Efficacy of laparoscopic low anterior resection for colorectal cancer patients with 3D-vascular reconstruction for left coronary artery preservation.

BACKGROUND: Laparoscopic low anterior resection (LLAR) has become a mainstream surgical method for the treatment of colorectal cancer, which has shown many advantages in the aspects of surgical trauma and postoperative rehabilitation. However, the effect of surgery on patients' left coronary artery and its vascular reconstruction have not been deeply discussed. With the development of medical imaging technology, 3D vascular reconstruction has become an effective means to evaluate the curative effect of surgery. AIM: To investigate the clinical value of preoperative 3D vascular reconstruction in LLAR of rectal cancer with the left colic artery (LCA) preserved. METHODS: A retrospective cohort study was performed to analyze the clinical data of 146 patients who underwent LLAR for rectal cancer with LCA preservation from January to December 2023 in our hospital. All patients underwent LLAR of rectal cancer with the LCA preserved, and the intraoperative and postoperative data were complete. The patients were divided into a reconstruction group (72 patients) and a nonreconstruction group (74 patients) according to whether 3D vascular reconstruction was performed before surgery. The clinical features, operation conditions, complications, pathological results and postoperative recovery of the two groups were collected and compared. RESULTS: A total of 146 patients with rectal cancer were included in the study, including 72 patients in the reconstruction group and 74 patients in the nonreconstruction group. There were 47 males and 25 females in the reconstruction group, aged (59.75 ± 6.2) years, with a body mass index (BMI) (24.1 ± 2.2) kg/m2, and 51 males and 23 females in the nonreconstruction group, aged (58.77 ± 6.1) years, with a BMI (23.6 ± 2.7) kg/m2. There was no significant difference in the baseline data between the two groups (P > 0.05). In the submesenteric artery reconstruction group, 35 patients were type I, 25 patients were type II, 11 patients were type III, and 1 patient was type IV. There were 37 type I patients, 24 type II patients, 12 type III patients, and 1 type IV patient in the nonreconstruction group. There was no significant difference in arterial typing between the two groups (P > 0.05). The operation time of the reconstruction group was 162.2 ± 10.8 min, and that of the nonreconstruction group was 197.9 ± 19.1 min. Compared with that of the reconstruction group, the operation time of the two groups was shorter, and the difference was statistically significant (t = 13.840, P < 0.05). The amount of intraoperative blood loss was 30.4 ± 20.0 mL in the reconstruction group and 61.2 ± 26.4 mL in the nonreconstruction group. The amount of blood loss in the reconstruction group was less than that in the control group, and the difference was statistically significant (t = -7.930, P < 0.05). The rates of anastomotic leakage (1.4% vs 1.4%, P = 0.984), anastomotic hemorrhage (2.8% vs 4.1%, P = 0.672), and postoperative hospital stay (6.8 ± 0.7 d vs 7.0 ± 0.7 d, P = 0.141) were not significantly different between the two groups. CONCLUSION: Preoperative 3D vascular reconstruction technology can shorten the operation time and reduce the amount of intraoperative blood loss. Preoperative 3D vascular reconstruction is recommended to provide an intraoperative reference for laparoscopic low anterior resection with LCA preservation.

Chronic activation of a negative engram induces behavioral and cellular abnormalities.

Negative memories engage a brain and body-wide stress response in humans that can alter cognition and behavior. Prolonged stress responses induce maladaptive cellular, circuit, and systems-level changes that can lead to pathological brain states and corresponding disorders in which mood and memory are affected. However, it is unclear if repeated activation of cells processing negative memories induces similar phenotypes in mice. In this study, we used an activity-dependent tagging method to access neuronal ensembles and assess their molecular characteristics. Sequencing memory engrams in mice revealed that positive (male-to-female exposure) and negative (foot shock) cells upregulated genes linked to anti- and pro-inflammatory responses, respectively. To investigate the impact of persistent activation of negative engrams, we chemogenetically activated them in the ventral hippocampus over 3 months and conducted anxiety and memory-related tests. Negative engram activation increased anxiety behaviors in both 6- and 14-month-old mice, reduced spatial working memory in older mice, impaired fear extinction in younger mice, and heightened fear generalization in both age groups. Immunohistochemistry revealed changes in microglial and astrocytic structure and number in the hippocampus. In summary, repeated activation of negative memories induces lasting cellular and behavioral abnormalities in mice, offering insights into the negative effects of chronic negative thinking-like behaviors on human health.

CRISPR/dCas9-Tet1-Mediated DNA Methylation Editing.

DNA methylation is a key epigenetic mechanism underlying many biological processes, and its aberrant regulation has been tightly associated with various human diseases. Precise manipulation of DNA methylation holds the promise to advance our understanding of this critical mechanism and to develop novel therapeutic methods. Previously, we were only able to alter genome-wide DNA methylation by treating with small molecules (e.g., 5-Aza-2-deoxycytidine) or perturbing relevant genes (e.g., DNA methyltransferase) targetlessly, which makes it challenging to investigate the functional significance of this epigenetic mark at specific genomic loci. By fusing the catalytic domain of a key enzyme in the DNA demethylation process (Ten-eleven translocation dioxygenases 1, Tet1) with a reprogrammable sequence-specific DNA-targeting molecular protein, dCas9, we developed a DNA methylation editing tool (dCas9-Tet1) to demethylate specific genomic loci in a targeted manner. This dCas9-Tet1 system allows us to study the role of DNA methylation at almost any given loci with only the replacement of a single-guide RNA. Here, we describe a protocol that enables modular and scalable manipulation of DNA methylation at specific genomic loci in various cell cultures with high efficiency and specificity using the dCas9-Tet1 system. Key features • Precisely editing the DNA methylation of specific genomic loci in a targeted manner. • Fine-tuning gene expression without changing DNA sequence. • Applicable to many types of cell cultures and with the potential for ex vitro and in vivo applications.

Complementary, alternative, and integrative medicine-specific COVID-19 misinformation on social media: A scoping review.

Background: The sharing of health-related information has become increasingly popular on social media. Unregulated information sharing has led to the spread of misinformation, especially regarding complementary, alternative, and integrative medicine (CAIM). This scoping review synthesized evidence surrounding the spread of CAIM-related misinformation on social media during the COVID-19 pandemic. Methods: This review was informed by a modified version of the Arksey and O'Malley scoping review framework. AMED, EMBASE, PsycINFO and MEDLINE databases were searched systematically from inception to January 2022. Eligible articles explored COVID-19 misinformation on social media and contained sufficient information on CAIM therapies. Common themes were identified using an inductive thematic analysis approach. Results: Twenty-eight articles were included. The following themes were synthesized: 1) misinformation prompts unsafe and harmful behaviours, 2) misinformation can be separated into different categories, 3) individuals are capable of identifying and refuting CAIM misinformation, and 4) studies argue governments and social media companies have a responsibility to resolve the spread of COVID-19 misinformation. Conclusions: Misinformation can spread more easily when shared on social media. Our review suggests that misinformation about COVID-19 related to CAIM that is disseminated online contributes to unsafe health behaviours, however, this may be remedied via public education initiatives and stricter media guidelines. The results of this scoping review are crucial to understanding the behavioural impacts of the spread of COVID-19 misinformation about CAIM therapies, and can inform the development of public health policies to mitigate these issues.

Suicide risk among veterans using VHA justice-involved services: a latent class analysis.

BACKGROUND: Justice-involved Veterans experience notable risk for psychosocial stressors (e.g., homelessness) and psychiatric multimorbidity, which can result in complex clinical presentations. However, research examining how such factors coalesce to impact risk for suicide remains limited. METHODS: We conducted a latent class analysis of 180,454 Veterans accessing Veterans Health Administration (VHA) justice-related services from 2005 to 2018. RESULTS: A four-model class membership solution was identified. Among these classes, risk for suicide was highest among Veterans with greater psychiatric burden, with risk most notable among those with high VA service use. Veterans seeking healthcare primarily focused on substance use disorders or with low psychiatric burden and service use had a lower risk for suicide. CONCLUSIONS: Psychiatric multimorbidity is salient as it relates to suicide among Veterans accessing VHA justice-related services. Further evaluation of existing VHA services for this population and methods of augmenting and enhancing care for justice-involved Veterans with histories of co-occurring psychiatric conditions may be beneficial in facilitating suicide prevention efforts.

A latent class analysis to identify subgroups of VHA using homeless veterans at greater risk for suicide mortality.

BACKGROUND: Homeless Veterans are at substantially elevated risk for suicide mortality; however, understanding of drivers of suicide in this population remains limited. METHOD: Building upon prior work, we conducted a retrospective chart review, comprised of a latent class analysis of 724,752 Veterans with use of Veterans Health Administration (VHA) homeless services 2005-2018. RESULTS: A five-model class membership solution was identified. Among these classes, risk for suicide mortality was greatest among Veterans with the highest psychiatric burden and high VHA service use. Those experiencing moderate psychiatric burden or primarily experiencing substance use disorders also experienced elevated risk for suicide mortality relative to those with low burden and service use. LIMITATIONS: Models were specific to Veterans accessing VHA homeless services and may not generalize to those not using such services outside VHA care. CONCLUSIONS: Continued research and programing remain necessary to determine how to address mental health conditions and engage homeless Veterans in services to facilitate suicide prevention.

Edaravone efficacy in amyotrophic lateral sclerosis with reduced forced vital capacity: Post-hoc analysis of Study 19 (MCI186-19) [clinical trial NCT01492686].

BACKGROUND: Edaravone slowed the rate of functional decline in subjects with amyotrophic lateral sclerosis (ALS) in phase 3 study MCI186-19 (Study 19). One of the Study 19 inclusion criteria was forced vital capacity (FVC) ≥80% of predicted (≥80%p). Therefore, the study provided no information on edaravone efficacy in subjects with FVC <80%p. In Study 19, 24-week, double-blind treatment was followed by open-label treatment where all subjects received edaravone. At 24 weeks, some subjects had FVC <80%p (FVC24 <80%p). This allowed for post-hoc assessment of the effects of edaravone in subgroups of subjects with FVC24 ≥80%p vs <80%p. OBJECTIVE: To address the question of the efficacy of edaravone in ALS patients with FVC <80%p. METHODS: Post-hoc analysis of Study 19 comparing edaravone efficacy at week 48 in subjects with FVC24 ≥80%p vs <80%p. RESULTS: With edaravone treatment, subjects in both the FVC24 ≥80%p and the FVC24 <80%p subgroups experienced a reduction in ALS Functional Rating Scale-Revised (ALSFRS-R) score loss vs placebo subjects through week 48. For the FVC24 ≥80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -7.63 for edaravone-edaravone vs -9.69 for placebo-edaravone, a difference of 2.05 (P = .034; 95% CI: 0.16, 3.94). For the FVC24 <80%p subgroup, the changes in ALSFRS-R scores from baseline to week 48 were -10.26 for edaravone-edaravone vs -15.20 for placebo-edaravone, a difference of 4.94 (P = .0038; 95% CI: 1.64, 8.25). Linear regression analysis indicated that, in the FVC24 <80%p subgroup, there was a notable change in the slope of the ALSFRS-R score-vs-time graph after the start of edaravone treatment. CONCLUSION: ALS subjects in the Study 19 placebo arm had a slowing in disease progression, even when edaravone was added with an FVC of <80%p prior to starting edaravone. A randomized, placebo-controlled study is needed to validate these post-hoc findings.

Establishing a Research Agenda for Suicide Prevention Among Veterans Experiencing Homelessness.

Suicide among Veterans experiencing or at risk for homelessness remains a significant public health concern. Conducting research to understand and meet the needs of this at-risk population remains challenging due to myriad factors (e.g., clinical complexity including multimorbidity, difficulty monitoring risk across systems). To address this challenge, the United States Department of Veterans Affairs (VA) convened the Health Services Research and Development (HSR&D) Suicide Prevention in Veterans Experiencing Homelessness: Research and Practice Development meeting, bringing together subject-matter experts in the fields of homelessness and suicide prevention, both from within and outside of VA. During the meeting, attendees identified 10 potential research priorities at the intersection of suicide prevention and homelessness. After the meeting, Delphi methodology was used to achieve consensus on the relative importance of the identified research domains. Through this iterative Delphi process, agreement was reached regarding the need to increase understanding of barriers and facilitators to suicide risk assessment and emergency intervention for Veterans experiencing homelessness by examining the perspectives of both Veterans and healthcare providers. Elucidating the complex relationships between risk periods, subgroups, suicide means, and drivers of suicide among Veterans experiencing homelessness was also considered a top priority. This article documents the Delphi process and provides a research agenda for researchers, funding agencies, and policymakers to prioritize the most relevant and potentially impactful research domains aimed at preventing suicide among Veterans experiencing or at risk for homelessness.

Understanding the Intersection of Homelessness and Justice Involvement: Enhancing Veteran Suicide Prevention Through VA Programming.

BACKGROUND: Veterans with a history of homelessness and justice involvement are at greater risk for mental health sequelae, including suicide. OBSERVATIONS: A bidirectional relationship exists between criminal justice involvement and housing instability (ie, the institutional circuit). Homelessness and justice involvement often represent a vicious cycle that is difficult to escape. The US Department of Veterans Affairs (VA) has a number of programs focused on connecting homeless and justice-involved veterans to health and social services. This paper reviews existing programing and initiatives within such services to detect risk for suicide and connect these veterans to appropriate evidence-based mental health care. CONCLUSIONS: The VA currently has several programs focused on enhancing care for homeless and justice-involved veterans, many of which currently incorporate suicide prevention initiatives. Understanding of factors that may impact health service delivery of suicide risk assessment and intervention may be beneficial in order to enhance veteran suicide prevention efforts.

Application of machine learning methods to pathogen safety evaluation in biological manufacturing processes.

The production of recombinant therapeutic proteins from animal or human cell lines entails the risk of endogenous viral contamination from cell substrates and adventitious agents from raw materials and environment. One of the approaches to control such potential viral contamination is to ensure the manufacturing process can adequately clear the potential viral contaminants. Viral clearance for production of human monoclonal antibodies is achieved by dedicated unit operations, such as low pH inactivation, viral filtration, and chromatographic separation. The process development of each viral clearance step for a new antibody production requires significant effort and resources invested in wet laboratory experiments for process characterization studies. Machine learning methods have the potential to help streamline the development and optimization of viral clearance unit operations for new therapeutic antibodies. The current work focuses on evaluating the usefulness of machine learning methods for process understanding and predictive modeling for viral clearance via a case study on low pH viral inactivation.

Long-term edaravone efficacy in amyotrophic lateral sclerosis: Post-hoc analyses of Study 19 (MCI186-19).

BACKGROUND: In a Phase 3 study, amyotrophic lateral sclerosis (ALS) patients experienced significantly less physical functional decline with 24-week edaravone vs placebo, followed by open-label treatment for an additional 24 weeks. METHODS: Outcome (the change in ALS Functional Rating Scale-Revised, ALSFRS-R, from baseline) was projected for placebo patients through 48 weeks and compared with 48-week edaravone or 24-week edaravone after switching from placebo. RESULTS: A total of 123 patients received open-label treatment (65 edaravone-edaravone; 58 placebo-edaravone). The projected ALSFRS-R decline for placebo from baseline through week 48 was greater than for 48-week edaravone (P < .0001). For patients switching from placebo to edaravone, ALSFRS-R slope approached that of continued edaravone for 48 weeks. ALSFRS-R decline did not differ between actual and projected edaravone through week 48. CONCLUSIONS: Compared with placebo, these analyses suggest that edaravone is beneficial in ALS patients even after 6 mo of receiving placebo, and efficacy is maintained for up to 1 year.

Post-hoc analyses of the edaravone clinical trials Study 16 and Study 19: a step toward more efficient clinical trial designs in amyotrophic lateral sclerosis.

Objectives: The edaravone development program established a study design in which a treatment effect slowing functional loss in amyotrophic lateral sclerosis (ALS) could be documented within a 24-week time frame. This report elucidates the strategic enrichment design utilized to create efficiency and precision in the development program. Methods: Post-hoc analyses describe learning, sequential iteration, and evolution in study design. Results: The first Phase 3 study of edaravone in ALS (Study MCI186-16) included a large proportion (35%) of placebo patients who were minimal progressors. These patients demonstrated high heterogeneity in change in ALSFRS-R score (-4 median with interquartile range [IQR] 7.5) and a modal distribution score of 0, suggesting evidence of minimal change in ALSFRS-R during the study. This level of variability and rate of progression may have made it difficult to detect a prospective treatment effect in the study. A strategic enrichment strategy provided the second Phase 3 study (Study MCI186-19) with the ability to detect a treatment effect. In Study MCI186-19, only 13% of the placebo patients were minimal progressors. Further, these placebo patients demonstrated less heterogeneity and greater functional progression of ALS, thereby providing greater likelihood of detecting a treatment effect. The enrichment strategy may have excluded some rapidly progressing patients, potentially supporting the detection of a treatment effect. As previously published, Study MCI186-19 prospectively documented a 33% reduction in rate of progression of ALS (p = 0.0013). Conclusions: Strategic choices in the design of Study MCI186-19 reduced the proportion of minimally progressing patients and supported detection of a treatment effect.

Post-hoc analysis of randomised, placebo-controlled, double-blind study (MCI186-19) of edaravone (MCI-186) in amyotrophic lateral sclerosis.

Post-hoc analyses of the ALS Functional Rating Scale-Revised (ALSFRS-R) score data, the primary endpoint in the 24-week double-blind placebo-controlled study of edaravone (MCI186-19, NCT01492686), were performed to confirm statistical robustness of the result. The previously reported original analysis had used a last observation carried forward (LOCF) method and also excluded patients with fewer than three completed treatment cycles. The post-hoc sensitivity analyses used different statistical methods as follows: 1) including all patients regardless of treatment cycles received (ALL LOCF); 2) a mixed model for repeated measurements (MMRM) analysis; and 3) the Combined Assessment of Function and Survival (CAFS) endpoint. Findings were consistent with the original primary analysis in showing superiority of edaravone over placebo. We also investigated the distribution of change in ALSFRS-R total score across all patients in the study as well as which ALSFRS-R items and domains may have contributed to the overall efficacy findings. The distribution of changes in ALSFRS-R total score from baseline to the end of cycle 6 (ALL LOCF) shifted in favour of edaravone compared to placebo. Edaravone was descriptively favoured for each ALSFRS-R item and each of the four ALSFRS-R domains at the end of cycle 6 (ALL LOCF), suggesting a generalised effect of edaravone in slowing functional decline across all anatomical regions. The effect of edaravone appeared to be similar in patients with bulbar onset and limb onset. Together, these observations would be consistent with its putative neuroprotective effects against the development of oxidative damage unspecific to anatomical regions.

Bystander fatigue and CPR quality by older bystanders: a randomized crossover trial comparing continuous chest compressions and 30:2 compressions to ventilations.

OBJECTIVES: This study sought to measure bystander fatigue and cardiopulmonary resuscitation (CPR) quality after five minutes of CPR using the continuous chest compression (CCC) versus the 30:2 chest compression to ventilation method in older lay persons, a population most likely to perform CPR on cardiac arrest victims. METHODS: This randomized crossover trial took place at three tertiary care hospitals and a seniors' center. Participants were aged ≥55 years without significant physical limitations (frailty score ≤3/7). They completed two 5-minute CPR sessions (using 30:2 and CCC) on manikins; sessions were separated by a rest period. We used concealed block randomization to determine CPR method order. Metronome feedback maintained a compression rate of 100/minute. We measured heart rate (HR), mean arterial pressure (MAP), and Borg Exertion Scale. CPR quality measures included total number of compressions and number of adequate compressions (depth ≥5 cm). RESULTS: Sixty-three participants were enrolled: mean age 70.8 years, female 66.7%, past CPR training 60.3%. Bystander fatigue was similar between CPR methods: mean difference in HR -0.59 (95% CI -3.51-2.33), MAP 1.64 (95% CI -0.23-3.50), and Borg 0.46 (95% CI 0.07-0.84). Compared to 30:2, participants using CCC performed more chest compressions (480.0 v. 376.3, mean difference 107.7; p<0.0001) and more adequate chest compressions (381.5 v. 324.9, mean difference. 62.0; p=0.0001), although good compressions/minute declined significantly faster with the CCC method (p=0.0002). CONCLUSIONS: CPR quality decreased significantly faster when performing CCC compared to 30:2. However, performing CCC produced more adequate compressions overall with a similar level of fatigue compared to the 30:2 method.

The Wnt Inhibitor Sclerostin Is Up-regulated by Mechanical Unloading in Osteocytes in Vitro.

Although bone responds to its mechanical environment, the cellular and molecular mechanisms underlying the response of the skeleton to mechanical unloading are not completely understood. Osteocytes are the most abundant but least understood cells in bones and are thought to be responsible for sensing stresses and strains in bone. Sclerostin, a product of the SOST gene, is produced postnatally primarily by osteocytes and is a negative regulator of bone formation. Recent studies show that SOST is mechanically regulated at both the mRNA and protein levels. During prolonged bed rest and immobilization, circulating sclerostin increases both in humans and in animal models, and its increase is associated with a decrease in parathyroid hormone. To investigate whether SOST/sclerostin up-regulation in mechanical unloading is a cell-autonomous response or a hormonal response to decreased parathyroid hormone levels, we subjected osteocytes to an in vitro unloading environment achieved by the NASA rotating wall vessel system. To perform these studies, we generated a novel osteocytic cell line (Ocy454) that produces high levels of SOST/sclerostin at early time points and in the absence of differentiation factors. Importantly, these osteocytes recapitulated the in vivo response to mechanical unloading with increased expression of SOST (3.4 ± 1.9-fold, p < 0.001), sclerostin (4.7 ± 0.1-fold, p < 0.001), and the receptor activator of nuclear factor κΒ ligand (RANKL)/osteoprotegerin (OPG) (2.5 ± 0.7-fold, p < 0.001) ratio. These data demonstrate for the first time a cell-autonomous increase in SOST/sclerostin and RANKL/OPG ratio in the setting of unloading. Thus, targeted osteocyte therapies could hold promise as novel osteoporosis and disuse-induced bone loss treatments by directly modulating the mechanosensing cells in bone.

Molecular analysis of gastric cancer identifies subtypes associated with distinct clinical outcomes.

Gastric cancer, a leading cause of cancer-related deaths, is a heterogeneous disease. We aim to establish clinically relevant molecular subtypes that would encompass this heterogeneity and provide useful clinical information. We use gene expression data to describe four molecular subtypes linked to distinct patterns of molecular alterations, disease progression and prognosis. The mesenchymal-like type includes diffuse-subtype tumors with the worst prognosis, the tendency to occur at an earlier age and the highest recurrence frequency (63%) of the four subtypes. Microsatellite-unstable tumors are hyper-mutated intestinal-subtype tumors occurring in the antrum; these have the best overall prognosis and the lowest frequency of recurrence (22%) of the four subtypes. The tumor protein 53 (TP53)-active and TP53-inactive types include patients with intermediate prognosis and recurrence rates (with respect to the other two subtypes), with the TP53-active group showing better prognosis. We describe key molecular alterations in each of the four subtypes using targeted sequencing and genome-wide copy number microarrays. We validate these subtypes in independent cohorts in order to provide a consistent and unified framework for further clinical and preclinical translational research.

Trifactorial classification system for osteotome sinus floor elevation based on an observational retrospective analysis of 926 implants followed up to 10 years.

OBJECTIVE: A novel osteotome trifactorial classification system is proposed for transcrestal osteotome-mediated sinus floor elevation (OSFE) sites that includes residual bone height (RBH), sinus floor anatomy (contour), and multiple versus single sites OSFE (tenting). METHOD AND MATERIALS: An analysis of RBH, contour, and tenting was retrospectively applied to a cohort of 926 implants placed using OSFE without added bone graft and followed up to 10 years. RBH was divided into three groups: high (RBH > 6 mm), mid (RBH = 4.1 to 6 mm), and low (RBH = 2 to 4 mm). The sinus "contour" was divided into four groups: flat, concave, angle, and septa. For "tenting", single versus multiple adjacent OSFE sites were compared. RESULTS: The prevalence of flat sinus floors increased as RBH decreased. RBH was a significant predictor of failure with rates as follows: low- RBH = 5.1%, mid-RBH = 1.5%, and high-RBH = 0.4%. Flat sinus floors and single sites as compared to multiple sites had higher observed failure rates but neither achieved statistical significance; however, the power of the study was limited by low numbers of failures. CONCLUSION: The osteotome trifactorial classification system as proposed can assist planning OSFE cases and may allow better comparison of future OSFE studies.

Genomic landscape and genetic heterogeneity in gastric adenocarcinoma revealed by whole-genome sequencing.

Gastric cancer (GC) is the second most common cause of cancer-related deaths. It is known to be a heterogeneous disease with several molecular and histological subtypes. Here we perform whole-genome sequencing of 49 GCs with diffuse (N=31) and intestinal (N=18) histological subtypes and identify three mutational signatures, impacting TpT, CpG and TpCp[A/T] nucleotides. The diffuse-type GCs show significantly lower clonality and smaller numbers of somatic and structural variants compared with intestinal subtype. We further divide the diffuse subtype into one with infrequent genetic changes/low clonality and another with relatively higher clonality and mutations impacting TpT dinucleotide. Notably, we discover frequent and exclusive mutations in Ephrins and SLIT/ROBO signalling pathway genes. Overall, this study delivers new insights into the mutational heterogeneity underlying distinct histologic subtypes of GC that could have important implications for future research in the diagnosis and treatment of GC.

Tibial adamantinoma with local recurrence and pulmonary metastasis: report of a case with histocytologic findings.

BACKGROUND: Adamantinoma is a rare primary bone neoplasm of low malignant potential that may recur or metastasize in a mall percentage of patients. The myriad histologic patterns may cause difficulty in distinguishing this tumor from other primary or metastatic neoplasms. The cytomorphologic findings of fine needle aspiration biopsy were reported previously in only a small number of cases. CASE: A 32-year-old man presented with a mass in the distal side of the left leg that was diagnosed as classic adamantinoma by open biopsy. Local recurrence and pulmonary metastases were confirmed by fine needle aspiration biopsy, which showed low grade, uniform cells with nuclear membrane grooves. The patient underwent a below-the-knee amputation and is receiving palliative treatment for progressive pulmonary spread. CONCLUSION: The diagnosis of adamantinoma requires knowledge of compatible clinical and radiologic studies as well as understanding of the variable histologic patterns that one may encounter. Fine needle aspiration biopsy is particularly useful in the diagnosis of recurrent and metastatic adamantinoma. This case report describes a distinctive cytomorphologic feature of nuclear grooves that may be a useful aid in distinguishing the tumor cells of adamantinoma from other cell types.