Natural History of Colorectal Polyps Undergoing Longitudinal in Vivo CT Colonography Surveillance.

Background The natural history of colorectal polyps is not well characterized due to clinical standards of care and other practical constraints limiting in vivo longitudinal surveillance. Established CT colonography (CTC) clinical screening protocols allow surveillance of small (6-9 mm) polyps. Purpose To assess the natural history of colorectal polyps followed with CTC in a clinical screening program, with histopathologic correlation for resected polyps. Materials and Methods In this retrospective study, CTC was used to longitudinally monitor small colorectal polyps in asymptomatic adult patients from April 1, 2004, to August 31, 2020. All patients underwent at least two CTC examinations. Polyp growth patterns across multiple time points were analyzed, with histopathologic context for resected polyps. Regression analysis was performed to evaluate predictors of advanced histopathology. Results In this study of 475 asymptomatic adult patients (mean age, 56.9 years ± 6.7 [SD]; 263 men), 639 unique polyps (mean initial diameter, 6.3 mm; volume, 50.2 mm3) were followed for a mean of 5.1 years ± 2.9. Of these 639 polyps, 398 (62.3%) underwent resection and histopathologic evaluation, and 41 (6.4%) proved to be histopathologically advanced (adenocarcinoma, high-grade dysplasia, or villous content), including two cancers and 38 tubulovillous adenomas. Advanced polyps showed mean volume growth of +178% per year (752% per year for adenocarcinomas) compared with +33% per year for nonadvanced polyps and -3% per year for unresected, unretrieved, or resolved polyps (P < .001). In addition, 90% of histologically advanced polyps achieved a volume of 100 mm3 and/or volume growth rate of 100% per year, compared with 29% of nonadvanced and 16% of unresected or resolved polyps (P < .001). Polyp volume-to-diameter ratio was also significantly greater for advanced polyps. For polyps observed at three or more time points, most advanced polyps demonstrated an initial slower growth interval, followed by a period of more rapid growth. Conclusion Small colorectal polyps ultimately proving to be histopathologically advanced neoplasms demonstrated substantially faster growth and attained greater overall size compared with nonadvanced polyps. Clinical trial registration no. NCT00204867 © RSNA, 2024 Supplemental material is available for this article. See also the editorial by Dachman in this issue.

Preclinical Models of Anal Cancer Combined-Modality Therapy.

INTRODUCTION: There have been no significant changes in anal cancer treatment options in 4 decades. In this study, we highlight two preclinical models designed to assess anal cancer treatments. MATERIALS AND METHODS: Transgenic K14E6/E7 mice were treated with 7, 12-dimethylbenz(a)anthracene until anal tumors developed. Mice were treated with localized radiation in addition to chemotherapy (combined-modality therapy [CMT]) and compared to no treatment control (NTC). K14E6/E7 mouse anal spheroids with and without Pik3ca mutations were isolated and treated with vehicle, LY3023414 (LY3) (a drug previously shown to be effective in cancer prevention), CMT, or CMT + LY3. RESULTS: In the in vivo model, there was a significant increase in survival in the CMT group compared to the NTC group (P = 0.0392). In the ex vivo model, there was a significant decrease in the mean diameter of CMT and CMT + LY3-treated spheroids compared to vehicle (P ≤ 0.0001). For LY3 alone compared to vehicle, there was a statistically significant decrease in spheroid size in the K14E6/E7 group without mutation (P = 0.0004). CONCLUSIONS: We have provided proof of concept for two preclinical anal cancer treatment models that allow for the future testing of novel therapies for anal cancer.

Growth rates and histopathological outcomes of small (6-9 mm) colorectal polyps based on CT colonography surveillance and endoscopic removal.

BACKGROUND AND AIMS: The natural history of small polyps is not well established and rests on limited evidence from barium enema studies decades ago. Patients with one or two small polyps (6-9 mm) at screening CT colonography (CTC) are offered CTC surveillance at 3 years but may elect immediate colonoscopy. This practice allows direct observation of the growth of subcentimetre polyps, with histopathological correlation in patients undergoing subsequent polypectomy. DESIGN: Of 11 165 asymptomatic patients screened by CTC over a period of 16.4 years, 1067 had one or two 6-9 mm polyps detected (with no polyps ≥10 mm). Of these, 314 (mean age, 57.4 years; M:F, 141:173; 375 total polyps) elected immediate colonoscopic polypectomy, and 382 (mean age 57.0 years; M:F, 217:165; 481 total polyps) elected CTC surveillance over a mean of 4.7 years. Volumetric polyp growth was analysed, with histopathological correlation for resected polyps. Polyp growth and regression were defined as volume change of ±20% per year, with rapid growth defined as +100% per year (annual volume doubling). Regression analysis was performed to evaluate predictors of advanced histology, defined as the presence of cancer, high-grade dysplasia (HGD) or villous components. RESULTS: Of the 314 patients who underwent immediate polypectomy, 67.8% (213/314) harboured adenomas, 2.2% (7/314) with advanced histology; no polyps contained cancer or HGD. Of 382 patients who underwent CTC surveillance, 24.9% (95/382) had polyps that grew, while 62.0% (237/382) remained stable and 13.1% (50/382) regressed in size. Of the 58.6% (224/382) CTC surveillance patients who ultimately underwent colonoscopic resection, 87.1% (195/224) harboured adenomas, 12.9% (29/224) with advanced histology. Of CTC surveillance patients with growing polyps who underwent resection, 23.2% (19/82) harboured advanced histology vs 7.0% (10/142) with stable or regressing polyps (OR: 4.0; p<0.001), with even greater risk of advanced histology in those with rapid growth (63.6%, 14/22, OR: 25.4; p<0.001). Polyp growth, but not patient age/sex or polyp morphology/location were significant predictors of advanced histology. CONCLUSION: Small 6-9 mm polyps present overall low risk to patients, with polyp growth strongly associated with higher risk lesions. Most patients (75%) with small 6-9 mm polyps will see polyp stability or regression, with advanced histology seen in only 7%. The minority of patients (25%) with small polyps that do grow have a 3-fold increased risk of advanced histology.

Esophageal and Esophagogastric Junction Cancers, Version 2.2023, NCCN Clinical Practice Guidelines in Oncology.

Cancers originating in the esophagus or esophagogastric junction constitute a major global health problem. Esophageal cancers are histologically classified as squamous cell carcinoma (SCC) or adenocarcinoma, which differ in their etiology, pathology, tumor location, therapeutics, and prognosis. In contrast to esophageal adenocarcinoma, which usually affects the lower esophagus, esophageal SCC is more likely to localize at or higher than the tracheal bifurcation. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability status, and the expression of programmed death-ligand 1, has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, ipilimumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with locally advanced esophageal or esophagogastric junction cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on the management of recurrent or metastatic disease.

Anal Cancer Prevention Through the Topical Use of Single or Dual PI3K/mTOR Inhibitors.

INTRODUCTION: Anal dysplasia and anal cancer are major health problems. This study seeks to determine if inhibition of mTOR and/or PI3K pathways is effective at anal cancer prevention in mice with/without established precancerous lesions of the anus (anal dysplasia). METHODS: K14E6/E7 mice were entered into the study at 5 wk, 15 wk, or 25 wk of age. Mice were treated with a topical carcinogen, 7,12-Dimethylbenz[a]anthracene (DMBA), which ensures carcinoma development within 20 wk. Treatment groups included: no treatment, DMBA only, topical Pictilisib (PI3K inhibitor) with/without DMBA, topical Sapanisertib (mTOR inhibitor) with/without DMBA, and topical Samotolisib (dual PI3K/mTOR inhibitor) with/without DMBA. Mice underwent weekly observations for anal tumor development (tumor-free survival). After 20 wk of treatment, anal tissue was harvested and evaluated histologically for squamous cell carcinoma (SqCC). RESULTS: All topical treatments in conjunction with DMBA increased tumor-free survival in mice that started treatment at 15 wk of age when compared to DMBA-only treatment, except for Pictilisib + DMBA in males. Topical Sapanisertib increased tumor-free survival in mice regardless of starting treatment age. When examining tissue for microscopic evidence of SqCC, only topical Samotolisib in males decreased SqCC in the 15 wk starting mice. CONCLUSIONS: Sapanisertib, the mTOR inhibitor, had the greatest effect, in terms of increasing tumor-free survival, regardless of starting time point or sex. Unlike the other treatments, Samotolisib, the dual PI3K/mTOR inhibitor, decreased microscopic evidence of SqCC when starting treatment at 15 wk of age but only in male mice.

Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Gastric cancer is the third leading cause of cancer-related deaths worldwide. Over 95% of gastric cancers are adenocarcinomas, which are typically classified based on anatomic location and histologic type. Gastric cancer generally carries a poor prognosis because it is often diagnosed at an advanced stage. Systemic therapy can provide palliation, improved survival, and enhanced quality of life in patients with locally advanced or metastatic disease. The implementation of biomarker testing, especially analysis of HER2 status, microsatellite instability (MSI) status, and the expression of programmed death-ligand 1 (PD-L1), has had a significant impact on clinical practice and patient care. Targeted therapies including trastuzumab, nivolumab, and pembrolizumab have produced encouraging results in clinical trials for the treatment of patients with locally advanced or metastatic disease. Palliative management, which may include systemic therapy, chemoradiation, and/or best supportive care, is recommended for all patients with unresectable or metastatic cancer. Multidisciplinary team management is essential for all patients with localized gastric cancer. This selection from the NCCN Guidelines for Gastric Cancer focuses on the management of unresectable locally advanced, recurrent, or metastatic disease.

PI3K/mTOR inhibition prevents anal cancer in mice with established low-grade anal dysplasia.

Low-grade anal dysplasia is a disease that can progress to high-grade anal dysplasia and eventually anal cancer if left untreated. Research has shown that low-grade anal dysplasia is marked by significant autophagic dysfunction. We hypothesized that systemic induction of autophagy, via phosphoinositide 3-kinase/mammalian target of rapamycin (PI3K/mTOR) inhibition, would be effective in preventing anal cancer development in human papillomavirus (HPV) mice (K14E6/E7) with established low-grade anal dysplasia. Mice began treatment at 15 weeks of age, when 75% of mice spontaneously develop low-grade anal dysplasia, and were divided into the following groups: no treatment, systemic LY3023414 (4.5 mg/kg, dual PI3K/mTOR inhibitor) alone, topical 7,12 dimethylbenz[a]anthracene (DMBA) alone, or systemic LY3023414 and topical DMBA. Groups were compared for final histology, PI3K activity, mTOR activity, autophagic induction (light chain 3B (LC3ß)), autophagic function (p62 protein), and tumor-free survival. Untreated mice or mice treated with LY3023414 alone did not progress to cancer. There was a statistically significant decrease in the number of mice that developed histologic evidence of cancer when comparing mice that received systemic LY3203414 with topical DMBA versus those that received topical DMBA alone (p = 0.0003). PI3K and mTOR activity decreased in groups treated with systemic LY3023414 and topical DMBA as compared with those treated with topical DMBA alone (p = 0.0005 and p = 0.0271, respectively). LC3ß and p62 expression was not statistically altered with systemic LY3023414 treatment. Mice developed less overt tumors and had increased tumor-free survival when treated with systemic LY3023414 in the presence of topical DMBA compared to topical DMBA alone (p = 0.0016 and p < 0.001, respectively). Systemic LY3023414 treatment is effective in anal cancer prevention in the setting of established low-grade anal dysplasia in an HPV-associated mouse model of anal cancer.

Detection of High-Risk Sessile Serrated Lesions: Multitarget Stool DNA Versus CT Colonography.

BACKGROUND. The serrated pathway for colorectal cancer (CRC) development is increasingly recognized. Sessile serrated lesions (SSLs) that are large (≥ 10 mm) and/or have dysplasia (i.e., high-risk SSLs) are at higher risk of progression to CRC. Detection of SSLs is challenging given their predominantly flat and right-sided location. The yield of noninvasive screening tests for detection of high-risk SSLs is unclear. OBJECTIVE. The aim of this study was to compare noninvasive screening detection of high-risk SSLs between the multitarget stool DNA (mt-sDNA) test and CT colonography (CTC). METHODS. This retrospective study included 7974 asymptomatic adults (4705 women, 3269 men; mean age, 60.0 years) who underwent CRC screening at a single center by mt-sDNA from 2014 to 2019 (n = 3987) or by CTC from 2009 to 2019 (n = 3987). Clinical interpretations of CTC examinations were recorded. Subsequent colonoscopy findings and histology of resected polyps were also recorded. Chi-square or two-sample t tests were used to compare results between mt-sDNA and CTC using 6-mm and 10-mm thresholds for test positivity. RESULTS. The overall colonoscopy referral rate for a positive screening test was 13.1% (522/3987) for mt-sDNA versus 12.2% (487/3987; p = .23) and 6.5% (260/3987; p < .001) for CTC at 6-mm and 10-mm thresholds, respectively. The PPV for high-risk SSLs was 5.5% (26/476) for mt-sDNA versus 14.4% (66/457; p < .001) and 25.9% (63/243; p < .001) for CTC at the 6-mm and 10-mm thresholds, respectively. The overall screening yield of high-risk SSLs was 0.7% (26/3987) for mt-sDNA versus 1.7% (66/3987; p < .001) and 1.6% (63/3987; p < .001) for CTC at 6-mm and 10-mm thresholds, respectively. CONCLUSION. CTC at 6-mm and 10-mm thresholds had significantly higher yield and PPV for high-risk SSLs compared with mt-sDNA. CLINICAL IMPACT. The significantly higher detection of high-risk SSLs by CTC than by mt-sDNA should be included in discussions with patients who decline colonoscopy and opt for noninvasive screening.

Chronic jetlag-induced alterations in pancreatic diurnal gene expression.

Cell-autonomous circadian clocks exist in nearly every organ and function to maintain homeostasis through a complex series of transcriptional-translational feedback loops. The response of these peripheral clocks to external perturbations, such as chronic jetlag and shift work, has been extensively investigated. However, an evaluation of the effects of chronic jetlag on the mouse pancreatic transcriptome is still lacking. Herein, we report an evaluation of the diurnal variations encountered in the pancreatic transcriptome following exposure to an established chronic jetlag protocol. We found approximately 5.4% of the pancreatic transcriptome was rhythmic. Following chronic jetlag, we found the number of rhythmic transcripts decreased to approximately 3.6% of the transcriptome. Analysis of the core clock genes, which orchestrate circadian physiology, revealed that nearly all exhibited a shift in the timing of peak gene expression-known as a phase shift. Similarly, over 95% of the rhythmically expressed genes in the pancreatic transcriptome exhibited a phase shift, many of which were found to be important for metabolism. Evaluation of the genes involved in pancreatic exocrine secretion and insulin signaling revealed many pancreas-specific genes were also rhythmically expressed and several displayed a concomitant phase shift with chronic jetlag. Phase differences were found 9 days after normalization, indicating a persistent failure to reentrain to the new light-dark cycle. This study is the first to evaluate the endogenous pancreatic clock and rhythmic gene expression in whole pancreas over 48 h, and how the external perturbation of chronic jetlag affects the rhythmic expression of genes in the pancreatic transcriptome.

Mucin-producing Cystic Hepatobiliary Neoplasms: Updated Nomenclature and Clinical, Pathologic, and Imaging Features.

Cystic hepatobiliary neoplasms with mucin-producing epithelium-mucinous cystic neoplasm of the liver (MCN) and intraductal papillary neoplasm of the bile duct (IPNB)-are rare and distinct entities that have unique clinical, pathologic, and imaging features. They are differentiated pathologically by the presence of subepithelial ovarian-like hypercellular stroma (OLS), which is the defining histopathologic feature of MCN. MCN is commonly a benign, large, solitary, symptomatic, multiloculated cystic mass without biliary communication that occurs in middle-aged women. On the other hand, IPNBs are a heterogeneous spectrum of tumors, which are commonly associated with invasive carcinoma, occur in older patients, and can be differentiated from MCN by communication with the biliary tree, intraductal masses, associated biliary ductal dilatation, and absent OLS. Understanding of these rare neoplasms has grown and evolved over time and continues to today, but uncertainty and controversy persist, related to the rarity of these tumors, relatively recent designation as separate entities, inherent clinicopathologic heterogeneity, overlapping imaging features, and the fact that many prior studies likely included MCN and cystic IPNB together as a single entity. Confusion regarding these neoplasms is evident by historical inconsistencies and nonstandardized nomenclature through the years. Awareness of these entities is important for the interpreting radiologist to suggest a particular diagnosis or generate a meaningful differential diagnosis in the appropriate setting, and is of particular significance as MCN and cystic IPNB have overlapping imaging features with other more common hepatobiliary cystic masses but have different management and prognosis. Online supplemental material is available for this article. Work of the U.S. Government published under an exclusive license with the RSNA.

Esophageal and Esophagogastric Junction Cancers, Version 2.2019, NCCN Clinical Practice Guidelines in Oncology.

Esophageal cancer is the sixth leading cause of cancer-related deaths worldwide. Squamous cell carcinoma is the most common histology in Eastern Europe and Asia, and adenocarcinoma is most common in North America and Western Europe. Surgery is a major component of treatment of locally advanced resectable esophageal and esophagogastric junction (EGJ) cancer, and randomized trials have shown that the addition of preoperative chemoradiation or perioperative chemotherapy to surgery significantly improves survival. Targeted therapies including trastuzumab, ramucirumab, and pembrolizumab have produced encouraging results in the treatment of patients with advanced or metastatic disease. Multidisciplinary team management is essential for all patients with esophageal and EGJ cancers. This selection from the NCCN Guidelines for Esophageal and Esophagogastric Junction Cancers focuses on recommendations for the management of locally advanced and metastatic adenocarcinoma of the esophagus and EGJ.

CT Colonography in Preoperative Staging of Colon Cancer: Evaluation of FOxTROT Inclusion Criteria for Neoadjuvant Therapy.

OBJECTIVE: The purpose of the present study is to evaluate the diagnostic performance of and interreader agreement for CT colonography (CTC) in the local staging of colon cancer, with emphasis given to the FOxTROT (Fluoropyrimidine, Oxaliplatin, and Targeted-Receptor pre-Operative Therapy [Panitumumab]) trial inclusion criteria, which propose a new tailored treatment paradigm for colon cancer that uses neoadjuvant therapy for patients with a high-risk of locoregional disease as determined by imaging. MATERIALS AND METHODS: This biinstitutional retrospective study involved 89 patients (with 93 tumors) who had colon cancer and underwent presurgical CTC. Two radiologists reviewed the CTC studies for local staging, including measurement of the tumor beyond the muscularis propria on a true orthogonal plane. Histopathologic findings for surgical colectomy specimens served as the reference standard for local pathologic staging. The sensitivity, specificity, positive predictive value, and negative predictive value for local determination of the T category, N category, and extramural vascular invasion (EMVI) were calculated separately for each reader. High-risk T category tumors were the same as those as used in the FOxTROT trial. Interreader agreement was assessed using the kappa statistic. RESULTS: Thirty-five of 93 tumors (37.6%) were histologically classified as high-risk tumors (T3c, T3d, or T4 tumors). The interreader agreement was substantial (κ = 0.68) for classifying high-risk tumors with the use of CTC, moderate for differentiating N0 from N1 and N2 (κ = 0.44), and slight for detecting EMVI (κ = 0.15). The diagnostic statistics for CTC for the two readers were as follows: for detection of high-risk tumors, sensitivity was 65.7% and 82.9%, and specificity was 81.0% and 87.9%; for detection of N category-positive disease, sensitivity was 50.9% and 69.8%, and specificity was 50.0% and 72.5%; and for detection of EMVI, sensitivity was 18.2% and 66.7%, and specificity was 60.0% and 91.7%. CONCLUSION: The present study shows that CTC might be a feasible imaging modality for preoperative local staging of higher-risk colon cancers for which neoadjuvant chemotherapy is more suitable on the basis of the FOxTROT trial criteria. However, further studies are required to allow a better generalization of our results.

Versican-Derived Matrikines Regulate Batf3-Dendritic Cell Differentiation and Promote T Cell Infiltration in Colorectal Cancer.

Colorectal cancer originates within immunologically complex microenvironments. To date, the benefits of immunotherapy have been modest, except in neoantigen-laden mismatch repair-deficient tumors. Approaches to enhance tumor-infiltrating lymphocytes in the tumor bed may substantially augment clinical immunotherapy responses. In this article, we report that proteolysis of the tolerogenic matrix proteoglycan versican (VCAN) strongly correlated with CD8+ T cell infiltration in colorectal cancer, regardless of mismatch repair status. Tumors displaying active VCAN proteolysis and low total VCAN were associated with robust (10-fold) CD8+ T cell infiltration. Tumor-intrinsic WNT pathway activation was associated with CD8+ T cell exclusion and VCAN accumulation. In addition to regulating VCAN levels at the tumor site, VCAN proteolysis results in the generation of bioactive fragments with novel functions (VCAN-derived matrikines). Versikine, a VCAN-derived matrikine, enhanced the generation of CD103+CD11chiMHCIIhi conventional dendritic cells (cDCs) from Flt3L-mobilized primary bone marrow-derived progenitors, suggesting that VCAN proteolysis may promote differentiation of tumor-seeding DC precursors toward IRF8- and BATF3-expressing cDCs. Intratumoral BATF3-dependent DCs are critical determinants for T cell antitumor immunity, effector T cell trafficking to the tumor site, and response to immunotherapies. Our findings provide a rationale for testing VCAN proteolysis as a predictive and/or prognostic immune biomarker and VCAN-derived matrikines as novel immunotherapy agents.

Restoration of metabolic health by decreased consumption of branched-chain amino acids.

KEY POINTS: We recently found that feeding healthy mice a diet with reduced levels of branched-chain amino acids (BCAAs), which are associated with insulin resistance in both humans and rodents, modestly improves glucose tolerance and slows fat mass gain. In the present study, we show that a reduced BCAA diet promotes rapid fat mass loss without calorie restriction in obese mice. Selective reduction of dietary BCAAs also restores glucose tolerance and insulin sensitivity to obese mice, even as they continue to consume a high-fat, high-sugar diet. A low BCAA diet transiently induces FGF21 (fibroblast growth factor 21) and increases energy expenditure. We suggest that dietary protein quality (i.e. the precise macronutrient composition of dietary protein) may impact the effectiveness of weight loss diets. ABSTRACT: Obesity and diabetes are increasing problems around the world, and although even moderate weight loss can improve metabolic health, reduced calorie diets are notoriously difficult to sustain. Branched-chain amino acids (BCAAs; leucine, isoleucine and valine) are elevated in the blood of obese, insulin-resistant humans and rodents. We recently demonstrated that specifically reducing dietary levels of BCAAs has beneficial effects on the metabolic health of young, growing mice, improving glucose tolerance and modestly slowing fat mass gain. In the present study, we examine the hypothesis that reducing dietary BCAAs will promote weight loss, reduce adiposity, and improve blood glucose control in diet-induced obese mice with pre-existing metabolic syndrome. We find that specifically reducing dietary BCAAs rapidly reverses diet-induced obesity and improves glucoregulatory control in diet-induced obese mice. Most dramatically, mice eating an otherwise unhealthy high-calorie, high-sugar Western diet with reduced levels of BCAAs lost weight and fat mass rapidly until regaining a normal weight. Importantly, this normalization of weight was mediated not by caloric restriction or increased activity, but by increased energy expenditure, and was accompanied by a transient induction of the energy balance regulating hormone FGF21 (fibroblast growth factor 21). Consumption of a Western diet reduced in BCAAs was also accompanied by a dramatic improvement in glucose tolerance and insulin resistance. Our results link dietary BCAAs with the regulation of metabolic health and energy balance in obese animals, and suggest that specifically reducing dietary BCAAs may represent a highly translatable option for the treatment of obesity and insulin resistance.

Metastatic Bulk Independently Predicts Outcomes for EGFR Precision Targeting in Colorectal Cancer.

Background: Molecular profiles guide the clinical management of metastatic colorectal cancer (mCRC), particularly related to the use of anti-epidermal growth factor receptor (EGFR) antibodies. Tumor sidedness has also been implicated in resistance to these therapies, but has largely been studied in the first-line setting. We examined the role of tumor sidedness and disease bulk in predicting clinical outcomes to anti-EGFR therapy in the treatment-refractory setting. Methods: We identified a retrospective cohort of 62 patients with KRAS wild-type mCRC who received anti-EGFR therapy in the late-line setting. Response was assessed per RECIST 1.1, with bulky disease defined as any single lesion >35 mm in longest cross-sectional diameter or nodal short axis. Primary sidedness was defined in relation to the splenic flexure. Results: Patients with right-sided primary tumors at time of late-line EGFR therapy presented with increased tumor bulk and worsened overall survival (OS) relative to left-sided primary tumors. Tumor bulk, defined as either a categorical or continuous variable, predicted worsened progression-free survival (PFS) and OS, which persisted when controlling for differences in the primary tumor location. Within the right-sided cohort, no objective responses were observed for bulky disease or during treatment with anti-EGFR monotherapy. The nonbulky cohort experienced clinical benefit with anti-EGFR monotherapy, showing similar PFS and an improved response rate compared with sequential chemotherapy. Conclusions: In an effort to expand understanding of the role of primary sidedness in clinical response to anti-EGFR therapy, we identified sidedness and tumor bulk as potential predictive biomarkers of clinical response in late-line mCRC. Future prospective studies of EGFR targeting should consider tumor bulk in addition to molecular profiling in the identification of populations most likely to achieve meaningful clinical benefit.

Genetic inhibition of autophagy in a transgenic mouse model of anal cancer.

BACKGROUND: The dynamic role of autophagy in cancer development is a topic of considerable research and debate. Previously published studies have shown that anal cancer development can be promoted or prevented with the pharmacologic inhibition or induction, respectively, of autophagy in a human papillomavirus (HPV) mouse model. However, these results are confounded by the fact that the drugs utilized are known to affect other pathways besides autophagy. It has also been shown that autophagic inhibition occurs in the setting of HPV16 oncoprotein expression (E6 and E7) and correlates with increased susceptibility to anal carcinogenesis. MATERIALS AND METHODS: In this study, we employed a conditional, genetic, autophagic (Atg7) knockout mouse model to determine conclusively that autophagy has a role in anal cancer development, in the absence or presence of E6 and E7. RESULTS: In mice lacking both HPV16 oncogenes, knockout of autophagy followed by exposure to a carcinogen resulted in a tumor incidence of 40%, compared to 0% in mice treated with a carcinogen alone with an intact autophagic pathway (P = 0.007). In mice expressing either one or both HPV16 oncoproteins, the addition of genetic knockout of autophagy to carcinogen treatment did not lead to a significant difference in tumor incidence compared to carcinogen treatment alone, consistent with the ability of HPV oncogenes to inhibit autophagy in themselves. CONCLUSIONS: These results provide the first conclusive evidence for the distinct role of autophagy in anal carcinogenesis, and suggest that autophagy is a plausible target for therapies aimed at reducing anal dysplasia and anal cancer development.

Subclonal diversity arises early even in small colorectal tumours and contributes to differential growth fates.

OBJECTIVE AND DESIGN: The goal of the study was to determine whether the mutational profile of early colorectal polyps correlated with growth behaviour. The growth of small polyps (6-9 mm) that were first identified during routine screening of patients was monitored over time by interval imaging with CT colonography. Mutations in these lesions with known growth rates were identified by targeted next-generation sequencing. The timing of mutational events was estimated using computer modelling and statistical inference considering several parameters including allele frequency and fitness. RESULTS: The mutational landscape of small polyps is varied both within individual polyps and among the group as a whole but no single alteration was correlated with growth behaviour. Polyps carried 0-3 pathogenic mutations with the most frequent being in APC, KRAS/NRAS, BRAF, FBXW7 and TP53. In polyps with two or more pathogenic mutations, allele frequencies were often variable, indicating the presence of multiple populations within a single tumour. Based on computer modelling, detectable mutations occurred at a mean polyp size of 30±35 crypts, well before the tumour is of a clinically detectable size. CONCLUSIONS: These data indicate that small colon polyps can have multiple pathogenic mutations in crucial driver genes that arise early in the existence of a tumour. Understanding the molecular pathway of tumourigenesis and clonal evolution in polyps that are at risk for progressing to invasive cancers will allow us to begin to better predict which polyps are more likely to progress into adenocarcinomas and which patients are at greater risk of developing advanced disease.

Colorectal Polyps Missed with Optical Colonoscopy Despite Previous Detection and Localization with CT Colonography.

PURPOSE: To retrospectively evaluate and characterize nondiminutive colorectal polyps prospectively detected by using computed tomographic (CT) colonography but not confirmed with subsequent nonblinded optical colonoscopy (OC). MATERIALS AND METHODS: This study was institutional review board approved; the need for signed informed consent was waived. Over 113 months, 9336 adults (mean age, 57.1 years) underwent CT colonography, which yielded 2606 nondiminutive (≥6 mm) polyps. Of 1731 polyps that underwent subsequent nonblinded OC (ie, endoscopists provided advanced knowledge of specific polyp size, location, and morphologic appearance at CT colonography), 181 (10%) were not confirmed with initial endoscopy (ie, discordant), of which 37 were excluded (awaiting or lost to follow-up). After discordant polyp review, 66 of the 144 lesions were categorized as likely CT colonography false-positive findings (no further action) and 78 were categorized as potential OC false-negative (FN) findings. RESULTS: Thirty-one of 144 (21.5%) of all discordant lesions were confirmed as FN findings at OC, including 40% (31 of 78) of those with OC and/or CT colonography follow-up. OC FN lesions were an average of 8.5 mm ± 3.3 in diameter and were identified with higher confidence at prospective CT colonography (on a 3-point confidence scale: mean, 2.8 vs 2.3; P = .001). OC FN findings were more likely than concordant polyps to be located in the right colon (respectively, 71% [22 of 31] vs 47% [723 of 1535]; P = .010). Most (81% [21 of 26]) OC FN lesions that were ultimately resected were neoplastic (adenomas or serrated lesions), of which 43% (nine of 21) were characterized as advanced lesions, and 89% (eight of nine) of advanced lesions occurred in the right colon. CONCLUSION: In clinical practice, polyps prospectively identified with CT colonography but not confirmed with subsequent nonblinded (ie, despite a priori knowledge of the CT colonography findings) OC require additional review because a substantial proportion may be FN findings. Most FN findings found with OC demonstrated clinically significant histopathologic results, and a majority of advanced lesions occurred in the right colon.

Serrated Polyps at CT Colonography: Prevalence and Characteristics of the Serrated Polyp Spectrum.

Purpose To report the prevalence and characteristics of serrated polyps identified in a large, average-risk population undergoing screening computed tomographic (CT) colonography. Materials and Methods This HIPAA-compliant retrospective study was approved by the institutional review board of the University of Wisconsin School of Medicine and Public Health. The need for informed consent was waived. Nine thousand six hundred examinations from 8289 patients were enrolled in a single-institution CT colonography-based screening program (from 2004 to 2011) and were evaluated for the presence of nondiminutive serrated lesions and advanced adenomas. The prevalence and characteristics of these lesions were tabulated. Generalized estimating equation regressions of polyp characteristics that may contribute to visualization of serrated lesions were investigated, including polyp size, location, and morphologic appearance; histologic findings; and presence or absence of contrast material tagging. Results Nondiminutive serrated lesions (≥6 mm) were seen at CT colonography-based screening with a prevalence of 3.1% (254 of 8289 patients). Sessile serrated adenomas (SSAs) and traditional serrated adenomas (TSAs) constituted 36.8% (137 of 372) and 4.3% (16 of 372) of serrated lesions, respectively; hyperplastic polyps (HPs) accounted for 58.9% (219 of 372 lesions). SSA and TSA tended to be large (mean size, 10.6 mm and 14.1 mm, respectively), with size categories and polyp subgroups significantly associated (P < .0001). SSA tended to be proximal in location (91.2%, 125 of 137 lesions) and flat in morphologic appearance (39.4%, 54 of 137 lesions) compared with TSA and HP. The presence of high-grade dysplasia in serrated lesions was uncommon when compared with advanced adenomas (one of 372 lesions vs 22 of 395 lesions, respectively; P < .0001). Multivariate analysis showed that contrast material tagging markedly improved serrated polyp detection with an odds ratio of 40.4 (95% confidence interval: 10.1, 161.4). Conclusion Serrated lesions are seen at CT colonography-based screening with a nondiminutive prevalence of 3.1%. These lesions tend to be large, flat, and proximal in location. Adherent contrast material coating on these polyps aids in their detection, despite an often flat morphologic appearance. (©) RSNA, 2016 Online supplemental material is available for this article.

Overactivation of the nuclear factor (erythroid-derived 2)-like 2-antioxidant response element pathway in hepatocytes decreases hepatic ischemia/reperfusion injury in mice.

Hepatic ischemia/reperfusion injury (IRI) is a critical component of hepatic surgery. Oxidative stress has long been implicated as a key player in IRI. In this study, we examine the cell-specific role of the nuclear factor (erythroid-derived 2)-like 2 (Nrf2)-antioxidant response element pathway in warm hepatic IRI. Nrf2 knockout (KO) and wild-type (WT) animals and novel transgenic mice expressing a constitutively active nuclear factor (erythroid-derived 2)-like 2 (caNrf2) mutant in hepatocytes (AlbCre+/caNrf2+) and their littermate controls underwent partial hepatic ischemia or sham surgery. The animals were killed 6 hours after reperfusion, and their serum and tissue were collected for analysis. As compared to WT animals after ischemia/reperfusion (IR), Nrf2 KO mice had increased hepatocellular injury with increased serum alanine aminotransferase and aspartate aminotransferase, Suzuki score, apoptosis, an increased inflammatory infiltrate, and enhanced inflammatory cytokine expression. On the other hand, AlbCre+/caNrf2+ that underwent IR had significantly reduced serum transaminases, less necrosis on histology, and a less pronounced inflammatory infiltrate and inflammatory cytokine expression as compared to the littermate controls. However, there were no differences in apoptosis. Taken together, Nrf2 plays a critical role in our murine model of warm hepatic IRI, with Nrf2 deficiency exacerbating hepatic IRI and hepatocyte-specific Nrf2 overactivation providing protection against warm hepatic IRI.