictive of response to NACRT. However, in line with the increasing recognition of microbial influence in cancer, RNA analysis of pre-treatment tumours suggested a greater abundance of Fusobacteria in intermediate and poor responders. In addition, we investigated tumour heterogeneity and evolution in response to NACRT. While matched pre-treatment, on-treatment and post-treatment tumours revealed minimal genome evolution overall, we identified cases in which microsatellite instability developed or was selected for during NACRT. Recent research has suggested a role for adaptive mutability to targeted therapy in colorectal cancer cells. We provide preliminary evidence of selection for mismatch repair deficiency in response to NACRT. Furthermore, pre-NACRT genomic landscapes do not predict treatment response but pre-NACRT microbiome characteristics may be informative.

Surgical Resection for Recurrence After Two-Stage Hepatectomy for Colorectal Liver Metastases Is Feasible, Is Safe, and Improves Survival.

BACKGROUND: Recurrence rates are high for patients who have undergone two-stage hepatectomy (TSH) for bilateral colorectal liver metastases, and there is no established treatment approach for recurrent disease. This study aimed to determine the feasibility, safety, and prognostic impact of surgical resection for recurrence after TSH and the prognostic role of RAS mutation in this cohort. METHODS: The study included 137 patients intended to undergo TSH for bilateral colorectal metastases during 2003-2016. Clinicopathologic factors were compared using univariate and multivariate analyses. RESULTS: One hundred eleven patients (81%) completed TSH. The median recurrence-free survival in these patients was 12 months. Of the 83 patients with subsequent recurrence, 31 (37%) underwent resection for recurrence, and 11 underwent multiple resections for recurrence. Forty-eight operations were performed for recurrence: 23 repeat hepatectomies, 14 pulmonary resections, 5 locoregional resections, and 6 concurrent resections in multiple organ sites. The median overall survival (OS) among patients with recurrence was 143 months for patients who underwent resection and 49 months for those who did not (P < 0.001). On multivariate analysis, resection for recurrence (hazard ratio [HR] 0.25; 95% CI 0.10-0.54, P < 0.001) was associated with better OS, whereas RAS mutation (HR 2.25; 95% CI 1.16-4.50, P = 0.016) and first recurrence in multiple sites (HR 2.28; 95% CI 1.17-4.37, P = 0.016) were independent predictors of worse overall survival. CONCLUSIONS: In patients who have undergone TSH for bilateral colorectal liver metastases, recurrence is frequent and should be treated with resection whenever possible. Patients with wild-type RAS fare particularly well with resection for recurrence.

Hyperfractionated Accelerated Reirradiation for Patients With Recurrent Anal Cancer Previously Treated With Definitive Chemoradiation.

OBJECTIVES: Although chemoradiation is the standard of care for anal cancer, limited data exist regarding pelvic reirradiation (re-RT) for recurrent disease. We investigated toxicity and outcomes in patients who received prior pelvic radiation therapy (RT), and subsequently underwent hyperfractionated accelerated re-RT to the pelvis for recurrent anal cancer. MATERIALS AND METHODS: We reviewed records of 10 patients with recurrent anal squamous cell carcinoma who previously received pelvic RT to at least 30 Gy as a component of their chemoradiation and underwent re-RT in 1.5 Gy twice daily fractions to the pelvis, with either preoperative (N=7) or definitive (N=3) intent. RESULTS: The 3-year disease-free survival and 3-year overall survival rates were 40% and 60%. Four patients recurred within the reirradiated field, with a 3-year freedom from local progression rate of 56%. Of the 7 patients treated with preoperative intent, 5 proceeded to surgery, of whom 3 are alive and disease-free at a median duration of 43 months. Of the 3 patients treated definitively with no surgery, all are alive and disease-free at a median duration of 84 months. Re-RT resulted in one grade 3 acute toxicity and no grade 3 or higher late complications. CONCLUSIONS: Hyperfractionated accelerated re-RT was well-tolerated in patients with previously irradiated anal cancer. Patients treated with either definitive re-RT or re-RT followed by surgical resection had excellent rates of overall survival and freedom from local progression.

Clinical and Economic Evaluation of Treatment Strategies for T1N0 Anal Canal Cancer.

OBJECTIVE: A comparative assessment of treatment alternatives for T1N0 anal canal cancer has never been conducted. We compared the outcomes associated with the treatment alternatives-chemoradiotherapy (CRT), radiotherapy (RT), and surgery or ablation techniques (surgery/ablation)-for T1N0 anal canal cancer. MATERIALS AND METHODS: This retrospective cohort study was conducted using the Surveillance, Epidemiology and End Results (SEER) registries linked with Medicare longitudinal data (SEER-Medicare database). Analysis included 190 patients who were treated for T1N0 anal canal cancer using surgery/ablation (n=44), RT (n=50), or CRT (n=96). The outcomes were reported in terms of survival and hazards ratios using Kaplan-Meier and Cox proportional hazards modeling, respectively; lifetime costs; and cost-effectiveness measured in terms of incremental cost-effectiveness ratio, that is, the ratio of the difference in costs between the 2 alternatives to the difference in effectiveness between the same 2 alternatives. RESULTS: There was no significant difference in the survival duration between the treatment groups as predicted by the Kaplan-Meier curves. After adjusting for patient characteristics and propensity score, the hazard ratio of death for the patients who received CRT compared with surgery/ablation was 1.742 (95% confidence interval, 0.793-3.829) and RT was 2.170 (95% confidence interval, 0.923-5.101); however, the relationship did not reach statistical significance. Surgery/ablation resulted in lower lifetime cost than RT or CRT. The incremental cost-effectiveness ratio associated with CRT compared with surgery/ablation was $142,883 per life year gained. CONCLUSIONS: There was no statistically significant difference in survival among the treatment alternatives for T1N0 anal canal cancer. Given that surgery/ablation costs less than RT or CRT and might be cost-effective compared with RT and CRT, it is crucial to explore this finding further in this era of limited health care resources.

Oncological Outcomes After Robotic Proctectomy for Rectal Cancer: Analysis of a Prospective Database.

OBJECTIVE: The aim of this study is to evaluate the oncological outcomes of robotic total mesorectal excision (TME) at an NCI designated cancer center. SUMMARY BACKGROUND DATA: The effectiveness of laparoscopic TME could not be established, but the robotic-assisted approach may hold some promise, with improved visualization and ergonomics for pelvic dissection. Oncological outcome data is presently lacking. METHODS: Patients who underwent total mesorectal excision or tumor-specific mesorectal excision for rectal cancer between April 2009 and April 2016 via a robotic approach were identified from a prospective single-institution database. The circumferential resection margin (CRM), distal resection margin, and TME completeness rates were determined. Kaplan-Meier analysis of disease-free survival and overall survival was performed for all patients treated with curative intent. RESULTS: A total of 276 patients underwent robotic proctectomy during the study period. Robotic surgery was performed initially by 1 surgeon with 3 additional surgeons progressively transitioning from open to robotic during the study period with annual increase in the total number of cases performed robotically. Seven patients had involved circumferential resection margins (2.5%), and there were no positive distal or proximal resection margins. One hundred eighty-six patients had TME quality assessed, and only 1 patient (0.5%) had an incomplete TME. Eighty-three patients were followed up for a minimum of 3 years, with a local recurrence rate of 2.4%, and a distant recurrence rate of 16.9%. Five-year disease-free survival on Kaplan-Meier analysis was 82%, and 5-year overall survival was 87%. CONCLUSIONS: Robotic proctectomy for rectal cancer can be performed with good short and medium term oncological outcomes in selected patients.

Three Different Approaches to the Inferior Mesenteric Artery during Robotic D3 Lymphadenectomy for Rectal Cancer.

BACKGROUND: In rectal cancer surgery, proximal ligation of the inferior mesenteric artery (IMA) with radical lymphadenectomy is the accepted standard of care.1 Our purpose is to describe three different standardized technical approaches for the management of the IMA during D3 lymphadenectomy.2 METHODS: Operative videos of three robotic D3 lymphadenectomy procedures for rectal cancer were reviewed and annotated with schematic anatomical descriptions for clarification. RESULTS: There are three methods for the management of the IMA during D3 lymphadenectomy for rectal cancer. Standard high ligation is technically the simplest to perform and provides excellent mesenteric length but relies solely on marginal vessel blood supply from the middle colic artery.3 Low ligation with ascending left colic artery preservation is more complex technically but affords excellent vascular supply due to preservation of IMA blood flow, while potentially limiting mesenteric length.4 The central vascular sparing technique is the most complex to perform but allows excellent mesenteric length due to the presence of two separate points of mesenteric division, while also potentially improving blood supply due to decreased vascular resistance and improved collateralization. With each technique, central ligation of the inferior mesenteric vein above the splenic flexure tributary is performed to release the mesentery. CONCLUSIONS: The three methods to manage the IMA vary in their technical complexity, preservation of colonic conduit blood supply, and provision of mesenteric length, with associated advantages and disadvantages. The choice of technique is dependent on anatomical and oncological considerations.

Hyperfractionated accelerated reirradiation for rectal cancer: An analysis of outcomes and toxicity.

BACKGROUND AND PURPOSE: To evaluate outcomes and toxicity in patients treated with hyperfractionated pelvic reirradiation for recurrent rectal cancer. MATERIALS AND METHODS: 102 patients with recurrent rectal adenocarcinoma were treated with pelvic reirradiation with a hyperfractionated accelerated approach, consisting of 1.5Gy twice daily fractions to a total dose of 30-45Gy (median 39Gy), with the most common total dose 39Gy (n=90, 88%). The median dose of prior pelvic radiation therapy (RT) was 50.4Gy (range: 25-63Gy). RESULTS: The median follow-up was 40months for living patients (range, 3-150months). The 3-year freedom from local progression (FFLP) rate was 40% and the 3-year overall survival (OS) rate was 39%. Treatment with surgery was significantly associated with improved FFLP and OS, with 3-year FFLP rate of 49% vs. 30% (P=0.013), and 3-year OS rate of 62% vs. 20% (P<0.0001), compared to those without surgery. The actuarial 3-year rate of grade 3-4 late toxicity was 34%; patients who underwent surgery had a significantly higher rate of grade 3-4 late toxicity compared to those without surgery (54% vs. 16%, P=0.001). CONCLUSIONS: This large, retrospective, single-institution study shows that hyperfractionated accelerated reirradiation was well tolerated. The rate of FFLP was promising, given that the study comprised heavily pre-treated patients with recurrences. Rates of FFLP and OS were particularly impressive in patients who underwent both reirradiation and surgery.

Role of microsatellite instability-low as a diagnostic biomarker of Lynch syndrome in colorectal cancer.

Lynch syndrome is the most common Mendelian disorder predisposing persons to hereditary colorectal cancer. Carriers of MSH6 mutations constitute less than 10% of the total of cases with Lynch syndrome and present with a weaker clinical phenotype, including low levels of microsatellite instability (MSI-L) in colorectal tumors. The frequency of MSH6 mutation carriers among patients presenting with MSI-L colorectal cancer has yet to be determined, as has the appropriate genetic workup in this context. We have reviewed here the clinicopathologic characteristics, immunohistochemistry, and genetic testing results for 71 patients at a single institution diagnosed with MSI-L colorectal cancers. Of 71 patients with MSI-L tumors, 21 underwent genetic testing for MSH6 mutations, three of whom presented with loss of staining of MSH6 and only one of whom carried a pathogenic germline MSH6 mutation in exon 4 (c.2677_2678delCT; p.Leu893Alafs*6). This latter patient had a significant family history of cancer and had a rectal primary tumor that showed instability only in mononucleotide markers. In this cohort of MSI-L patients, we detected no notable clinicopathologic or molecular characteristic that would help to distinguish a group most likely to harbor germline MSH6 mutations. Therefore, we conclude that the prevalence of MSH6 mutations among patients with MSI-L tumors is very low. Microsatellite instability analysis combined with immunohistochemistry of mismatch repair proteins adequately detects potential MSH6 mutation carriers among MSI-L colorectal cancers.

Effects of medium-chain triglycerides, long-chain triglycerides, or 2-monododecanoin on fatty acid composition in the portal vein, intestinal lymph, and systemic circulation in rats.

BACKGROUND: Fatty acid absorption patterns can have a major impact on the fatty acid composition in the portal, intestinal lymph, and systemic circulation. This study sought to determine the effects of long-chain triglycerides (LCT), medium-chain triglycerides (MCT), and 2-monododecanoin (2mono) on intestinal fatty acid composition during continuous feeding over a brief period. METHODS: The lipid sources were 100% LCT, 100% MCT, a 50:50 mixture of LCT and MCT (LCT/MCT), and a 50:50 mixture of LCT and 2mono (LCT/2mono). A total of 27 rats were randomly given 1 of the 4 diets at 200 kcal/kg/d, with 30% of total calories from lipids over 3 hours. RESULTS: MCT significantly increased each of the medium-chain fatty acids (C6:0, C8:0, and C10:0) as free fatty acids in the portal vein and about 10%/mol of C10:0 as triglycerides in the lymph compared with the other groups. There was significantly less C10:0 in lymphatic triglycerides with LCT/MCT than with MCT, but more than in the LCT and LCT/2mono diets. MCT also significantly increased the contents of C16:0, C18:0, C18:1, and C20:4 in the lymphatic triglycerides compared with all other groups including LCT/MCT. The amount of linoleic acid (C18:2) in lymphatic triglycerides followed the relative amounts of this fatty acid in the diet, with the greatest in LCT followed by LCT/MCT and LCT/2mono and least in MCT. A so-called structured lipid composed of the medium-chain fatty acid dodecanoic acid on the 2 position and long-chain fatty acids on the 1 and 3 positions appeared to be endogenously synthesized in response to the LCT/2mono diet. CONCLUSIONS: The original differences in MCT and LCT content in the diets were preserved in the fatty acid composition in the intestinal free fatty acids and triglycerides during feeding. In addition, the duration of lipid administration can play a role in altering fatty acid composition in the intestine.