bluuebunny/crossref_metadata_2025 huggingface dataset:
Assessing the clinical utility of genetic risk scores for targeted cancer screening
Authors: Conran Carly A. , Shi Zhuqing , Resurreccion William Kyle , Na Rong , Helfand Brian T. , Genova Elena , Zheng Siqun Lilly , Brendler Charles B. , Xu Jianfeng
Published: January 2021

Background

Genome-wide association studies have identified thousands of disease-associated single nucleotide polymorphisms (SNPs). A subset of these SNPs may be additively combined to generate genetic risk scores (GRSs) that confer risk for a specific disease. Although the clinical validity of GRSs to predict risk of specific diseases has been well established, there is still a great need to determine their clinical utility by applying GRSs in primary care for cancer risk assessment and targeted intervention.

Methods

This clinical study involved 281 primary care patients without a personal history of breast, prostate or colorectal cancer who were 40–70 years old. DNA was obtained from a pre-existing biobank at NorthShore University HealthSystem. GRSs for colorectal cancer and breast or prostate cancer were calculated and shared with participants through their primary care provider. Additional data was gathered using questionnaires as well as electronic medical record information. A t-test or Chi-square test was applied for comparison of demographic and key clinical variables among different groups.

Results

The median age of the 281 participants was 58 years and the majority were female (66.6%). One hundred one (36.9%) participants received 2 low risk scores, 99 (35.2%) received 1 low risk and 1 average risk score, 37 (13.2%) received 1 low risk and 1 high risk score, 23 (8.2%) received 2 average risk scores, 21 (7.5%) received 1 average risk and 1 high risk score, and no one received 2 high risk scores. Before receiving GRSs, younger patients and women reported significantly more worry about risk of developing cancer. After receiving GRSs, those who received at least one high GRS reported significantly more worry about developing cancer. There were no significant differences found between gender, age, or GRS with regards to participants’ reported optimism about their future health neither before nor after receiving GRS results.

Conclusions

Genetic risk scores that quantify an individual’s risk of developing breast, prostate and colorectal cancers as compared with a race-defined population average risk have potential clinical utility as a tool for risk stratification and to guide cancer screening in a primary care setting.
Locked compression plating versus retrograde intramedullary nailing in the treatment of periprosthetic supracondylar knee fractures: a systematic review and meta-analysis
Authors: Magill Henry , Ponugoti Nikhil , Selim Amr , Platt James
Published: January 2021

Background

Periprosthetic fractures of the distal femur above a total knee arthroplasty (TKA) have traditionally been managed by locking compression plating (LCP). This technique is technically demanding and is associated with high rates of non-union and revision. More recently, retrograde intramedullary nailing (RIMN) has been proposed as an acceptable alternative. This meta-analysis aims to evaluate clinical outcomes in patients with periprosthetic supracondylar femoral fractures who were treated with LCP and RIMN.

Methods

An up-to-date literature search was carried out using the pre-defined search strategy. All studies that met the inclusion criteria were assessed for methodological quality with the Cochrane’s collaboration tool. Operative time, functional score, time-to-union, non-union rates and revision rates were all considered.

Conclusion

Ten studies with a total of 531 periprosthetic fractures were included. This meta-analysis has suggested that there is no significant difference in any of the outcome measures assessed. Further, more extensive literature is required on the subject to draw more robust conclusions.
In vivo performance of Al2O3-Ti bone implants in the rat femur
Authors: Bahraminasab Marjan , Arab Samaneh , Safari Manouchehr , Talebi Athar , Kavakebian Fatemeh , Doostmohammadi Nesa
Published: January 2021

Background

Alumina-titanium (Al2O3-Ti) biocomposites have been recently developed with improved mechanical properties for use in heavily loaded orthopedic sites. Their biological performance, however, has not been investigated yet.

Methods

The aim of the present study was to evaluate the in vivo biological interaction of Al2O3-Ti. Spark plasma sintering (SPS) was used to fabricate Al2O3-Ti composites with 25 vol.%, 50 vol.%, and 75 vol.% Ti content. Pure alumina and titanium were also fabricated by the same procedure for comparison. The fabricated composite disks were cut into small bars and implanted into medullary canals of rat femurs. The histological analysis and scanning electron microscopy (SEM) observation were carried out to determine the bone formation ability of these materials and to evaluate the bone-implant interfaces.

Results

The histological observation showed the formation of osteoblast, osteocytes with lacuna, bone with lamellar structures, and blood vessels indicating that the healing and remodeling of the bone, and vasculature reconstruction occurred after 4 and 8 weeks of implantation. However, superior bone formation and maturation were obtained after 8 weeks. SEM images also showed stronger interfaces at week 8. There were differences between the composites in percentages of bone area (TB%) and the number of osteocytes. The 50Ti composite showed higher TB% at week 4, while 25Ti and 75Ti represented higher TB% at week 8. All the composites showed a higher number of osteocytes compared to 100Ti, particularly 75Ti.

Conclusions

The fabricated composites have the potential to be used in load-bearing orthopedic applications.
Feature selection using distributions of orthogonal PLS regression vectors in spectral data
Authors: Lee Geonseok , Lee Kichun
Published: January 2021

Feature selection, which is important for successful analysis of chemometric data, aims to produce parsimonious and predictive models. Partial least squares (PLS) regression is one of the main methods in chemometrics for analyzing multivariate data with inputXand responseYby modeling the covariance structure in theXandYspaces. Recently, orthogonal projections to latent structures (OPLS) has been widely used in processing multivariate data because OPLS improves the interpretability of PLS models by removing systematic variation in theXspace not correlated toY. The purpose of this paper is to present a feature selection method of multivariate data through orthogonal PLS regression (OPLSR), which combines orthogonal signal correction with PLS. The presented method generates empirical distributions of features effects uponYin OPLSR vectors via permutation tests and examines the significance of the effects of the input features onY. We show the performance of the proposed method using a simulation study in which a three-layer network structure exists in compared with the false discovery rate method. To demonstrate this method, we apply it to both real-life NIR spectra data and mass spectrometry data.
High-school students and self-injurious thoughts and behaviours: clues of emotion dysregulation
Authors: Zanus Caterina , Battistutta Sara , Aliverti Renata , Monasta Lorenzo , Montico Marcella , Ronfani Luca , Carrozzi Marco
Published: January 2021

Background

Suicide attempts and self-harm in adolescence are a major public health concern: they are among the main causes of disability-adjusted life-years worldwide, with severe long-term health consequences in terms of mental illness and psychiatric hospitalisation and a significantly increased risk of suicide. Several studies recently focused on the hypothesis that adolescents may be particularly vulnerable to emotional dysregulation and on the relation between problems with emotion regulation and suicidal and self-harming behaviours.

Italian epidemiological data about prevalence of these behaviours at the community level are lacking.

Our study aimed to estimate the prevalence of self-injurious thoughts and behaviours (SITBs) in a representative sample of community adolescents, and to examine the association between SITBs and the emotional and behavioural profiles.

Methods

Anonymous self-report questionnaires were completed by 1507 students aged 11–18 years from 24 high schools in the North-eastern Italian region of Friuli Venezia Giulia. Information was collected on SITBs, on the socio-environmental context, and on the psychological profile (‘Achenbach’s YSR questionnaire 11–18, Multidimensional Test of Self-harm and Multi-Attitude Suicide Tendency Scale).

Results

Overall, 11.1% of adolescents reported self-harming behaviours without suicide ideation or attempts, 6.4% declared having thought to suicide without acting a suicide attempt or self-harm, 1.4% declared having attempted suicide and really thought to take away their life. Access to health services following a suicide thought, a self-harming behaviour or suicide attempt was infrequent, particularly for suicide ideation. At the YSR, all the SITBs groups reported high scores in almost all scales, with the most evident differences in the self-harming groups in which adolescents reported significantly higher scores in all scales, both internalising and externalising. An emotion dysregulation profile was found in almost all the groups.

Conclusions

This study provides us with an estimate of the prevalence of SITBs in the adolescent population and confirms the importance of further investigating the association between SITBs and emotion dysregulation. The naturalistic setting of community studies appears to be useful for studies in this field, and it allows to approach the onerous and often neglected issue of adolescent suicidality.
Sensitivity of soil nitrifying and denitrifying microorganisms to nitrogen deposition on the Qinghai–Tibetan plateau
Authors: Xu Minjie , Li Tingting , Liu Wei , Ding Junjun , Gao Lili , Han Xingguo , Zhang Ximei
Published: January 2021

Purpose

Nitrogen deposition at rate not more than 50 kg ha−1 year−1 is generally considered to stimulate soil nitrifying and denitrifying microorganisms via increases in soil nitrogen content. However, this phenomenon in alpine ecosystems remains largely untested.

Methods

We conducted an 8-year nitrogen deposition experiment on the Qinghai–Tibetan Plateau, with four nitrogen deposition rates of 10 (atmospheric deposition), 20, 30, and 50 kg ha−1 year−1.

Results

The abundances of two nitrifying genes and four denitrifying genes and the N2O emission rate initially increased and subsequently decreased as the nitrogen deposition rate increased. The observed decrease in these indices at the rate of 50 kg ha−1 year−1 was caused by the toxicity of excessive NH4+.

Conclusions

Our study demonstrates the vulnerability of alpine microorganisms under global changes.
Exosomes derived from stem cells from apical papilla promote craniofacial soft tissue regeneration by enhancing Cdc42-mediated vascularization
Authors: Liu Yao , Zhuang Xueying , Yu Si , Yang Ning , Zeng Jianhong , Liu Xuemei , Chen Xu
Published: January 2021

Background

Reconstruction of complex critical-size defects (CSD) in the craniofacial region is a major challenge, and soft tissue regeneration is crucial in determining the therapeutic outcomes of craniofacial CSD. Stem cells from apical papilla (SCAP) are neural crest-derived mesenchymal stem cells (MSCs) that are homologous to cells in craniofacial tissue and represent a promising source for craniofacial tissue regeneration. Exosomes, which contain compound bioactive compounds, are the key factors in stem cell paracrine action. However, the roles of exosomes derived from SCAP (SCAP-Exo) in tissue regeneration are not fully understood. Here, we explored the effects and underlying mechanisms of SCAP-Exo on CSD in maxillofacial soft tissue.

Methods

SCAP-Exo were isolated and identified by transmission electron microscopy and nanoparticle tracking analysis. The effects of SCAP-Exo on wound healing and vascularization were detected by measuring the wound area and performing histological and immunofluorescence analysis on the palatal gingival CSD of mice. Real-time live-cell imaging and functional assays were used to assess the effects of SCAP-Exo on the biological functions of endothelial cells (ECs). Furthermore, the molecular mechanisms of SCAP-Exo-mediated EC angiogenesis in vitro were tested by immunofluorescence staining, Western blot, and pull-down assays. Finally, in vivo experiments were carried out to verify whether SCAP-Exo could affect vascularization and wound healing through cell division cycle 42 (Cdc42).

Results

We found that SCAP-Exo promoted tissue regeneration of palatal gingival CSD by enhancing vascularization in the early phase in vivo and that SCAP-Exo improved the angiogenic capacity of ECs in vitro. Mechanistically, SCAP-Exo elevated cell migration by improving cytoskeletal reorganization of ECs via Cdc42 signalling. Furthermore, we revealed that SCAP-Exo transferred Cdc42 into the cytoplasm of ECs and that the Cdc42 protein could be reused directly by recipient ECs, which resulted in the activation of Cdc42-dependent filopodium formation and elevation in cell migration of ECs.

Conclusion

This study demonstrated that SCAP-Exo had a superior effect on angiogenesis and effectively promoted craniofacial soft tissue regeneration. These data provide a new option for SCAP-Exo to be used in a cell-free approach to optimize tissue regeneration in the clinic.
Activation of regulated cell death in the lung of piglets infected with virulent PRRSV-1 Lena strain occurs earlier and mediated by cleaved Caspase-8
Authors: Sánchez-Carvajal Jose María , Ruedas-Torres Inés , Carrasco Librado , Pallarés Francisco José , Mateu Enric , Rodríguez-Gómez Irene Magdalena , Gómez-Laguna Jaime
Published: January 2021

PRRSV-1 virulent strains cause high fever, marked respiratory disease and severe lesions in lung and lymphoid organs. Regulated cell death (RCD), such as apoptosis, necroptosis and pyroptosis, is triggered by the host to interrupt viral replication eliminating infected cells, however, although it seems to play a central role in the immunopathogenesis of PRRSV, there are significant gaps regarding their sequence and activation upon PRRSV-infection. The present study evaluated RCD events by means of caspases expression in the lung of PRRSV-1-infected pigs and their impact on pulmonary macrophage subpopulations and lung lesion. Conventional piglets were intranasally inoculated with the virulent subtype 3 Lena strain or the low virulent subtype 1 3249 strain and euthanised at 1, 3, 6, 8 and 13 dpi. Lena-infected piglets showed severe and early lung damage with a high frequency of PRRSV-N-protein+ cells, depletion of CD163+ cells and high viral load in the lung. The number of TUNEL+ cells was significantly higher than cCasp3+ cells in Lena-infected piglets during the first week post-infection. cCasp8 and to a lesser extent cCasp9 were activated by both PRRSV-1 strains after one week post-infection together with a replenishment of both CD163+ and Arg-1+ pulmonary macrophages. These results highlight the induction of other forms of RCD beyond apoptosis, such as, necroptosis and pyroptosis during the first week post-infection followed by the activation of, mainly, extrinsic apoptosis during the second week post-infection. The recovery of CD163+ macrophages at the end of the study represents an attempt to restore pulmonary macrophage subpopulations lost during the early stages of the infection but also a macrophage polarisation into M2 macrophages.
Development of a laboratory monitoring system for elastic waves transmitted through sand under dry and nearly saturated conditions
Authors: Nakayama Masayuki , Kawakata Hironori , Hirano Shiro , Doi Issei
Published: January 2021

Laboratory experiments with seismic measurements have the potential to be highly useful for understanding the physical process of water-induced landslides, and fundamental experiments are helpful for the appropriate interpretation of recorded seismograms. We developed a laboratory measurement system to investigate the relationships between wave propagation and water saturation in sand. We considered that the wavelength should be comparable to or sufficiently shorter than the sensing intervals. Furthermore, we embedded a wave source that can repeatedly emit an arbitrary and identical signal in an octave frequency band under both dry and nearly saturated conditions. We measured the transmitted waves by embedded accelerometers over 24 h under dry and nearly saturated conditions. The difference in the slowness between the two conditions was one-thousand-fold larger than the fluctuations in slowness over 24 h for each condition. Also, the difference in amplitude between the two conditions was about double the fluctuations in amplitude over 24 h for each condition. These results suggested that our system can monitor the water content change in sand via the change in spectral amplitude and phase slowness.
An investigation into the cause of road failure along Sagamu-Papalanto highway southwestern Nigeria
Authors: Emmanuel Ubido Oyem , Ogbonnaya Igwe , Uche Ukah Bernadette
Published: January 2021

Investigation into the cause of road failure has been carried out along a 60 km long Sagamu –Papalanto highway southwestern Nigeria. Geochemical, mineralogical, geotechnical and geophysical analyses were conducted to evaluate the cause of failure along the study area. The results of the laboratory tests showed that the percentage amount of fines ranges from 12 to 61.3%, natural moisture content from 6.8 to 19.7%, liquid limit in the range of 25.1–52.2%, linear shrinkage between 3.96 to 12.71%, plastic limit ranges from 18.2–35%, plasticity index ranges from 5.2 to 24.6%, free swell in the range from 5.17–43.9%, maximum dry density ranges from 1.51–1.74 g /cm3, specific gravity ranges from 2.52–2.64 and CBR between 3 and 12%. The Cone Penetrometer Test (CPT) shows a resistance value of 20–138 kgf/cm2. The major clay mineral that is predominant in the studied soil is kaolinite. The major oxides present are SiO2, Al2O3, Fe2O3, K2O, Na2O, MgO and CaO. The result of the 2D Electrical Resistivity Imaging revealed a low resistivity values for profile 2 and 3 ranging from 100 Ωm – 300 Ωm, between a distance of 20 m – 240 m along the profile to a depth of 7.60 m and a low resistivity value ranging from 50 Ωm – 111Ωm, between a distance of 80 m − 120 m along the profile to a depth of 15 m. It was concluded that the low CBR, low MDD and the class of subsoils namely A-26, A-7, A-2-7 (clayey soils) which were identified are responsible for the cause of failure experienced in the study area. These makes the soils unsuitable as road construction materials and hence, there is need for stabilization during the reconstruction and rehabilitation of the road.
Amelioration of oxidative and inflammatory changes by Peganum harmala seeds in experimental arthritis
Authors: Singhai Ashish , Patil Umesh Kumar
Published: January 2021

Background

The present study was designed to investigate the therapeutic effects against oxidative stress and alleviative effects of Peganum harmala seeds (PH) in rats with Complete Freund’s Adjuvant (CFA) induced arthritis.

Methods

The extract was evaluated for its phytoconstituents, antiarthritic and antioxidant properties. The action of chloroform (PHC) and ethanolic (PHE) extracts of PH was evaluated in adult Lewis rats (150-200 g).with CFA induced arthritis. Arthritic rats received PH extracts 100 mg/kg orally for 28 consecutive days (Prophylactic treatment) and from 14th day of CFA injection (Therapeutic treatment).

Results

PHE significantly suppressed the arthritis severity in rats than PHC in 28 days. All complications shown significant reduction (p< 0.05) in arthritic rats including paw volume (63.09%), body weight loss, decreased locomotor activity, erythrocyte sedimentation rate and synovial/hepatic tissues lipid peroxidation and increase in cellular antioxidants superoxide dismutase (U/mg) activities and hemoglobin counts. The results showed the presence of alkaloids and flavonoids in PHE. Histology and radiographic analysis of arthritic ankle joints indicated abnormal changes. Marked reduction in inflammation and arthritic changes were observed after treatment with PHE.

Conclusion

Therefore, the investigation suggests that PHE at 100 mg/kg will be useful in the management of rheumatoid arthritis complications which may possibly be due to boosting the intracellular antioxidant defense.
Spatial scale in prescribed fire regimes: an understudied aspect in conservation with examples from the southeastern United States
Authors: Mason David S. , Lashley Marcus A.
Published: January 2021

The idea that not all fire regimes are created equal is a central theme in fire research and conservation. Fire frequency (i.e., temporal scale) is likely the most studied fire regime attribute as it relates to conservation of fire-adapted ecosystems. Generally, research converges on fire frequency as the primary filter in plant community assembly and structure, which is often critical to conservation goals. Thus, conservation success is commonly linked to fire frequency in fire regimes.

The spatial scale of fire may also be vital to conservation outcomes, but this attribute is underrepresented in the primary literature. In our global, contemporary literature search, we found 37 published syntheses concerning the effects of prescribed fire in conservation over the last decade. In those syntheses, only 16% included studies that reported data-based inferences related to the spatial scale of the fire, whereas 73% included discussion of empirical studies on the temporal scale. Only one of the syntheses discussed studies that explicitly tested the effects of spatial extent, and none of those studies were experiments manipulating spatial scale. Further, understanding spatial-scale-dependent patterns may be relevant because two databases of fire-occurrence data from the United States indicated that spatial scale among lightning-ignited and prescribed fires may have been mismatched over the past few decades.

Based on a rich ecological literature base that demonstrates pervasive scale-dependent effects in ecology, spatial-scale-dependent relationships among prescribed fire regimes and conservation outcomes are likely. Using examples from the southeastern United States, we explored the potential for scale-dependent ecological effects of fire. In particular, we highlighted the potential for spatial scale to (a) influence wildlife populations by manipulating the dispersion of habitat components, and (b) modulate plant community assembly and structure by affecting seed dispersal mechanics and spatial patterns in herbivory. Because spatial-scale-dependent outcomes are understudied but likely occurring, we encourage researchers to address the ecological effects of spatial scale in prescribed-fire regimes using comparative and manipulative approaches.
Semiautomatic fault-surface generation and interpretation using topological metrics
Authors: Lou Yihuai , Zhang Bo , Yong Pan , Fang Huijing , Zhang Yijiang , Cao Danping
Published: January 2021

Seismic fault surfaces are compulsory input for structure modeling that unravels the structural deformation history of the subsurface. Seismic fault attributes provide geoscientists with alternative images of faults. However, seismic fault attributes only highlight possible fault locations and do not directly provide fault surfaces that are required inputs for structural modeling. Interpreters construct seismic fault surfaces using interpreted seismic fault sticks on vertical seismic slices. Interpreting fault sticks on hundreds of seismic slices is time consuming. We have semiautomatically constructed fault surfaces by simulating the procedure of manual seismic fault interpretation. Our algorithm consists of three main steps: (1) obtaining fault sticks in the inline, crossline, and time slices; (2) grouping the fault sticks according to the connectivity and mutual exclusion (topology) between the fault sticks on the inline, crossline, and time slices; and (3) generating the fault surface patches by merging the fault sticks time slice by time slice through the topology analysis. Our algorithm contains one optional step: manually merging the fault patches if needed. We test our algorithm on open access seismic data and our workflow accurately generates fault surfaces for most faults including conjugate faults in the seismic data. Considering that it usually helps to weight the estimation according to the quality of the computed fault attribute, the algorithm computes fault parameters such as fault dip and strike using weighted principal component analysis.
Minimal residual disease (MRD) detection with circulating tumor DNA (ctDNA) from personalized assays in stage II-III colorectal cancer patients in a U.K. multicenter prospective study (TRACC).
Authors: Anandappa Gayathri , Starling Naureen , Begum Ruwaida , Bryant Annette , Sharma Shruti , Renner Derrick , Aresu Maria , Peckitt Clare , Sethi Himanshu , Feber Andrew , Potter Vanessa Alice , Paraoan Marius , Abulafi Muti , George Nicol , Branagan Graham , Duff Sarah , West Nicholas , Aleshin Alexey , Chau Ian , Cunningham David ,   UK Colorectal Cancer TRACC Study Group
Published: January 2021

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Background: Numerous studies have shown the clinical utility of ctDNA, a non-invasive biomarker to detect MRD and stratify CRC patients who are more likely to relapse. We present an analysis of MRD detection in CRC patients from a prospective multicentre UK study, who were monitored pre- and post-surgery before adjuvant chemotherapy (ACT). Methods: The study recruited patients diagnosed with stage II-III CRC (n=122), including a subset of rectal patients who underwent tri-modality treatment (TMT). All patients had their primary tumor resected and 56% (68/122) received ACT. Paired plasma samples (n=244) were collected before surgery/neaodjuvant chemoradiotherapy and after surgery; median follow-up for survival was 15.48 months (0.16 - 42.1 months). Individual tumors and matched germline DNA were whole-exome sequenced and somatic single nucleotide variants (SNVs) identified. Multiplex PCR assays were designed to track tumor-specific SNVs (Signatera, bespoke mPCR NGS assay) in plasma samples. The study evaluated ctDNA status and clinical outcomes including radiologic imaging. Cox regression was used to calculate recurrence-free survival (RFS) in patients stratified by post-op ctDNA status. Patients were also stratified into low and high-risk groups based on the clinicopathological features. Multivariate analysis was performed with covariates: ctDNA, age, gender, laterality, stage, number of lymph node resected, MSI & TMB. Results: Pre-treatment ctDNA was detected in 93.4% (100/107) of patients. Post-operative ctDNA status prior to ACT was assessed in 107 patients, of whom, 13% (14/107) were MRD-positive (MRDpos). Of the MRDpos patients 42.9% (6/14) eventually relapsed. In contrast, only 8.6% (8/93) of MRD-negative (MRDneg) cases relapsed (HR: 10; 95% CI: 3.3-30; p<0.001). MRD rates stratified by risk features in each of the stages with respective recurrence rates are shown in Table. In stage III patients (n=64), 45.4% (5/11) of the MRDpos patients relapsed, whilst only 17% (9/53) of the MRDneg cases relapsed (HR: 9; 95% CI:2.6-32; p<0.0001). In the multivariate analysis, ctDNA status was the most significant prognostic factor associated with RFS (HR: 28.8, 95% CI: 3.5-234.1; p<0.001). Conclusions: Postoperative ctDNA analysis with tumor informed assay enables detection of CRC patients at high-risk of recurrence. Early detection of MRD could guide ACT decisions in intervention trials and is currently underway in TRACC. Clinical trial information: NCT04050345. [Table: see text]
Inactivation of E-cadherin by Trop-2 drives colon cancer metastasis.
Authors: Alberti Saverio , Guerra Emanuela , Altomare Donato F. , Depalo Raffaella , Trerotola Marco
Published: January 2021

105

Background: Tumor metastasis is the main cause of death of colon cancer patients and the biggest hurdle for cancer cure. We set to identify decisive drivers and of pivotal therapy targets for colon cancer metastasis. Methods: IHC analysis quantified the expression of target molecules in primary tumors and metastases. Cell-cell adhesion capacity was assessed in vitro and in HCT116 colon cancer cell spheroids. Pre-clinical models of orthotopic growth of KM12SM colon cancer cells and metastatic diffusion to the liver were utilized to assess metastatic spreading force of wtTrop-2 and of the constitutively-active, tail-less form of Trop-2 (Δcyto). Xenotransplant and metastasis transcriptomes were analyzed for differential induction of EMT determinants. Kaplan–Meier plots were used to illustrate survival and metastatic relapse in independent case series of colon cancer patients. Results: wtTrop-2 was shown to induce wound-healing. ΔcytoTrop-2 further increased cell migration ability. Both wtTrop-2 and ΔcytoTrop-2 induced resistance to apoptosis in vitro and in vivo. wtTrop-2 strikingly increased the metastatic capacity of KM12SM cells, raising metastasis rates from 45% for control cells to 90% for wtTrop-2 transfectants. The constitutively-active ΔcytoTrop-2 further boosted metastatic spreading, with metastatic livers reaching up to four times their normal size. Cancer metastases revealed high levels of E-cadherin, in the absence of transcriptional down-regulation. EMT transcription factors were largely missing from Trop-2-activated cells. Rather, binding to Trop-2 was shown to cause the release of E-cadherin from the cytoskeleton, loss of cell-cell adhesion and activation of β-catenin. This global, Trop-2/E-cadherin/β-catenin-driven pro-metastatic program was recapitulated in colon cancer patients and was shown to impact on colon cancer metastatic relapse and overall patient survival. Conclusions: We identify Trop-2-driven functional inactivation of E-cadherin as a widespread driver of metastatic diffusion in colon cancer, opening novel avenues for personalized diagnostic procedures and anti-cancer therapies. [Table: see text]
Characteristics of genomic alterations in circulating tumor DNA (ctDNA) in patients (Pts) with advanced gastrointestinal (GI) cancers in nationwide large-scale ctDNA screening:SCRUM-Japan Monstar-Screen.
Authors: Nakamura Yoshiaki , Fujisawa Takao , Kadowaki Shigenori , Takahashi Naoki , Goto Masahiro , Yoshida Kazuhiro , Kawakami Takeshi , Esaki Taito , Oki Eiji , Nishida Naohiro , Nishina Tomohiro , Komatsu Yoshito , Ohta Takashi , Kuramoto Naomi , Horasawa Satoshi , Sakamoto Yasutoshi , Taniguchi Hiroya , Yoshino Takayuki
Published: January 2021

106

Background: Analysis of ctDNA has been utilized in pts with advanced GI cancer for identification of genomic alterations for targeted therapy. However, the characteristics of ctDNA genomic alterations of GI cancers compared to non-GI cancers remains unclear. Methods: Pts with advanced solid tumors were eligible in MONSTAR-SCREEN, a nationwide ctDNA screening project in Japan. Plasma samples were analyzed by an NGS-based 70-gene ctDNA assay, FoundationOne Liquid (F1L) at a CLIA-certified and CAP-accredited laboratory since Jul 2019. For treatment-naïve pts, tumor tissue samples were analyzed by FoundationOne CDx (F1CDx), a 324-gene tissue-based panel. Results: As of Jun 18 2020, out of enrolled 540 pts with advanced solid tumor, 470 pts, consisting of 133 with advanced GI cancers (67 colorectal, 48 gastric, 14 esophageal, 2 gastrointestinal tumor (GIST) and 2 small intestinal) and 337 non-GI cancers (103 hepatobiliary and pancreatic, 70 genitourinary, 64 breast, 46 head and neck, 33 gynecologic, and 21 skin), had an available ctDNA result. Sequencing success rate was similar between GI and non-GI cancers (91.7% vs. 89.3%, P = 0.50). GI cancers had a significantly higher ctDNA level (maximum variant allele fraction) than non-GI cancers (median, 11.8% vs. 0.57%; P = 1.6E-7). The most frequently altered genes were TP53 (73%), APC (73%), KRAS (30%), BRAF (15%), and PIK3CA (12%) in colorectal cancer, TP53 (44%), KRAS (19%), PIK3CA (15%), ATM (10%), and ERBB2 (10%) in gastric cancer, and TP53 (79%), ATM (21%), ERBB2 (21%) in esophageal cancer. Mutations in genes in pathways related to RAS/RAF/MEK (39.1 % vs. 21.4 %, P = 1.8E-4), receptor tyrosine kinase (20.3% vs 11.9%, P = 0.027), p53 (66.2% vs 49.6%, P = 0.0014), and Wnt (41.4% vs 4.7%, P = 4.4E-21) were significantly enriched in GI cancers compared to non-GI cancers. Tumor tissue samples were analyzed using F1CDx for 63 treatment-naïve pts, in which 51 (31.3%) of 132 alterations identified by F1L were not detected by F1CDx. Conclusions: GI cancers had higher ctDNA levels and distinct characteristics of ctDNA genomic alterations from non-GI cancers with an enrichment in several oncogenic pathways. One-third of ctDNA alterations were detected in only ctDNA, indicating the potential of ctDNA analysis to identify heterogenous genomic alterations in advanced GI cancer. Clinical trial information: UMIN000036749.
Expression of PD-L1 and PD-L2 in colorectal cancer (CRC): A post-hoc integrated analysis of SCRUM-Japan GI-SCREEN CRC.
Authors: Yuki Satoshi , Nakamura Yoshiaki , Taniguchi Hiroya , Denda Tadamichi , Nishina Tomohiro , Hamamoto Yasuo , Hara Hiroki , Esaki Taito , Kawakami Hisato , Takashima Atsuo , Satoh Taroh , Sunakawa Yu , Masuishi Toshiki , Shinozaki Eiji , Moriwaki Toshikazu , Miki Izumi , Shitara Kohei , Yoshino Takayuki
Published: January 2021

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Background: PD-1, PD-L1/L2 axis is responsible for cancer immune escape which facilitate disease progression. However, expression of these proteins in CRC and its significance in clinical prognosis are yet to be fully clarified. Methods: This was a post-hoc analysis using FFPE tumor samples from the Nationwide Cancer Genome Screening Project, SCRUM-Japan GI-SCREEN for metastatic CRC. Patients (Pts) with MSI-H or BRAF V600E mutant tumors were prioritized to be included. PD-L1 (22C3) and PD-L2 expressions were centrally assessed using immunohistochemical assays at QualTek and NeoGenomics, respectively. Tumor infiltrating lymphocytes (TILs) were morphologically evaluated by H&E staining. Clinical information including biomarker status and overall survival (OS) were extracted from SCRUM-Japan GI-SCREEN database. Results: In total, 200 pts were included in this study with a median age of 65 (range, 29–88) years; male/female (116/84); MSI status MSI-H/non-MSI-H/unknown (8/189/3); RAS wild-type/mutant (113/87); and BRAF V600E wild-type/mutant (173/27). Positivity rate of PD-L1 in tumor cells (TC), immune cells (IC), PD-L2 on TC and IC were 10.8%, 46.9%, 0% and 20.3%, respectively. Expression of PD-L1 on TC or IC and PD-L2 on IC were associated with TIL (p = 0.023, p = 0.009, respectively). PD-L1 on TC was highly seen in BRAF V600E-mutated tumors (p = 0.043), but not related to other factors including RAS and MSI status. The pts with PD-L1+ tumors on TC or IC had longer OS than those with PD-L1- (Median, 31.9 vs 23.5 months; HR = 0.67, 95% CI, 0.46–0.99; p = 0.040), while OS in pts with PD-L2+ tumors was similar to that with PD-L2- (Median, 21.4 vs 27.3 months; HR = 0.87, 95% CI, 0.53–1.44; p = 0.60). The PD-L1 expression was also associated with the longer OS in pts with BRAF wild-type or non-MSI-H tumors. Conclusions: Our study suggested different prognostic impact of PD-L1 and PD-L2 expression in CRC pts, which require further evaluations as potential therapeutic targets for CRC. Clinical trial information: UMIN000016343.
Differential gain of chromosomal regions 20q or 13q with loss of 8p and 18q differentiates disease-free survival in colorectal cancer.
Authors: Chao Eva , Xu Qi , Capasso Anna , Eckhardt S. Gail , Kowalski Jeanne
Published: January 2021

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Background: In microsatellite stable (MSS) colorectal cancer (CRC) cases, frequent amplifications in 13q and 20q regions have been reported with limited understanding of their potential role for prognosis and treatment. Based on an internal research molecular tumor board case analysis of a KRAS WT, MSS left-sided (LS), metastatic CRC patient, we noted 50% of the 11 listed variants of unknown significance were on 20q. This study aims to investigate the potential prognostic role for gain of 20q chromosomal regions relative to other chromosomal imbalances using a retrospective cohort. Methods: We performed a genome-wide CN cluster analysis using the TCGA data with resulting patient clusters compared based on Kaplan-Meier estimated disease-free interval (DFI) in months (mos) using a log-rank. We examined associations between CN-derived clusters and CRC phenotypes. Results: Using TCGA data, we identified four CN-derived patient clusters of which two had significantly different DFI’s. One longer DFI cluster (n = 83; median DFI = 28mos) was defined by a signature of copy neutral genes along Chr8p and 18q regions. The shorter DFI cluster (n = 46; median DFI = 20mos) was defined by a signature of Chr8p and 18q regions of loss. The two clusters significantly differed in terms of site (85% right-sided in the shorter vs. 85% LS in the longer DFI cluster) and MS status (81% MSS in the shorter vs. 72% MSI in the longer DFI cluster) with no significant differences in age (mean of 70 years at diagnosis) and KRAS status (around 50% WT) between clusters. The shorter DFI was able to be further differentiated based on gain of chromosomal regions 20q (n = 26; median DFI = 24mos) and 13q (n = 20; median DFI = 18mos). No significant differences in mean age, tumor stage, site, and MS status between the shorter DFI subgroups were noted. Enriched pathways in the Chr20q gain sub-cluster include cell differentiation (Hippo, Rap1, VEGF), whereas metabolic signaling pathways via AGE-RAGE and AMPK, as well as cell growth and malignant transformation via RAS are enriched in the Chr13q gain sub-cluster. Conclusions: Clinical sequencing is able to identify regions of gain in Chr20q and Chr13q as part of VUS’s. Gain of Chr20q has been reported with better survival in mCRC patients. Gain of chromosomal region 20q and loss of 18q has been reported to discriminate between Lynch Syndrome and familial colorectal cancer. Herein, we show that gain of the 20q region with 18q and 8p regions of loss is associated with shorter DFI and gain of 13q region with loss of 8p even worse prognosis.
The impact of sociodemographic characteristics on gastric cancer outcomes: A retrospective review of a large single center study.
Authors: Findakly Dawood , Forlemu Arnold , Kosa Dimas , Amar Surabhi
Published: January 2021

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Background: Gastric cancer (GC) remains a pervasive condition in the US with high morbidity and mortality. Race/ethnicity, lack of insurance, and poverty may all be contributing to this burden, especially in select populations. We evaluated the impact of these sociodemographic factors on GC outcomes at a hospital with high immigrant-patient populations. Methods: We conducted a retrospective study to identify patients diagnosed with GC between year 2010 and 2019. Data obtained from our institution database regarding patients' sociodemographic factors, including age, gender, race/ethnicity, insurance status and type, and neighborhood socioeconomic status. Likewise, information on tumor histology, anatomic location, and stage were also obtained. Kaplan-Meier analysis was used to plot survival curves and analyze the impact of insurance on survival outcome. Results: One hundred eleven patients were analyzed in this study, with a male-to-female ratio of 1.26:1. The median age at the time of GC diagnosis was 52.9 (range 27-87) years, with median survival time (±SD, range) of 12.7 (±17.7, 0.25-84) months. Most patients (69.4%) were uninsured—out of which 76.7% presented with advanced-stage disease. Among those, the majority (70.3%) were Hispanic, and 60.4% were non-U.S. citizens. The most common tumor histology was diffuse-type adenocarcinoma in 55% of patients. Patients insured were on public coverage (Medicaid), private insurance, and Medicare at 11.7%, 9.9%, and 9.0%, respectively. In terms of survival, lack of insurance (p = 0.012) and Medicaid insurance (p = 0.046) were associated with the worst survival outcomes in GC patients. Conclusions: Our study reflects the trends in GC outcomes distinctly linked to significant sociodemographic disparities. Patients who lack insurance coverage had the worst survival outcomes. Therefore, efforts such as increasing healthcare access for this population-type at risk of sociodemographic incongruities may enhance outcomes and are crucial in fighting GC.
Using breath analysis as a screening tool to detect gastric cancer: A systematic review.
Authors: Haddad Ghazal , Schouwenburg Stef , Altesha Ashraf , Xu Wei , Liu Geoffrey
Published: January 2021

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Background: In its early stages, gastric cancer symptoms are frequently lacking, resulting in an often late and incurable diagnosis. A non-invasive, cheap, and reliable screening method for gastric cancer could improve outcomes and increase the number of surgically resectable gastric cancers. Breath analysis has emerged as an experimental method of non-invasive screening of gastric cancer and identification of individuals suitable for confirmatory, diagnostic upper gastrointestinal endoscopy. We aimed to evaluate the accuracy and applicability of breath analysis for gastric cancer detection in adults. Methods: This systematic review searched MEDLINE, EMBASE, BIOSIS, CENTRAL, and Compendex until 11 July 2019 for original studies analyzing exhaled breath to detect gastric cancer in patients. Two authors then independently screened the abstracts, titles, and full texts. Summary sensitivity and specificity analyses were obtained using a hierarchical bivariate method. Positive predictive value and number needed to screen (NNS) of breath analysis methods for gastric cancer detection were calculated for each country using gastric cancer prevalence by country obtained from the Global Cancer Observatory. Non-quantitative results were descriptively summarized. Risk of bias was assessed using the QUADAS-2 tool. This study protocol was pre-registered in PROSPERO (CRD42020139422). Results: Twenty studies were included. Together, the studies included 2,976 subjects. The pooled mean age of the subjects in the gastric cancer groups was 60.5 ± 11 years while the pooled mean age for control groups was 55.4 ± 12 years. Within these twenty studies, breath analysis technologies most commonly used were mass spectrometry (MS)-based methods; other methods included volatile organic compound sensors, thermal desorption tubes, and silicon nanowire field effect transistors. Across all included studies, we found and summarized the characteristics of 131 chemical compounds found in the exhaled breath of study subjects. Eleven studies (total n = 1905) involving all technologies reported quantitative results, with sensitivities ranging from 67-100% and specificities from 71-98%. The summary sensitivity across six studies utilizing MS-based breath analysis methods was 85.3% (95% CI: 82-96%); summary specificity was 81.7%. (95% CI: 78-85%). Based on the MS-based values, we estimated that screening with MS-based breath tests could lower the NNS by more than four-fold in the 15 countries with the highest prevalence of gastric cancer. Conclusions: Breath analysis is a promising method for gastric cancer detection with good diagnostic performance and potential to decrease the NNS for endoscopy-based gastric cancer detection. However, due to the heterogeneity of breath analysis technologies, rigorous studies with standardized, reproducible methods are needed to evaluate the clinical applicability of these technologies.
Chemotherapy use in early-stage anal canal squamous cell carcinoma and its impact on outcome.
Authors: Huffman Deanna , Jayakrishnan Thejus Thayyil , Wegner Rodney E. , Vannatter Brittany , Monga Dulabh K. , Finley Gene Grant , McCormick James , Kirichenko Alexander V.
Published: January 2021

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Background: The standard of care for non-metastatic squamous cell carcinoma of the anal canal (SCCA) is concurrent chemoradiotherapy with high rates of local control. There is some thought that perhaps chemotherapy can be omitted for the earliest stages without worse outcomes. We used the National Cancer Database (NCDB) to identify predictors of chemotherapy receipt or omission to assess the impact on outcomes. Methods: We queried the NCDB from 2004-2016 for patients with cT1N0M0 SCCA treated non-operatively with radiation with and without chemotherapy and at least 2 months of follow-up. Logistic regression was used to generate predictors of chemotherapy use. Cox regression identified predictors of survival. Propensity matching was done to help account for indication bias. Results: We identified 2,959 patients meeting eligibility, of which 8% (n = 237) were treated without chemotherapy. The vast majority (n = 2722, 92%) were recorded as having multi-agent chemotherapy. Median radiation dose was 50.4 Gy (IQR 45-54) in 28 fractions (IQR 49.4-59.4) with chemotherapy and 54.0 Gy (IQR 49.4-59.4) in 30 fractions (IQR 25-33) in those who had chemotherapy omitted. Predictors of omission of chemotherapy were older age (OR 0.66, 95% CI [0.49-0.90], P = 0.0087), higher comorbidity score (OR 0.62, 95% CI [0.38-0.99], P = 0.0442), African American race (OR 0.57, 95% CI [0.36-0.90], P = 0.0156) and more remote year of treatment (OR 1 1 for years 2004-2006). Predictors of survival were younger age (HR 1.73 for age > 58 years, 95% CI [1.41-2.11], P < 0.001), multi-agent chemotherapy use (HR 0.48, 95% CI [0.38-0.62], P < 0.0001), higher income (HR 0.57, 95% CI [0.40-0.81], P = 0.0016), female gender (HR 0.68, 95% CI [0.57-0.82], P = 0.0016), and private insurance (HR 0.54, 95% CI [0.34-0.87], P = 0.0104). After propensity matching, overall survival at 120 months for patients treated with and without chemotherapy was 86% and 65%, respectively (p < 0.0001). Conclusions: Chemotherapy is utilized the majority of the time in early stage SCCA. Being mindful of the limitations of a retrospective database analysis, our results suggest an association with worse survival outcomes when chemotherapy is omitted.