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Background Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. Methods We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. Results We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. Conclusion These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.

BackgroundIn patients with resectable colorectal liver metastases (CRLM), distinct histopathological growth patterns (HGPs) develop at the interface between the tumour and surrounding tissue. The desmoplastic (d) HGP is characterised by angiogenesis and a peripheral fibrotic rim, whereas non-angiogenic HGPs co-opt endogenous sinusoidal hepatic vasculature. Evidence from previous studies has suggested that patients with dHGP in their CRLM have improved prognosis as compared to patients with non-desmoplastic HGPs. However, these studies were relatively small and applied arbitrary cut-off values for the determination of the predominant HGP. We have now investigated the prognostic effect of dHGP in a large cohort of patients with CRLM resected either with or without neoadjuvant chemotherapy.MethodsAll consecutive patients undergoing a first partial hepatectomy for CRLM between 2000 and 2015 at a tertiary referral centre were considered for inclusion. HGPs were assessed in archival H&E stained slides according to recently published international consensus guidelines. The dHGP was defined as desmoplastic growth being present in 100% of the interface between the tumour and surrounding liver.ResultsIn total, HGPs in CRLMs from 732 patients were assessed. In the chemo-naive patient cohort (n = 367), the dHGP was present in 19% (n = 68) and the non-dHGP was present in 81% (n = 299) of patients. This dHGP subgroup was independently associated with good overall survival (OS) (HR: 0.39, p < 0.001) and progression-free survival (PFS) (HR: 0.54, p = 0.001). All patients with any CRLM with a non-dHGP had significantly reduced OS compared to those patients with 100% dHGP, regardless of the proportion of non-dHGP (all p values ≤ 0.001). In the neoadjuvantly treated patient cohort (n = 365), more patients were found to express dHGP (n = 109, 30%) (adjusted odds ratio: 2.71, p < 0.001). On univariable analysis, dHGP was associated with better OS (HR 0.66, p = 0.009) and PFS (HR 0.67, p = 0.002). However, after correction for confounding by means of multivariable analysis no significant association of dHGP with OS (HR 0.92, p = 0.623) or PFS (HR 0.76, p = 0.065) was seen.ConclusionsThe current study demonstrates that the angiogenic dHGP in CRLM resected from chemo-naive patients acts as a strong, positive prognostic marker, unmatched by any other prognosticator. This observation warrants the evaluation of the clinical utility of HGPs in prospective clinical trials.

Cancer cells can use existing blood vessels to acquire a vasculature. This process is termed ‘vessel co-option’. Vessel co-option is an alternative to the growth of new blood vessels, or angiogenesis, and is adopted by a wide range of human tumour types growing within numerous tissues. A complementary aspect of this process is extravascular migratory tumour spread using the co-opted blood vessels as a trail. Vessel co-opting tumours can be discriminated from angiogenic tumours by specific morphological features. These features give rise to distinct histopathological growth patterns that reflect the interaction of cancer cells with the microenvironment of the organ in which they thrive. We will discuss the histopathological growth patterns of vessel co-option in the brain, the liver and the lungs. The review will also highlight evidence for the potential clinical value of the histopathological growth patterns of cancer. Vessel co-option can affect patient outcomes and resistance to cancer treatment. Insight into the biological drivers of this process of tumour vascularization will yield novel therapeutic strategies.

Background At present, Astragalus mongholicus products on the market represent two growth patterns: imitative wild A. mongholicus (WAM) and cultivated A. mongholicus (CAM) . The 6-year-old WAM (A6) and 2-year-old CAM (B2) products are often sold as commodities. This study aimed to explore the effects of the abovementioned growth patterns on the biosynthetic mechanisms of isoflavone accumulation in A. mongholicus products. Results In this paper, the content of calycosin-7- O -β-D-glucoside in 6-year-old WAM (A6) was significantly higher than that in 2-year-old CAM (B2) based on high-performance liquid chromatography. Tissue anatomy indicated that A6 has developed phloem fibers, thickened secondary walls, and a more well-developed vascular system than B2. Thirteen differentially accumulated metabolites were found in A6 and B2 by UHPLC-ESI-Q-TOF-MS/MS, of which isoflavones were highly and significantly enriched in A6. By combining transcriptomics and metabolomics analysis, we found that the metabolomics profile was the same as the transcriptomics profile in both A6 and B2. In total, 11 novel isoflavone-related genes were isolated using BLAST and functional annotation through RNA-Seq and Iso-Seq. The results of integrated analysis, Short Time-series Expression Miner analysis, and Pearson correlation analysis showed that the regulation of four key enzymes, cinnamate 4-hydroxylase, 6-deoxychalcone synthase, chalcone reductase, and chalcone isomerase, led to the high accumulation of isoflavones in A6. In addition, Am UFGT (c778119) and Am UCGT (c303354) were predicted to be 7- O -glycosyltransferases by phylogenetic analysis; these genes catalyze formononetin and calycosin, respectively. Conclusions The findings of this work will clarify the differences in the biosynthetic mechanism of isoflavone accumulation between A6 and B2, which will guide the cultivation of A. mongholicus .

Aim Spatial variations of environmental conditions translate into biogeographical patterns of tree growth. This fact is used to identify the origin of timber by means of dendroprovenancing. Yet, dendroprovenancing attempts are commonly only based on ring‐width measurements, and largely neglect additional tree–ring variables. We explore the potential of using wood anatomy as a dendroprovenancing tool, and investigate whether it increases the precision of identifying the origin of oak wood. Since different tree–ring variables hold different information on environmental conditions prevailing at specific times of the growing season—which vary between source regions—we hypothesize that their inclusion allows more precise dendroprovenancing. Location Europe, Spain. Taxon Quercus robur L., Quercus petraea (Matt.) Liebl., Quercus faginea Lam., Quercus pyrenaica Willd. Methods We sampled four oak species across Northern Spain, i.e. from the Basque country and Cantabria and—in the Basque country—from low to high elevation (topographic/latitudinal gradient). We measured multiple tree–ring variables to (a) extract complementary variables; (b) present statistical relations among them; (c) analyse region‐specific variation in their patterns based on time–series of individual trees; and (d) determine underlying climate–growth relationships. Leave‐one‐out analysis was used to test whether a combination of selected variables allowed dendroprovenancing of a randomly selected tree within the area. Results A combination of latewood width (LW) and earlywood vessel size was used to pinpoint the origin of oak wood with higher precision than ring width or LW only. Variation in LW pinpointed the wood to east and west areas, whereas variation in vessels assigned wood to locations along a latitudinal/topographic gradient. The climatic triggers behind these gradients are respectively an east–west gradient in June–July temperature and a north–south gradient in winter/spring temperatures. The leave‐one‐out analyses supported the robustness of these results. Main conclusions Integration of multiple wood–xylem anatomical variables analysed with multivariate techniques leads to higher precision in the dendroprovenancing of ring‐porous oak species.

Abstract Context The natural history of benign thyroid nodules is typically characterized by slow growth and minimal risk of malignant transformation. Available data have, to date, been unable to elucidate the diversity of benign nodule growth patterns over time nor predictive of which patients follow which pattern. Objective We aimed to better define the diverse patterns of benign nodule behavior and their predictors. Methods We prospectively studied 389 consecutive patients with solitary, solid, cytologically benign thyroid nodules ≥1 cm and follow-up ultrasound for at least 4 years. Demographic, sonographic, biochemical data were collected at initial evaluation, and subsequent growth patterns were identified over the follow-up. Predictors of growth at initial evaluation and 3 years of follow-up were defined. Results The mean (±SD) follow-up was 7.7 (±2.7) years. Three distinct growth patterns were identified: A) stagnant nodules with average growth rate < 0.2 mm/year; B) slow-growing nodules with a rate 0.2 to 1.0 mm/year; and C) fast-growing nodules increasing > 1.0 mm/year. Fast-growing nodules represented 17.2% of the cohort, and were more frequent in patients younger than 50 years (OR 2.2 [1.2-4.1], P = 0.016), and in larger nodules (2.0-2.9 cm, OR 3.5 [1.7-7.1], P = 0.001; >3.0 cm, OR 4.4 [1.8-10.4], P = 0.001 vs reference 1-1.9 cm). In a multiple regression model, nodule growth at 3 years at an average growth rate over 0.2 mm/year over 3 years since initial evaluation was an independent predictor of longer-term fast nodule growth, even after adjusting for age, biological sex, TSH level, and nodule size (P < 0.001). Conclusion The natural history of benign nodule growth is diverse, with over 80% of nodules demonstrating minimal to no growth long-term. Nearly 20% of cytologically benign nodules may exhibit a fast, continued growth pattern, which can be predicted by the 3-year growth rate pattern. These findings can help inform decision making for tailored benign nodule follow-up and monitoring.

Purpose To develop a computed tomography (CT)-based radiomics nomogram for pre-treatment prediction of histopathologic growth patterns (HGPs) in colorectal liver metastases (CRLM) and to validate its accuracy and clinical value. Materials and methods This retrospective study included a total of 197 CRLM from 92 patients. Lesions from CRLM were randomly divided into the training study ( n  = 137) and the validation study ( n  = 60) with the ratio of 3:1 for model construction and internal validation. The least absolute shrinkage and selection operator (LASSO) was used to screen features. Radiomics score (rad-score) was calculated to generate radiomics features. A predictive radiomics nomogram based on rad-score and clinical features was developed using random forest (RF). The performances of clinical model, radiomic model and radiomics nomogram were thoroughly evaluated by the DeLong test, decision curve analysis (DCA) and clinical impact curve (CIC) allowing for generation of an optimal predictive model. Results The radiological nomogram model consists of three independent predictors, including rad-score, T-stage, and enhancement rim on PVP. Training and validation results demonstrated the high-performance level of the model of area under curve (AUC) of 0.86 and 0.84, respectively. The radiomic nomogram model can achieve better diagnostic performance than the clinical model, yielding greater net clinical benefit compared to the clinical model alone. Conclusions A CT-based radiomics nomogram can be used to predict HGPs in CRLM. Preoperative non-invasive identification of HGPs could further facilitate clinical treatment and provide personalized treatment plans for patients with liver metastases from colorectal cancer.

Background The histopathological growth patterns (HGPs) are a prognostic and predictive biomarker in colorectal cancer liver metastasis (CRLM). This study evaluates the relationship between the HGP and primary colorectal cancer (CRC) histopathology. Methods A total of 183 treatment-naive patients with resected CRC and CRLM were included. Thirteen CRC histopathology markers were determined and compared between the desmoplastic and non-desmoplastic HGP; tumour sidedness, pT&pN stage, tumour grade, tumour deposits, perineural- (lympho-)vascular- and extramural venous invasion, peritumoural budding, stroma type, CRC growth pattern, Crohn’s-like lymphoid reaction, and tumour-infiltrating lymphocyte (TIL) density. Logistic regression analysis was performed using both CRC and CRLM characteristics. Results Unfavourable CRC histopathology was more frequent in non-desmoplastic CRLM for all markers evaluated, and significantly so for a lower TIL density, absent Crohn’s-like lymphoid reaction, and a “non-mature” stroma (all p  < 0.03). The cumulative prevalence of unfavourable CRC histopathology was significantly higher in patients with non-desmoplastic compared to desmoplastic CRLM, with a median (IQR) of 4 (3–6) vs 2 (1–3.5) unfavourable characteristics observed, respectively ( p  < 0.001). Multivariable regression with 9 CRC histopathology markers and 2 CRLM characteristics achieved good discriminatory performance (AUC = 0.83). Conclusions The results of this study associates primary CRC histopathology with the HGP of corresponding liver metastases.

The aim of this study was to evaluate hepatectomy cases that underwent preoperative chemotherapy to examine the relationship between the development of desmoplastic histopathological growth pattern (dHGP) and prognosis and recurrence and determine whether it is useful for evaluating preoperative chemotherapy. A total of 133 cases with hepatic metastasis for colorectal cancer that underwent surgical resection. Of the 102 cases that underwent preoperative chemotherapy, 34 (33%) were determined to be dHGP positive, which was statistically significantly higher than the 2 of 31 cases (6.5%) that had not undergone preoperative chemotherapy. Regarding the 5-year recurrence-free survival, the dHGP group had a value of 50.3%, whereas the non-dHGP group had a value of 7.1%. For the 5-year overall survival, the dHGP group had a better prognosis than the non-dHGP group (57.6% vs. 37.1%, respectively), with a statistically significant difference. Univariate analysis of recurrence-free survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and the presence or absence of dHGP were prognostic factors, whereas multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor. Univariate analysis of the overall survival showed that the number of tumours, the Response Evaluation Criteria in Solid Tumors, and presence or absence of dHGP were prognostic factors. Multivariate analysis showed that the presence or absence of dHGP was an independent prognostic factor. dHGP is useful as a new evaluation method for evaluating the efficacy of preoperative chemotherapy.

ContextUrbanization has profoundly changed urban landscape patterns and morphologies. Understanding the spatiotemporal evolution of these changes and their driving forces is vital to decision making for urban planning and sustainable urban development.ObjectivesThis study aims to quantify the spatiotemporal pattern of urban growth in Shanghai, China for testing urban growth hypotheses, to identify its driving factors, and to provide insights for sustainable urban planning.MethodsWe fitted a nonlinear curve to the urbanization pattern, employed landscape expansion indices to quantify the spatiotemporal evolution of urbanization, utilized partial least square regression to differentiate contribution of main socioeconomic driving factors.ResultsUrbanized land in Shanghai exhibited a logistic growth pattern from 1985 to 2015. The annual growth rate of urban area showed a wave-like pattern and peaked in 2000–2005. Urban growth modes of leapfrog, edge expansion, and infilling were identified, and these patterns alternates in dominance over time. The urbanization process in Shanghai followed the spiraling diffusion-coalescence hypothesis. The net increase of year-end residential population, urban infrastructure investment, and the total investment in fixed assets were the dominant driving factors to urban growth.ConclusionA logistic curve well quantified the temporal pattern of urbanization in Shanghai. Urbanization has slowed down, approaching the plateau of the curve, implying that urban growth driven by population increase and investment should switch to sustainable urban renewal and ecological constructions. Investment to urban green and blue infrastructures could help achieve “negative growth” targeted by the Shanghai Master Plan (2017–2035) for the overall developed land.