How is vaping promoted in an illegal market? A qualitative study of Singaporeans' social media encounters.

BACKGROUND: Although Singapore has completely banned vaping, it is heavily promoted on social media. This study explored vaping-related social media content that Singaporeans are exposed to, and how it shapes vaping-related perceptions and experiences in the context of Singapore's strict regulations. METHODS: We held 10 focus group discussions with 63 Singaporeans aged 21-40 years, with diversity by sociodemographics, smoking history, vaping history and self-reported exposure to vaping-related social media content. Participants provided screenshots of any vaping-related content they encountered on their social media. Subsequently, in focus groups, they were shown a variety of this content and asked to discuss. We coded transcripts using inductive methods. RESULTS: Participants had encountered vape advertisements from neighbouring countries featuring attractive products, flavours, celebrity endorsements and entertainment shows, which they found highly appealing. Participants encountered posts that did not overtly advertise vaping but depicted people vaping in social settings, thereby normalising vaping despite its illegal status. They perceived government campaigns to deter vaping as biased and agenda driven, calling for a more nuanced message and use of local influencers and personal stories to communicate the rationale of the vaping regulations to the public. CONCLUSION: Having a law that bans vaping may not be enough; it needs to be complemented with more comprehensive marketing restrictions on social media platforms and effective enforcement of bans on social media promotions from overseas.

Interplay between desmoglein2 and hypoxia controls metastasis in breast cancer.

Metastasis is the major cause of cancer death. An increased level of circulating tumor cells (CTCs), metastatic cancer cells that have intravasated into the circulatory system, is particularly associated with colonization of distant organs and poor prognosis. However, the key factors required for tumor cell dissemination and colonization remain elusive. We found that high expression of desmoglein2 (DSG2), a component of desmosome-mediated intercellular adhesion complexes, promoted tumor growth, increased the prevalence of CTC clusters, and facilitated distant organ colonization. The dynamic regulation of DSG2 by hypoxia was key to this process, as down-regulation of DSG2 in hypoxic regions of primary tumors led to elevated epithelial-mesenchymal transition (EMT) gene expression, allowing cells to detach from the primary tumor and undergo intravasation. Subsequent derepression of DSG2 after intravasation and release of hypoxic stress was associated with an increased ability to colonize distant organs. This dynamic regulation of DSG2 was mediated by Hypoxia-Induced Factor1α (HIF1α). In contrast to its more widely observed function to promote expression of hypoxia-inducible genes, HIF1α repressed DSG2 by recruitment of the polycomb repressive complex 2 components, EZH2 and SUZ12, to the DSG2 promoter in hypoxic cells. Consistent with our experimental data, DSG2 expression level correlated with poor prognosis and recurrence risk in breast cancer patients. Together, these results demonstrated the importance of DSG2 expression in metastasis and revealed a mechanism by which hypoxia drives metastasis.

Neuropsychological profiles of adolescents sentenced to detention in Western Australia with and without prenatal alcohol exposure.

BACKGROUND/AIMS: Youth with prenatal alcohol exposure (PAE) are under-recognised in the justice system, warranting improved identification. This study aimed to compare neuropsychological profiles of adolescents, with and without PAE and identify neuropsychological tasks predictive of PAE-group membership. It was hypothesised that participants with PAE would score significantly lower on neuropsychological tests. METHODS: Participants included 85 young people sentenced to detention (mean 15.7 years, 78 males), 46 with PAE. A one-way-multivariate analysis of variance tested differences in neuropsychological functioning between PAE/No-PAE groups, while logistic regression determined tests predictive of PAE. RESULTS: No statistically significant difference in test scores emerged between groups, and regression was not indicative of any models predictive of PAE-group membership. Neuropsychological profiles were characterised by both strengths and weaknesses, with lower verbal and mathematical skills. CONCLUSION(S): While no statistically significant differences were found between the groups, the results provided a unique insight into the neurocognitive profile of Australian youth in detention. Routine screening assessments were recommended for young people sentenced to detention.

Commercial milk formula marketing following increased restrictions in Singapore: A qualitative study.

The promotion of commercial milk formula (CMF) negatively impacts breastfeeding outcomes. In 2019, Singapore updated its 1979 Code of Ethics of the Sale of Infant Foods Ethics Committee Singapore (SIFECS) to increase marketing restrictions on CMF for infants 0-12 months. However, little is known about industry tactics to undermine these restrictions. This qualitative study explores health workers' and mothers' experiences with CMF marketing in Singapore following the 2019 restrictions. We conducted a qualitative study, using semistructured interviews with 14 mothers of infants aged less than 5 months and 20 health workers with expertise in antenatal, maternity, or paediatric care. We analysed data thematically using inductive coding. Five themes were identified. Mothers and health workers reported digital marketing, product line extensions with toddlers' milk and milk for mothers, and CMF sponsorships in the healthcare setting. Expert endorsement, competitive price, nutritional claims, and brand reputation influenced mothers' infant formula choices, yet both mothers and health workers appeared to be unaware of the impact of CMF marketing tactics on their own perceptions. The restriction of CMF marketing and infant feeding practices varied widely between hospitals, with private hospitals and practices having less strict controls on CMF marketing. Despite the updated SIFECS restrictions, CMF companies continue to target mothers and health workers in Singapore. SIFECS restrictions should be tightened to align with international guidelines, by increasing their scope to include toddlers' milk and prohibiting cross-promotion, digital marketing, and any sponsorships of events targeting health workers that may create a conflict of interest.

Nylon Suture Loop for Tagging Lymphatic Channels during Lymphaticovenular Anastomosis.

Background Lymphaticovenular anastomosis (LVA) requires special supermicrosurgery techniques designed for vessels less than 0.8 mm in size. While preparing the field for LVA, it is often difficult to handle the lymphatic vessel directly without injuring it or fracturing it entirely. Method We propose a novel technique, which is used in LVA for tagging of lymphatic vessels, with the use of a nylon 6-0 suture and micro-ligaclip. Results We have successfully performed 78 LVAs in 26 cases with this method. The average lymphatic vessel size was 0.3 mm (0.15-0.8 mm). Conclusion This novel technique to implement the use of a nylon suture with a micro-ligaclip to use as a vessel loop for lymphatics has not been previously described in the literature. It is a useful technique that we find beneficial to lymphatic identification through tagging of the lymphatic channels, contributing to greater success in each anastomosis.

Influx of podoplanin-expressing inflammatory macrophages into the genital tract following Chlamydia infection.

Genital Chlamydia trachomatis infection remains a major health issue as it causes severe complications including pelvic inflammatory disease, ectopic pregnancy and infertility in females as a result of infection-associated chronic inflammation. Podoplanin, a transmembrane receptor, has been previously reported on inflammatory macrophages. Thus, strategies that specifically target podoplanin might be able to reduce local inflammation. This study investigated the expression level and function of podoplanin in a C. trachomatis infection model. C57BL/6 mice infected with the mouse pathogen Chlamydia muridarum were examined intermittently from days 1 to 60 using flow cytometry analysis. Percentages of conventional macrophages (CD11b+ CD11c- F4/80+ ) versus inflammatory macrophages (CD11b+ CD11c+ F4/80+ ), and the expression of podoplanin in these cells were investigated. Subsequently, a podoplanin-knockout RAW264.7 cell was used to evaluate the function of podoplanin in C. trachomatis infection. Our findings demonstrated an increased CD11b+ cell volume in the spleen at day 9 after the infection, with augmented podoplanin expression, especially among the inflammatory macrophages. A large number of podoplanin-expressing macrophages were detected in the genital tract of C. muridarum-infected mice. Furthermore, analysis of the C. trachomatis-infected patients demonstrated a higher percentage of podoplanin-expressing monocytes than that in the noninfected controls. Using an in vitro infection in a transwell migration assay, we identified that macrophages deficient in podoplanin displayed defective migratory function toward C. trachomatis-infected HeLa 229 cells. Lastly, using immunoprecipitation-mass spectrometry method, we identified two potential podoplanin interacting proteins, namely, Cofilin 1 and Talin 1 actin-binding proteins. The present study reports a role of podoplanin in directing macrophage migration to the chlamydial infection site. Our results suggest a potential for reducing inflammation in individuals with chronic chlamydial infections by targeting podoplanin.

Randomized Controlled Trial Investigating Perioperative Immunonutrition for Patients Undergoing Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC).

BACKGROUND: Immunonutrition has been shown to reduce hospital stay and postoperative morbidity in patients undergoing gastrointestinal, and head and neck surgery. However, its use has not been demonstrated in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CRS-HIPEC). This study aims to determine the effectiveness of perioperative immunonutrition on patients undergoing CRS-HIPEC in reducing length of hospitalization and postoperative complications. PATIENTS AND METHODS: From April 2017 to December 2018, patients undergoing CRS-HIPEC for peritoneal metastases in a single center were enrolled in a randomized controlled trial. Patients with evidence of intestinal obstruction or with diabetes mellitus were excluded. Patients were randomly assigned in a 1:1 fashion to receive perioperative oral immunonutrition or standard nutritional feeds. Length of hospital stay and rates of wound infection and complications were recorded and compared between the two groups in an intention-to-treat manner. RESULTS: A total of 62 patients were recruited and randomized into two groups. Compliance to nutritional feeds in the preoperative period was significantly higher in the standard nutrition group (95.2% versus 75.4%, p = 0.004). There was no difference in postoperative compliance rates. Length of hospital stay and rates of wound infection and postoperative complications were higher in the standard nutrition group when compared with patients on immunonutrition (15.5 versus 11.1 days, p = 0.186; 19% versus 9.7%, p = 0.473; 16% versus 9.7%, p = 0.653; respectively). CONCLUSIONS: Patients undergoing CRS-HIPEC who received perioperative immunonutrition had shorter hospitalization and less wound infections and postoperative complications, although the differences with the standard nutrition group were not statistically significant. Potential benefits of perioperative immunonutrition need to be further evaluated in larger studies.

Expanding the genetic causes of small-fiber neuropathy: SCN genes and beyond.

Small-fiber neuropathy (SFN) is a disorder that exclusively affects the small nerve fibers, sparing the large nerve fibers. Thinly myelinated Aδ-fibers and unmyelinated C-fibers are damaged, leading to development of neuropathic pain, thermal dysfunction, sensory symptoms, and autonomic disturbances. Although many SFNs are secondary and due to immunological causes or metabolic disturbances, the etiology is unknown in up to half of the patients. Over the years, this proportion of "idiopathic SFN" has decreased, as familial and genetic causes have been discovered, thus shifting a proportion of once "idiopathic" cases to the genetic category. After the discovery of SCN9A-gene variants in 2012, SCN10A and SCN11A variants have been found to be pathogenic in SFN. With improved accessibility of SFN diagnostic tools and genetic tests, many non-SCN variants and genetically inherited systemic diseases involving the small nerve fibers have also been described, but only scattered throughout the literature. There are 80 SCN variants described as causing SFN, 8 genes causing hereditary sensory autonomic neuropathies (HSAN) described with pure SFN, and at least 7 genes involved in genetically inherited systemic diseases associated with SFN. This systematic review aims to consolidate and provide an updated overview on the genetic variants of SFN to date---SCN genes and beyond. Awareness of these genetic causes of SFN is imperative for providing treatment directions, prognostication, and management of expectations for patients and their health-care providers.

Tobacco industry's 'behind the scenes' tactics in Singapore.

BACKGROUND: Tobacco companies have maintained a profitable business in Singapore, despite its strong anti-tobacco climate and commitment to protect public health policymaking from tobacco industry interference in line with Framework Convention on Tobacco Control Article 5.3. This study describes how tobacco companies influence policymaking in a highly regulated environment such as Singapore's, where there is a strong government commitment to Article 5.3. METHODS: Analysis of internal tobacco industry documents detailing the industry's lobbying activities in Singapore, retrieved via snowball searches in the Truth Tobacco Industry Documents Library. Subsequently, we conducted one-on-one interviews with key informants from sectors mentioned in the documents (academia, arts, government, public health, media, trade, education) to fill gaps in information and provide context to events described in the documents. RESULTS: In the 1980s and 1990s, tobacco companies observed that, to influence policy within Singapore's 'hostile' environment, they needed to use 'behind the scenes' tactics, targeting influential individuals at social functions or industry-sponsored events. Tobacco companies used arts and education sponsorships primarily for political purposes, to gain visibility with policymakers. Tobacco companies cultivated relationships with academic researchers and the media to avoid smoke-free legislation in the 1990s and, in the 2010s, appear to have used similar tactics to challenge Singapore's e-cigarette ban. CONCLUSIONS: Countries with a strong commitment to Article 5.3 should consider the tobacco industry's potential interference in policymaking beyond relationships in the government sector, particularly in academia, arts, education and the media, and the more subtle or indirect manners in which these relationships are built.

Tobacco industry strategies for flavour capsule cigarettes: analysis of patents and internal industry documents.

BACKGROUND: The global market for flavour capsule variants (FCVs), cigarettes with a crushable flavour capsule, has grown exponentially. To inform further regulatory efforts, it is important to understand tobacco industry strategies for FCVs. METHODS: Analysis of data from 65 patents and 179 internal tobacco industry documents, retrieved via snowball searches in Patsnap and the Truth Tobacco Industry Documents Library, describing tobacco industry developments related to FCVs. We used an inductive coding method to identify themes relating to FCV features or developments. RESULTS: Tobacco companies were developing FCVs since the 1960s, with little market success until the 2000s following the launch of Camel Crush, a brand which targeted millennials (in their teens or early 20s at the time). Tobacco companies have patented, but not yet marketed, FCVs with microcapsule surface coatings, adjustable or heat-triggered flavour release systems, airflow manipulation features, transparent filters to visualise flavour release, and various flavours and additives for capsules including nicotine/tobacco extracts for an on-demand nicotine hit. Tobacco companies developed FCVs purported to be reduced harm, although their own tests showed that FCVs have higher toxicant concentrations. They have also developed loose flavour capsule units designed to fit into cigarettes, packs, or recessed filters to enable users to customise cigarettes and circumvent tobacco flavour bans. CONCLUSIONS: To prevent tobacco companies from targeting young people and exploiting regulatory loopholes, regulations on tobacco products should ban flavours and consider the broad variety of FCV designs, additives and loose products designed to impart flavour into tobacco products.

Exploring offending characteristics of young people with foetal alcohol spectrum disorder in Western Australia.

Neurodevelopmental impairments resulting from Foetal Alcohol Spectrum Disorder (FASD) can increase the likelihood of justice system involvement. This study compared offence characteristics in young people with FASD to demographically matched controls (n = 500) in Western Australia. A novel approach (i.e. association rule mining) was adopted to uncover relationships between personal attributes and offence characteristics. For FASD participants (n = 100), file records were reviewed retrospectively. Mean age of the total sample was 15.60 years (range = 10-24), with 82% males and 88% Australian Aboriginal. After controlling for demographic factors, regression analyses showed FASD participants were more likely than controls to be charged with reckless driving (odds ratio, OR = 4.20), breach of bail/community orders (OR = 3.19), property damage (OR = 1.84), and disorderly behaviour (OR = 1.54). Overall, our findings suggest justice-involved individuals with FASD have unique offending profiles. These results have implications for sentencing, diversionary/crime prevention programs and interventions.

Systems and policies to reduce secondhand smoke in multiunit housing in Singapore: a qualitative study.

BACKGROUND: Multiunit housing residents are often exposed to neighbours' secondhand smoke (SHS). Little is known on the current systems available to protect residents in places not covered by a residential smoking ban, or what constitutes an appropriate policy approach. This study explores relevant systems and policies in Singapore, a densely populated city-state where the vast majority live in multiunit housing and discussions on regulating smoking in homes are ongoing. METHODS: In-depth interviews with 18 key informants involved in thought leadership, advocacy, policy or handling SHS complaints, and 14 smokers and 16 non-smokers exposed to SHS at home. RESULTS: The current system to address neighbours' SHS comprises three steps: moral suasion, mediation and legal dispute. Moral suasion and mediation are often ineffective as they depend on smokers to willingly restrict their smoking habits. Legal dispute can yield a court order to stop smoking inside the home, but the process places a high evidence burden on complainants. While setting up designated smoking points or running social responsibility campaigns may help to create no-smoking norms, more intractable cases will likely require regulation, a polarising approach which raises concerns about privacy. CONCLUSIONS: Without regulations to limit SHS in multiunit housing, current systems are limited in their enforceability as they treat SHS as a neighbourly nuisance rather than a public health threat.

Automated lung ultrasound image assessment using artificial intelligence to identify fluid overload in dialysis patients.

BACKGROUND: Fluid assessment is challenging, and fluid overload poses a significant problem among dialysis patients, with pulmonary oedema being the most serious consequence. Our study aims to develop a simple objective fluid assessment strategy using lung ultrasound (LUS) and artificial intelligence (AI) to assess the fluid status of dialysis patients. METHODS: This was a single-centre study of 76 hemodialysis and peritoneal dialysis patients carried out between July 2020 to May 2022. The fluid status of dialysis patients was assessed via a simplified 8-point LUS method using a portable handheld ultrasound device (HHUSD), clinical examination and bioimpedance analysis (BIA). The primary outcome was the performance of 8-point LUS using a portable HHUSD in diagnosing fluid overload compared to physical examination and BIA. The secondary outcome was to develop and validate a novel AI software program to quantify B-line count and assess the fluid status of dialysis patients. RESULTS: Our study showed a moderate correlation between LUS B-line count and fluid overload assessed by clinical examination (r = 0.475, p < 0.001) and BIA (r = 0.356. p < 0.001). The use of AI to detect B-lines on LUS in our study for dialysis patients was shown to have good agreement with LUS B lines observed by physicians; (r = 0.825, p < 0.001) for the training dataset and (r = 0.844, p < 0.001) for the validation dataset. CONCLUSION: Our study confirms that 8-point LUS using HHUSD, with AI-based detection of B lines, can provide clinically useful information on the assessment of hydration status and diagnosis of fluid overload for dialysis patients in a user-friendly and time-efficient way.

Residential secondhand smoke in a densely populated urban setting: a qualitative exploration of psychosocial impacts, views and experiences.

BACKGROUND: People remain exposed to secondhand smoke, a serious health hazard, inside their home as households face challenges in setting no-smoking rules or are exposed to secondhand smoke drifting in from neighbouring homes. This study explores the psychosocial impacts, views, and experiences with residential secondhand smoke in a densely populated urban setting.  METHODS: In-depth online or face to face interviews with 18 key informants who had been involved in public discourse, policy, advocacy or handling complaints related to residential secondhand smoke, 14 smokers, and 16 non-smokers exposed to secondhand smoke inside their home. All participants were residents of Singapore, a densely populated, multi-ethnic city-state. Interview transcripts were coded in NVivo using a deductive and inductive coding process. FINDINGS: Secondhand smoke has wide-reaching impacts on physical and psychosocial wellbeing, even if smokers tried to minimise secondhand smoke. Feelings of anxiety and stress are generally tied to feeling discomfort in one's personal space, a perceived lack of control over the situation, resentment towards smokers, and concerns over the health effects. Family, community, and cultural dynamics add complexities to tackling the issue, especially in patriarchal households. Secondhand smoke exposure from neighbours is considered a widespread issue, exacerbated by structural factors such as building layout and the COVID-19 pandemic. Resolving the issue amicably is considered challenging due to the absence of regulations and a reluctance to stir up conflict with neighbours. While smokers took measures to reduce secondhand smoke, these were described as ineffective by other participants. Smokers appeared to have contrasting views from other participants on what it means to smoke in a socially responsible manner. CONCLUSION: Given the wide-reaching psychosocial impacts of residential secondhand smoke, there is a case for stronger interventions, especially in densely populated urban settings where it is more difficult to avoid.

Adverse childhood experiences, associated stressors and comorbidities in children and youth with fetal alcohol spectrum disorder across the justice and child protection settings in Western Australia.

BACKGROUND: Individuals with Fetal Alcohol Spectrum Disorder (FASD) are at risk of having adverse childhood experiences (ACEs), especially those with child protection and/or justice system involvement. The complex relationship between FASD and psychosocial vulnerabilities in the affected individual is an important clinical risk factor for comorbidity. This study (1) explored the ACEs and associated stressors in individuals with FASD; (2) investigated the association between ACEs and negative outcomes, i.e., justice/child protection system involvement; and (3) examined the relationship between ACEs and comorbid conditions such as mood and neurodevelopmental disorders. METHODS: Data were collected retrospectively via file review from diagnostic clinics in Western Australia. Life adversity was coded using a standardised ACEs questionnaire. A total of 211 participants (72% males) with FASD with a mean age of 11 years (range = 2-21) were included in the final sample. 70% of the total sample had been involved with the child protection system and 40% had trouble with the law. RESULTS: Exposure to drinking/substance misuse at home (70%) and domestic violence (52%) were the two most common ACEs across the total sample. In the entire cohort, 39% had four or more ACEs, indicating higher risks of poor health outcomes. Additional stressors recorded were disengagement from school (43%), transiency (19%), victims of bullying (12%), traumatic brain injury (9%) and homelessness (5%). ACEs such as drinking/substance misuse at home, emotional neglect and physical neglect were positively associated with child protection system involvement. Additionally, exposure to domestic violence was positively correlated with justice system involvement. Higher rates of life adversity in this clinical population were associated with an increased number of comorbidities. Specifically, those with FASD who had comorbidities such as attachment disorder, substance use disorder, and PTSD also reported higher ACEs scores. CONCLUSION: ACEs were common in this clinical population. Increased ACEs in this sample were associated with increased comorbidities and involvement with the child protection and/or justice system. This highlights that prevention, intervention and early diagnosis of FASD are important for at risk children to reduce the negative effects of ACEs.

Autosomal dominant Emery-Dreifuss muscular dystrophy caused by a mutation in the lamin A/C gene identified by exome sequencing: a case report.

BACKGROUND: Emery-Dreifuss Muscular Dystrophy (EDMD) is an uncommon genetic disease among the group of muscular dystrophies. EDMD is clinically heterogeneous and resembles other muscular dystrophies. Mutation of the lamin A/C (LMNA) gene, which causes EDMD, also causes many other diseases. There is inter and intrafamilial variability in clinical presentations. Precise diagnosis can help in patient surveillance, especially before they present with cardiac problems. Hence, this paper shows how a molecular work-out by next-generation sequencing can help this group of disorders. CASE PRESENTATION: A 2-year-10-month-old Javanese boy presented to our clinic with weakness in lower limbs and difficulty climbing stairs. The clinical features of the boy were Gower's sign, waddling gait and high CK level. His father presented with elbow contractures and heels, toe walking and weakness of limbs, pelvic, and peroneus muscles. Exome sequencing on this patient detected a pathogenic variant in the LMNA gene (NM_170707: c.C1357T: NP_733821: p.Arg453Trp) that has been reported to cause Autosomal Dominant Emery-Dreifuss muscular dystrophy. Further examination showed total atrioventricular block and atrial fibrillation in the father. CONCLUSION: EDMD is a rare disabling muscular disease that poses a diagnostic challenge. Family history work-up and thorough neuromuscular physical examinations are needed. Early diagnosis is essential to recognize orthopaedic and cardiac complications, improving the clinical management and prognosis of the disease. Exome sequencing could successfully determine pathogenic variants to provide a conclusive diagnosis.

Innate Immunity Crosstalk with Helicobacter pylori: Pattern Recognition Receptors and Cellular Responses.

Helicobacter pylori is one of the most successful gastric pathogens that has co-existed with human for centuries. H. pylori is recognized by the host immune system through human pattern recognition receptors (PRRs), such as toll-like receptors (TLRs), C-type lectin like receptors (CLRs), NOD-like receptors (NLRs), and RIG-I-like receptors (RLRs), which activate downstream signaling pathways. Following bacterial recognition, the first responders of the innate immune system, including neutrophils, macrophages, and dendritic cells, eradicate the bacteria through phagocytic and inflammatory reaction. This review provides current understanding of the interaction between the innate arm of host immunity and H. pylori, by summarizing H. pylori recognition by PRRs, and the subsequent signaling pathway activation in host innate immune cells.

The orphan nuclear receptor NR0B2 could be a novel susceptibility locus associated with microsatellite-stable, APC mutation-negative early-onset colorectal carcinomas with metabolic manifestation.

Colorectal cancer (CRC) is a high incidence cancer and major cause of cancer mortality. Though disease-causing tumor suppressors for major syndromes are well characterized, about 10% of CRC is familial but without mutations in known tumor suppressors. We exhaustively screened 100 polyposis families for APC germline mutations and identified 13, which are APC mutation-negative, microsatellite-stable (MSS), and with undetectable mutation in known tumor suppressors. Whole exome sequencing in three probands uncovered two with germline frameshift NR0B2 mutations, c.293_301delTTGGGTTGGinsAC and c.227delT. Sanger Sequencing identified a third proband with NR0B2 c.157_166delCATCGCACCT frameshift mutation. All three mutations deleted the C-terminus activation/repression domain of NR0B2, thus are loss-of-function mutations. Real-time RT-PCR performed on tumor and matched mucosa of one patient revealed that NR0B2 downstream targets, SMAD3 was derepressed while GLI1 was downregulated in the colonic mucosa compared to healthy controls. Truncated NR0B2 molecule was predicted to have weakened binding with interacting partners SMAD3, GLI1, BCL2, and RXRα, implying perturbation of TGF-ß, Hedgehog, anti-apoptotic and nuclear hormone receptor signaling pathways. Immunostaining also revealed nuclear retention of the most severely truncated NR0B2 molecule compared to the wildtype. Microsatellite and sequencing analysis did not detect loss of wildtype allele in probands' tumors. The patient who acquired somatic KRAS mutation progressed rapidly whist the other two patients manifested with late-onset obesity and diabetes. We propose that haploinsufficiency of NR0B2 is associated with a novel CRC syndrome with metabolic phenotypes.

Bizarre giant cells in human angiosarcoma exhibit chemoresistance and contribute to poor survival outcomes.

Giant cells (GC) are a poorly understood subset of tumor cells that have been increasingly recognized as a potential contributor to tumor heterogeneity and treatment resistance. We aimed to characterize the biological and clinical significance of GC in angiosarcoma, an aggressive rare cancer of endothelial origin. Archival angiosarcoma samples were examined for the presence of GC and compared with clinicopathological as well as NanoString gene expression data. GC were examined in angiosarcoma cell lines MOLAS and ISOHAS using conventional and electron microscopy, single cell whole genome profiling, and other assays. In the cell lines, GC represented a rare population of mitotically active, non-senescent CD31+ cells, and shared similar genomic profiles with regular-sized cells, consistent with a malignant endothelial phenotype. GC remained viable and persisted in culture following exposure to paclitaxel and doxorubicin. In patient samples, GC were present in 24 of 58 (41.4%) cases. GC was correlated with poorer responses to chemotherapy (25.0% vs 73.3%, P = 0.0213) and independently contributed to worse overall survival outcomes (hazard ratio 2.20, 95% confidence interval 1.17-4.15, P = 0.0142). NanoString profiling revealed overexpression of genes, including COL11A1, STC1, and ERO1A, accompanied by upregulation of immune-related metabolic stress and metastasis/matrix remodeling pathways in GC-containing tumors. In conclusion, GC may contribute to chemoresistance and poor prognosis in angiosarcoma.

Predicting Early and Late Readmissions Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Postoperative readmissions not only burden the healthcare system but may also affect clinical outcomes of cancer patients. Despite this, little is known about readmissions after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC), or their impact on survival outcomes. PATIENTS AND METHODS: A single-institution retrospective cohort study of CRS-HIPEC procedures from April 2001 and September 2019 was performed. Early readmission (ERA) was defined as hospitalization within 30 days of discharge post-CRS/HIPEC, while late readmission (LRA) was defined as hospitalization between day 31 and 90 after discharge. Patient demographic, oncological, and perioperative factors were analyzed to identify predictors of readmission, and comparison of survival outcomes was performed. RESULTS: Overall, 342 patients who underwent CRS-HIPEC were included in the study. The incidence of ERA and LRA was 18.5% and 7.4%, respectively. High-grade postoperative complication was the only independent predictor of ERA (HR 3.64, 95% CI 1.47-9.02), while comorbid hypertension (HR 2.71, 95% CI 1.17-6.28) and stoma creation (HR 2.83, 95% CI 1.23-6.50) were independent predictors for LRA. Patients with readmission had significantly worse disease-free survival than patients who had no readmission (NRA) (LRA 1.1 years, ERA 1.2 years, NRA 1.8 years, p = 0.002), and patients with LRA had worse median overall survival (2.1 years) than ERA patients (3.3 years) or patients without readmission (4.4 years) (p < 0.001). CONCLUSIONS: Readmission following CRS-HIPEC is associated with adverse survival outcomes. In particular, LRA may portend worse prognosis than ERA.