Widespread somatic L1 retrotransposition in normal colorectal epithelium.

Throughout an individual's lifetime, genomic alterations accumulate in somatic cells1-11. However, the mutational landscape induced by retrotransposition of long interspersed nuclear element-1 (L1), a widespread mobile element in the human genome12-14, is poorly understood in normal cells. Here we explored the whole-genome sequences of 899 single-cell clones established from three different cell types collected from 28 individuals. We identified 1,708 somatic L1 retrotransposition events that were enriched in colorectal epithelium and showed a positive relationship with age. Fingerprinting of source elements showed 34 retrotransposition-competent L1s. Multidimensional analysis demonstrated that (1) somatic L1 retrotranspositions occur from early embryogenesis at a substantial rate, (2) epigenetic on/off of a source element is preferentially determined in the early organogenesis stage, (3) retrotransposition-competent L1s with a lower population allele frequency have higher retrotransposition activity and (4) only a small fraction of L1 transcripts in the cytoplasm are finally retrotransposed in somatic cells. Analysis of matched cancers further suggested that somatic L1 retrotransposition rate is substantially increased during colorectal tumourigenesis. In summary, this study illustrates L1 retrotransposition-induced somatic mosaicism in normal cells and provides insights into the genomic and epigenomic regulation of transposable elements over the human lifetime.

The mTORC1 pathway stimulates glutamine metabolism and cell proliferation by repressing SIRT4.

Proliferating mammalian cells use glutamine as a source of nitrogen and as a key anaplerotic source to provide metabolites to the tricarboxylic acid cycle (TCA) for biosynthesis. Recently, mammalian target of rapamycin complex 1 (mTORC1) activation has been correlated with increased nutrient uptake and metabolism, but no molecular connection to glutaminolysis has been reported. Here, we show that mTORC1 promotes glutamine anaplerosis by activating glutamate dehydrogenase (GDH). This regulation requires transcriptional repression of SIRT4, the mitochondrial-localized sirtuin that inhibits GDH. Mechanistically, mTORC1 represses SIRT4 by promoting the proteasome-mediated destabilization of cAMP-responsive element binding 2 (CREB2). Thus, a relationship between mTORC1, SIRT4, and cancer is suggested by our findings. Indeed, SIRT4 expression is reduced in human cancer, and its overexpression reduces cell proliferation, transformation, and tumor development. Finally, our data indicate that targeting nutrient metabolism in energy-addicted cancers with high mTORC1 signaling may be an effective therapeutic approach.

Leucyl-tRNA synthetase is an intracellular leucine sensor for the mTORC1-signaling pathway.

Amino acids are required for activation of the mammalian target of rapamycin (mTOR) kinase, which regulates protein translation, cell size, and autophagy. However, the amino acid sensor that directly couples intracellular amino acid-mediated signaling to mTORC1 is unknown. Here we show that leucyl-tRNA synthetase (LRS) plays a critical role in amino acid-induced mTORC1 activation by sensing intracellular leucine concentration and initiating molecular events leading to mTORC1 activation. Mutation of LRS amino acid residues important for leucine binding renders the mTORC1 pathway insensitive to intracellular levels of amino acids. We show that LRS directly binds to Rag GTPase, the mediator of amino acid signaling to mTORC1, in an amino acid-dependent manner and functions as a GTPase-activating protein (GAP) for Rag GTPase to activate mTORC1. This work demonstrates that LRS is a key mediator for amino acid signaling to mTORC1.

Dimensionality Engineering of Magnetic Anisotropy from the Anomalous Hall Effect in Synthetic SrRuO3 Crystals.

Magnetic anisotropy in atomically thin correlated heterostructures is essential for exploring quantum magnetic phases for next-generation spintronics. Whereas previous studies have mostly focused on van der Waals systems, here we investigate the impact of dimensionality of epitaxially grown correlated oxides down to the monolayer limit on structural, magnetic, and orbital anisotropies. By designing oxide superlattices with a correlated ferromagnetic SrRuO3 and nonmagnetic SrTiO3 layers, we observed modulated ferromagnetic behavior with the change of the SrRuO3 thickness. Especially, for three-unit-cell-thick layers, we observe a significant 1500% improvement of the coercive field in the anomalous Hall effect, which cannot be solely attributed to the dimensional crossover in ferromagnetism. The atomic-scale heterostructures further reveal the systematic modulation of anisotropy for the lattice structure and orbital hybridization, explaining the enhanced magnetic anisotropy. Our findings provide valuable insights into engineering the anisotropic hybridization of synthetic magnetic crystals, offering a tunable spin order for various applications.

Polygenic risk score model for renal cell carcinoma in the Korean population and relationship with lifestyle-associated factors.

BACKGROUND: The polygenic risk score (PRS) is used to predict the risk of developing common complex diseases or cancers using genetic markers. Although PRS is used in clinical practice to predict breast cancer risk, it is more accurate for Europeans than for non-Europeans because of the sample size of training genome-wide association studies (GWAS). To address this disparity, we constructed a PRS model for predicting the risk of renal cell carcinoma (RCC) in the Korean population. RESULTS: Using GWAS analysis, we identified 43 Korean-specific variants and calculated the PRS. Subsequent to plotting receiver operating characteristic (ROC) curves, we selected the 31 best-performing variants to construct an optimal PRS model. The resultant PRS model with 31 variants demonstrated a prediction rate of 77.4%. The pathway analysis indicated that the identified non-coding variants are involved in regulating the expression of genes related to cancer initiation and progression. Notably, favorable lifestyle habits, such as avoiding tobacco and alcohol, mitigated the risk of RCC across PRS strata expressing genetic risk. CONCLUSION: A Korean-specific PRS model was established to predict the risk of RCC in the underrepresented Korean population. Our findings suggest that lifestyle-associated factors influencing RCC risk are associated with acquired risk factors indirectly through epigenetic modification, even among individuals in the higher PRS category.

Risk Factor Analysis of Lymph Node Metastasis for Rectal Neuroendocrine Tumors: Who Needs a Radical Resection in Rectal Neuroendocrine Tumors Sized 1-2 cm?

BACKGROUND: Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial. OBJECTIVE: This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1‒2 cm in size. METHODS: Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods. RESULTS: LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013). CONCLUSIONS: Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.

Investigation of the Effect of the Passivation on the Charge Transfer from MAPbI3 to Electron Transport Layer Using a Heterodyne Transient Grating Spectroscopic Technique.

We fabricated MAPbI3 perovskite thin films with ZnO on a glass substrate, in which a passivation layer (Phenethylammonium iodide (PEAI); p-methoxyphenethylammonium iodide (CH3O-PEAI); 2-methoxyethylammonium iodide (MEAI)) was inserted between two layers. In order to understand the effect of the insertion of each passivation material on the transfer efficiency of the photo-generated electrons from MAPbI3 to ZnO, we observed the near-field heterodyne transient grating (NF-HD-TG) responses of each film and investigated the component arising from the recombination of the trapped electrons at the ZnO surface. Based on the accelerated recombination between photo-generated holes remaining in the MAPbI3 layer and surface-trapped electrons in ZnO and the increase in the number of the trapped electrons in ZnO when either CH3O-PEAI or PEAI was applied, we successfully revealed that the charge transfer efficiency was enhanced by the insertion of the passivation materials including a benzene ring stabilizing the defect states. Particularly, it was demonstrated that CH3O-PEAI showed the highest increase in the charge transfer efficiency, which could be attributed to the high electron density in the benzene ring, resulting from the existence of the electron donating group, CH3O, and its role in the effective transition from 3D to 2D perovskite phases.

Are sporadic colorectal cancers in young patients distinct from those in elderly patients?

AIM: The aim of this study was to compare the clinicopathological and oncological characteristics of sporadic colorectal cancer (CRC) between young and elderly patients without any genetic mutations that cause hereditary CRC. METHOD: In this cross-sectional, retrospective study conducted at three tertiary referral hospitals, we enrolled 1599 patients with CRC who underwent surgery between January 2010 and December 2017, including 157 young patients (age ≤ 40 years; yCRC) and 1442 elderly patients (age ≥ 70 years; eCRC). The clinicopathological and oncological outcomes were compared between the two groups. RESULTS: The median age at diagnosis was 37 years in the yCRC group (range 33.0-39.2 years) and 76 years in the eCRC group (range 72.0-79.0 years). The yCRC group did not present with advanced stages at diagnosis compared with the eCRC group, and the distribution of tumour stages was similar between the two groups. Microsatellite instability (MSI) testing revealed no difference in the frequency of tumours with high MSI (7.8% in yCRC, 5.8% in eCRC), and the frequency of mutations in the KRAS, NRAS and BRAF genes was also similar. The 3-year overall survival was better in the yCRC group than in the eCRC group (97.4% vs. 83.5%, p < 0.001); however, no such difference was observed in cancer-specific survival. CONCLUSION: Genetically proven sporadic CRCs did not differ significantly between young and elderly patients in terms of tumour stage, tumour location and various molecular features. CLINICAL TRIAL REGISTRATION NUMBER: The study was retrospectively registered with Clinical Trials.gov (no. NCT05601609).

Herbicide Bioassay Using a Multi-Well Plate and Plant Spectral Image Analysis.

A spectral image analysis has the potential to replace traditional approaches for assessing plant responses to different types of stresses, including herbicides, through non-destructive and high-throughput screening (HTS). Therefore, this study was conducted to develop a rapid bioassay method using a multi-well plate and spectral image analysis for the diagnosis of herbicide activity and modes of action. Crabgrass (Digitaria ciliaris), as a model weed, was cultivated in multi-well plates and subsequently treated with six herbicides (paraquat, tiafenacil, penoxsulam, isoxaflutole, glufosinate, and glyphosate) with different modes of action when the crabgrass reached the 1-leaf stage, using only a quarter of the recommended dose. To detect the plant's response to herbicides, plant spectral images were acquired after herbicide treatment using RGB, infrared (IR) thermal, and chlorophyll fluorescence (CF) sensors and analyzed for diagnosing herbicide efficacy and modes of action. A principal component analysis (PCA), using all spectral data, successfully distinguished herbicides and clustered depending on their modes of action. The performed experiments showed that the multi-well plate assay combined with a spectral image analysis can be successfully applied for herbicide bioassays. In addition, the use of spectral image sensors, especially CF images, would facilitate HTS by enabling the rapid observation of herbicide responses at as early as 3 h after herbicide treatment.

Mutational evolution after chemotherapy-progression in metastatic colorectal cancer revealed by circulating tumor DNA analysis.

Emerging new mutations after treatment can provide clues to acquired resistant mechanisms. Circulating tumor DNA (ctDNA) sequencing has enabled noninvasive repeated tumor mutational profiling. We aimed to investigate newly emerging mutations in ctDNA after disease progression in metastatic colorectal cancer (mCRC). Blood samples were prospectively collected from mCRC patients receiving palliative chemotherapy before treatment and at radiological evaluations. ctDNA from pretreatment and progressive disease (PD) samples were sequenced with a next-generation sequencing panel targeting 106 genes. A total of 712 samples from 326 patients were analyzed, and 381 pretreatment and PD pairs (163 first-line, 85 second-line and 133 later-line [≥third-line]) were compared. New mutations in PD samples (mean 2.75 mutations/sample) were observed in 49.6% (189/381) of treatments. ctDNA samples from later-line had more baseline mutations (P = .002) and were more likely to have new PD mutations (adjusted odds ratio [OR] 2.27, 95% confidence interval [CI]: 1.40-3.69) compared to first-line. RAS/BRAF wild-type tumors were more likely to develop PD mutations (adjusted OR 1.87, 95% CI: 1.22-2.87), independent of cetuximab treatment. The majority of new PD mutations (68.5%) were minor clones, suggesting an increasing clonal heterogeneity after treatment. Pathways involved by PD mutations differed by the treatment received: MAPK cascade (Gene Ontology [GO]: 0000165) in cetuximab and regulation of kinase activity (GO: 0043549) in regorafenib. The number of mutations revealed by ctDNA sequencing increased during disease progression in mCRC. Clonal heterogeneity increased after chemotherapy progression, and pathways involved were affected by chemotherapy regimens.

Personalised circulating tumour DNA assay with large-scale mutation coverage for sensitive minimal residual disease detection in colorectal cancer.

BACKGROUND: Postoperative minimal residual disease (MRD) detection using circulating-tumour DNA (ctDNA) requires a highly sensitive analysis platform. We have developed a tumour-informed, hybrid-capture ctDNA sequencing MRD assay. METHODS: Personalised target-capture panels for ctDNA detection were designed using individual variants identified in tumour whole-exome sequencing of each patient. MRD status was determined using ultra-high-depth sequencing data of plasma cell-free DNA. The MRD positivity and its association with clinical outcome were analysed in Stage II or III colorectal cancer (CRC). RESULTS: In 98 CRC patients, personalised panels for ctDNA sequencing were built from tumour data, including a median of 185 variants per patient. In silico simulation showed that increasing the number of target variants increases MRD detection sensitivity in low fractions (<0.01%). At postoperative 3-week, 21.4% of patients were positive for MRD by ctDNA. Postoperative positive MRD was strongly associated with poor disease-free survival (DFS) (adjusted hazard ratio 8.40, 95% confidence interval 3.49-20.2). Patients with a negative conversion of MRD after adjuvant therapy showed significantly better DFS (P < 0.001). CONCLUSION: Tumour-informed, hybrid-capture-based ctDNA assay monitoring a large number of patient-specific mutations is a sensitive strategy for MRD detection to predict recurrence in CRC.

Fatty acid oxidation supports melanoma cell migration through autophagy regulation.

Metastasis is one of the most malignant characteristics of cancer cells, in which metabolic reprogramming is crucial for promoting and sustaining multi-steps of metastasis, including invasion, migration and infiltration. Recently, it has been shown that melanoma cells undergo a metabolic switching toward the upregulation of fatty acid oxidation (FAO) during metastasis. However, the underlying mechanisms by which FAO contributes to metastasis of melanoma cells remain obscure. Here, we report that FAO contributes to melanoma cell migration and invasion by regulating the formation of autophagosomes. Pharmacological or genetic inhibition of FAO impairs migration of melanoma cells, which seems not to be linked to energy production or redox homeostasis. Importantly, we reveal that acetyl-CoA production by FAO contributes to melanoma cell migration through autophagy regulation. Mechanistically, FAO inhibition results in increased autophagosome formation, which suppresses migration and invasion properties of melanoma cells. Our results underscore the crucial role of FAO in melanoma cell migration and support the potential therapeutic relevance of modulating cellular acetyl-CoA levels to inhibit cancer metastasis.

Exotic Magnetic Anisotropy Near Digitized Dimensional Mott Boundary.

The magnetic anisotropy of low-dimensional Mott systems exhibits unexpected magnetotransport behavior useful for spin-based quantum electronics. Yet, the anisotropy of natural materials is inherently determined by the crystal structure, highly limiting its engineering. The magnetic anisotropy modulation near a digitized dimensional Mott boundary in artificial superlattices composed of a correlated magnetic monolayer SrRuO3 and nonmagnetic SrTiO3 , is demonstrated. The magnetic anisotropy is initially engineered by modulating the interlayer coupling strength between the magnetic monolayers. Interestingly, when the interlayer coupling strength is maximized, a nearly degenerate state is realized, in which the anisotropic magnetotransport is strongly influenced by both the thermal and magnetic energy scales. The results offer a new digitized control for magnetic anisotropy in low-dimensional Mott systems, inspiring promising integration of Mottronics and spintronics.

Dysbiotic microbiome variation in colorectal cancer patients is linked to lifestyles and metabolic diseases.

BACKGROUND: Differences in the composition and diversity of the gut microbial communities among individuals are influenced by environmental factors. However, there is limited research on factors affecting microbiome variation in colorectal cancer patients, who display lower inter-individual variations than that of healthy individuals. In this study, we examined the association between modifiable factors and the microbiome variation in colorectal cancer patients. METHODS: A total of 331 colorectal cancer patients who underwent resection surgery at the Department of Surgery, Seoul National University Hospital between October 2017 and August 2019 were included. Fecal samples from colorectal cancer patients were collected prior to the surgery. Variations in the gut microbiome among patients with different lifestyles and metabolic diseases were examined through the network analysis of inter-connected microbial abundance, the assessment of the Anna Karenina principle effect for microbial stochasticity, and the identification of the enriched bacteria using linear discrimination analysis effect size. Associations of dietary diversity with microbiome variation were investigated using the Procrustes analysis. RESULTS: We found stronger network connectivity of microbial communities in non-smokers, non-drinkers, obese individuals, hypertensive subjects, and individuals without diabetes than in their counterparts. The Anna Karenina principle effect was found for history of smoking, alcohol consumption, and diabetes (with significantly greater intra-sample similarity index), whereas obesity and hypertension showed the anti-Anna Karenina principle effect (with significantly lower intra-sample similarity index). We found certain bacterial taxa to be significantly enriched in patients of different categories of lifestyles and metabolic diseases using linear discrimination analysis. Diversity of food and nutrient intake did not shape the microbial diversity between individuals (pProcrustes>0.05). CONCLUSIONS: Our findings suggested an immune dysregulation and a reduced ability of the host and its microbiome in regulating the community composition. History of smoking, alcohol consumption, and diabetes were shown to affect partial individuals in shifting new microbial communities, whereas obesity and history of hypertension appeared to affect majority of individuals and shifted to drastic reductions in microbial compositions. Understanding the contribution of modifiable factors to microbial stochasticity may provide insights into how the microbiome regulates effects of these factors on the health outcomes of colorectal cancer patients.

The association between prescription drugs and colorectal cancer prognosis: a nationwide cohort study using a medication-wide association study.

BACKGROUND: With the availability of health insurance claim data, pharmacovigilance for various drugs has been suggested; however, it is necessary to establish an appropriate analysis method. To detect unintended drug effects and to generate new hypotheses, we conducted a hypothesis-free study to systematically examine the relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients. METHODS: We used the Korean National Health Insurance Service-National Sample Cohort database. A total of 2,618 colorectal cancer patients diagnosed between 2004 and 2015 were divided into drug discovery and drug validation sets (1:1) through random sampling. Drugs were classified using the Anatomical Therapeutic Chemical (ATC) classification system: 76 drugs classified as ATC level 2 and 332 drugs classified as ATC level 4 were included in the analysis. We used a Cox proportional hazard model adjusted for sex, age, colorectal cancer treatment, and comorbidities. The relationship between all prescription nonanticancer drugs and the mortality of colorectal cancer patients was analyzed, controlling for multiple comparisons with the false discovery rate. RESULTS: We found that one ATC level-2 drug (drugs that act on the nervous system, including parasympathomimetics, addictive disorder drugs, and antivertigo drugs) showed a protective effect related to colorectal cancer prognosis. At the ATC level 4 classification, 4 drugs were significant: two had a protective effect (anticholinesterases and opioid anesthetics), and the other two had a detrimental effect (magnesium compounds and Pregnen [4] derivatives). CONCLUSIONS: In this hypothesis-free study, we identified four drugs linked to colorectal cancer prognosis. The MWAS method can be useful in real-world data analysis.

Total neoadjuvant therapy with short-course radiotherapy Versus long-course neoadjuvant chemoradiotherapy in Locally Advanced Rectal cancer, Korean trial (TV-LARK trial): study protocol of a multicentre randomized controlled trial.

BACKGROUND: For locally advanced rectal cancer (LARC), total neoadjuvant therapy (TNT) may enhance tumour response, reduce recurrence, and improve patient compliance compared to upfront surgery. Recent studies have shown that chemoradiotherapy (CRT) followed by consolidation chemotherapy leads to higher rate of pathologic complete response (pCR) than induction chemotherapy followed by CRT. However, an optimal TNT regimen that maximise the pCR rate and minimise toxicity has not been established. Therefore, the aim of this trial was to investigate whether preoperative short-course radiotherapy followed by chemotherapy with four cycles of CAPOX can double the pCR rate compared to a standard schedule of long-course preoperative CRT in patients with LARC. METHODS: This is a multi-centre, prospective, open label, randomised controlled trial. Patients with clinical primary tumour stage 3 and higher or regional node-involved rectal cancer located within 10 cm from the anal verge were randomly assigned equally to short-course radiotherapy (25 Gy in 5 fractions over 1 week) followed by four cycles of CAPOX (intravenous oxaliplatin [130 mg/m2, once a day] on day 1 and capecitabine [1,000 mg/m2, twice a day] from days 1 to 14) (TNT) or CRT (50.4 Gy in 28 fractions over 5 weeks, concurrently with concomitant oral capecitabine 825 mg/m2 twice a day). After preoperative treatment, total mesorectal excision was performed 2-4 weeks in the TNT group and 6-10 weeks in the CRT group, followed by optional additional adjuvant chemotherapy. The primary endpoint is the pCR rate, and secondary endpoints include disease-related treatment failure, quality of life, and cost-effectiveness. Assuming a pCR rate of 28% and 15% in the TNT and CRT groups, respectively, and one-side alpha error rate of 0.025 and power of 80%, 348 patients will be enrolled considering 10% dropout rate. DISCUSSION: The TV-LARK trial will evaluate the superiority of employed TNT regimen against the standard CRT regimen for patients with LARC. We aimed to identify a TNT regimen that will improve the pCR rate and decrease systemic recurrence in these patients. TRIAL REGISTRATION: Cris.nih.go.kr ID: KCT0007169 (April 08, 2022). The posted information will be updated as needed to reflect the protocol amendments and study progress.

Tubular damage marker as a predictive factor for pathologically upstaged renal cell carcinoma.

PURPOSE: To investigate if increased tubular damage biomarker can predict pathologically upstaged renal cell carcinoma (RCC), which may possess sub-radiologic invasive behavior, leading to surrounding tubular damage. MATERIALS AND METHODS: We examined 1563 patients with surgically resected RCC between March 2016 and June 2021 from the prospective database SUPER-RCC-Nx. Exclusion criteria were cancer not originating from the kidneys, benign renal tumor, and end-stage renal disease. RESULTS: Of 1297 patients, 131 had a clinically high T stage (T3-4), whereas 1166 had a low one. Patients with a clinically low T stage were subgrouped into identical-stage (n = 1041) and upstaged (n = 125) groups, who were confirmed as a pathologically high T stage. The upstaged group had older age (p = 0.003), larger tumor size (5.72 ± 3.24 vs. 3.12 ± 2.08, p < 0.001), higher Fuhrman grade (grades 3-4) (57.3% vs. 47.1%, p = 0.032), and higher urine N-acetyl-beta-D-glucosaminidase/creatinine (NAG/Cr) (5.13 ± 4.78 vs. 4.05 ± 2.84, p = 0.026). Tumor size (> 4 cm; odds ratio = 10.2, p < 0.001) and urine NAG/Cr (odds ratio = 1.16, p = 0.003) were independently associated with pathological upstaging in patients with normal renal function, while age and tumor size were significant risk factors in those with decreased renal function. The receiver operating characteristic curve analysis showed that the model using tumor size and urine NAG/Cr strongly predicted pathological upstaging (area under the curve, 0.84). CONCLUSION: Urine NAG/Cr may be a useful biomarker predicting pathologically upstaged RCC. Clinicians should be prudent in making management decisions when a large RCC is accompanied by an increased urine NAG/Cr.

Prognostic Impact of Extramural Lymphatic, Vascular, and Perineural Invasion in Stage II Colon Cancer: A Comparison With Intramural Invasion.

BACKGROUND: Lymphatic invasion, vascular invasion, and perineural invasion are prognostic factors for colon cancer. However, the prognostic significance of those factors according to the location of permeation (intramural and extramural invasion) in stage II colon cancer is still unclear. OBJECTIVE: This study aimed to clarify whether the location of lymphatic invasion, vascular invasion, and perineural invasion could affect the survival of patients with stage II colon cancer. DESIGN: This was a retrospective cohort study. SETTINGS: This study took place at a university teaching hospital. PATIENTS: A total of 1130 patients with stage II colon cancers who underwent radical surgery at the Seoul National University Hospital between July 2003 and December 2015 were included. MAIN OUTCOME MEASURES: Patients were classified according to the location of lymphatic invasion, vascular invasion, and perineural invasion. Survival outcomes were compared among those without invasion and those with intramural and extramural invasion. Primary end point is overall survival and secondary end point is disease-free survival. RESULTS: Disease-free survival and overall survival of patients with extramural invasion were worse than those of patients without invasion and those with intramural invasion. Multivariate analysis for survival outcomes confirmed that extramural invasion was a significant independent prognostic factor. However, both disease-free survival and overall survival were not significantly different between patients without invasion and those with intramural invasion. LIMITATIONS: This study was limited by its retrospective design. CONCLUSIONS: Extramural invasion was associated with worse prognosis in stage II colon cancer, but intramural invasion was not. Therefore, pathologic reports about the location of lymphatic invasion, vascular invasion, and perineural invasion might be helpful for predicting prognosis and for determining the need of adjuvant chemotherapy in stage II colon cancers. See Video Abstract at http://links.lww.com/DCR/B939 . IMPACTO PRONSTICO DE LA INVASION EXTRAMURAL LINFTICA, VASCULAR Y PERINEURAL EN EL CNCER DE COLON ESTADO II ESTUDIO COMPARATIVO CON RELACIN A LA INVASIN INTRAMURAL: ANTECEDENTES:La invasión linfática, vascular y perineural son factores pronósticos para el cáncer de colon. Sin embargo, la importancia pronóstica de estos factores de acuerdo con la ubicación de la permeabilidad (invasión intramural y extramural) del cáncer de colon en estadío II aún no está aclarada.OBJETIVO:El presente estudio tiene por objetivo, el de aclarar si la localización de la invasión linfática, vascular y perineural podría afectar la sobrevida en los pacientes con cáncer de colon en estadío II.DISEÑO:Estudio de cohortes de caracter retrospectivo.AJUSTES:Nuestro estudio se llevó a cabo en un hospital docente universitario.PACIENTES:Se incluyeron un total de 1130 pacientes diagnosticados con cáncer de colon en estadío II, los cuales fueron sometidos a cirugía radical en el Hospital Universitario Nacional de Seúl, entre julio de 2003 y diciembre de 2015.PRINCIPALES MEDIDAS DE RESULTADO:Los pacientes fueron clasificados según la localización de la invasión linfática, vascular y perineural. Los resultados de la sobrevida fueron comparados con aquellos sin invasión y los otros con invasión intramural y extramural. El objetivo final primario fué la sobrevida global, el objetivo final secundario fué la sobrevida libre de enfermedad.RESULTADOS:La sobrevida libre de enfermedad y la sobrevida global de los pacientes con invasión extramural fueron mucho peores en relacion a las de los pacientes sin invasión y aquellos con invasión intramural. El análisis multivariado de los resultados de la sobrevida confirmaron que la invasión extramural es un factor pronóstico independiente muy significativo. Sin embargo, tanto la sobrevida libre de enfermedad, como la sobrevida global no fueron significativamente diferentes entre los pacientes sin invasión y aquellos con invasión intramural.LIMITACIONES:Estudio limitado por su diseño con caracter retrospectivo.CONCLUSIONES:La invasión extramural fué asociada con un peor pronóstico en el cáncer de colon en estadío II, pero la invasión intramural no lo fué. Por tanto, los informes anatomopatológicos sobre la ubicación de la invasión linfática, vascular y perineural, podrían ser útiles para predecir el pronóstico y determinar el menester de la quimioterapia adyuvante en los cánceres de colon en estadío II. Consulte Video Resumen en http://links.lww.com/DCR/B939 . (Traducción-Dr. Xavier Delgadillo ).

Standard versus longer interval of radical resection after neoadjuvant chemoradiotherapy in locally advanced rectal cancer: A 20-year single-center experience & propensity-score matching.

BACKGROUND AND OBJECTIVES: Despite the standard interval of 6-8 weeks between neoadjuvant chemoradiotherapy (nCRT) and surgery, it is debated whether an interval of >8 weeks increases the pathologic complete response (pCR) rate. We investigated the interval between nCRT and surgery, and its impact on oncological outcomes and postoperative complications in patients with locally advanced rectal cancer. METHODS: We retrospectively reviewed patients with rectal cancer who underwent total mesorectal excision after long-course nCRT between 2000 and 2020. They were divided into two groups-those who underwent surgery at 6-8 and >8 weeks after nCRT. Surgical outcomes (stoma rate and postoperative complications), pCR, tumor regression grade (TRG), recurrence-free survival (RFS), and overall survival (OS) were compared. RESULTS: We selected 770/1153 patients with rectal cancer, including 502 and 268 patients surgically treated at 6-8 and >8 weeks after nCRT, respectively. The pCR rates were similar between the two groups (14.7% vs. 15.3%, p = 0.836), while the TRG was significantly better in the >8 weeks group (p = 0.267). Additionally, the postoperative complications, recurrence, 5-year RFS, and OS rates were not significantly different between the two groups. CONCLUSIONS: Although tumor regression increased in the >8 weeks group, the oncological benefits of surgery >8 weeks after nCRT remain uncertain.