A comparative analysis of Charlson's weighted index of comorbidity and perforated peptic ulcer scores in predicting postoperative mortality and high comprehensive complication index.

BACKGROUND: Limited data exists on Charlson's weighted index of comorbidity (WIC) predictability for postoperative outcomes following perforated peptic ulcer (PPU) surgery. This study assesses the utility of WIC and other predictive scores in forecasting both postoperative mortality and morbidity in PPU. MATERIALS & METHODS: Patients with PPUs operated between 2018 and 2021 in a Malaysian tertiary referral center were included. Clinical data were retrospectively analyzed for association with mortality and morbidity measured with the Comprehensive Complication Index (CCI). Predictability of WIC and other predictors were examined using area under receiver-operator characteristic (ROC) curve (AUC). RESULTS: Among 110 patients included, 18 died (16.4%) and 36 (32.7%) had significant morbidity postoperatively (High CCI, ≥26.2). Both mortality and high CCI were associated with age >65 years, female sex, comorbidities (diabetes mellitus, hypertension, and renal disease), and American Society of Anesthesiologist score >2. Most patients who died had renal dysfunction, metabolic acidosis, lactate >2 mmol/L upon presentation preoperatively. While surgery >24 h after presentation correlated with mortality and high CCI, the benefit of earlier surgery <6 h or <12 h was not demonstrated. WIC (AUC, 0.89; 95% CI, 0.81-0.99) showed similar predictability to Peptic Ulcer Perforation (PULP) (AUC, 0.97; 95% CI, 0.93-1.00) for mortality. PULP effectively predicted high CCI (AUC, 0.83; 95% CI, 0.73-0.93; p < 0.001). CONCLUSION: WIC is valuable in predicting mortality, highlighting the importance of comorbidity in risk assessment. PULP score was effective in predicting both mortality and high CCI. Early identification of patients with high perioperative risk will facilitate patients' triage for escalated care, leading to a better outcome.

CXCL9/10-engineered dendritic cells promote T cell activation and enhance immune checkpoint blockade for lung cancer.

Immune checkpoint blockade (ICB) with PD-1/PD-L1 inhibition has revolutionized the treatment of non-small cell lung cancer (NSCLC). Durable responses, however, are observed only in a subpopulation of patients. Defective antigen presentation and an immunosuppressive tumor microenvironment (TME) can lead to deficient T cell recruitment and ICB resistance. We evaluate intratumoral (IT) vaccination with CXCL9- and CXCL10-engineered dendritic cells (CXCL9/10-DC) as a strategy to overcome resistance. IT CXCL9/10-DC leads to enhanced T cell infiltration and activation in the TME and tumor inhibition in murine NSCLC models. The antitumor efficacy of IT CXCL9/10-DC is dependent on CD4+ and CD8+ T cells, as well as CXCR3-dependent T cell trafficking from the lymph node. IT CXCL9/10-DC, in combination with ICB, overcomes resistance and establishes systemic tumor-specific immunity in murine models. These studies provide a mechanistic understanding of CXCL9/10-DC-mediated host immune activation and support clinical translation of IT CXCL9/10-DC to augment ICB efficacy in NSCLC.

CCL21-DC in situ vaccination in murine NSCLC overcomes resistance to immunotherapy and generates systemic tumor-specific immunity.

BACKGROUND: Despite recent advances in immunotherapy, many patients with non-small cell lung cancer (NSCLC) do not respond to immune checkpoint inhibitors (ICI). Resistance to ICI may be driven by suboptimal priming of antitumor T lymphocytes due to poor antigen presentation as well as their exclusion and impairment by the immunosuppressive tumor microenvironment (TME). In a recent phase I trial in patients with NSCLC, in situ vaccination (ISV) with dendritic cells engineered to secrete CCL21 (CCL21-DC), a chemokine that facilitates the recruitment of T cells and DC, promoted T lymphocyte tumor infiltration and PD-L1 upregulation. METHODS: Murine models of NSCLC with distinct driver mutations (KrasG12D/P53+/-/Lkb1-/- (KPL); KrasG12D/P53+/- (KP); and KrasG12D (K)) and varying tumor mutational burden were used to evaluate the efficacy of combination therapy with CCL21-DC ISV plus ICI. Comprehensive analyses of longitudinal preclinical samples by flow cytometry, single cell RNA-sequencing (scRNA-seq) and whole-exome sequencing were performed to assess mechanisms of combination therapy. RESULTS: ISV with CCL21-DC sensitized immune-resistant murine NSCLCs to ICI and led to the establishment of tumor-specific immune memory. Immunophenotyping revealed that CCL21-DC obliterated tumor-promoting neutrophils, promoted sustained infiltration of CD8 cytolytic and CD4 Th1 lymphocytes and enriched progenitor T cells in the TME. Addition of ICI to CCL21-DC further enhanced the expansion and effector function of T cells both locally and systemically. Longitudinal evaluation of tumor mutation profiles revealed that CCL21-DC plus ICI induced immunoediting of tumor subclones, consistent with the broadening of tumor-specific T cell responses. CONCLUSIONS: CCL21-DC ISV synergizes with anti-PD-1 to eradicate murine NSCLC. Our data support the clinical application of CCL21-DC ISV in combination with checkpoint inhibition for patients with NSCLC.

Single-Cell Characterization of Pulmonary Nodules Implicates Suppression of Immunosurveillance across Early Stages of Lung Adenocarcinoma.

A greater understanding of molecular, cellular, and immunological changes during the early stages of lung adenocarcinoma development could improve diagnostic and therapeutic approaches in patients with pulmonary nodules at risk for lung cancer. To elucidate the immunopathogenesis of early lung tumorigenesis, we evaluated surgically resected pulmonary nodules representing the spectrum of early lung adenocarcinoma as well as associated normal lung tissues using single-cell RNA sequencing and validated the results by flow cytometry and multiplex immunofluorescence (MIF). Single-cell transcriptomics revealed a significant decrease in gene expression associated with cytolytic activities of tumor-infiltrating natural killer and natural killer T cells. This was accompanied by a reduction in effector T cells and an increase of CD4+ regulatory T cells (Treg) in subsolid nodules. An independent set of resected pulmonary nodules consisting of both adenocarcinomas and associated premalignant lesions corroborated the early increment of Tregs in premalignant lesions compared with the associated normal lung tissues by MIF. Gene expression analysis indicated that cancer-associated alveolar type 2 cells and fibroblasts may contribute to the deregulation of the extracellular matrix, potentially affecting immune infiltration in subsolid nodules through ligand-receptor interactions. These findings suggest that there is a suppression of immune surveillance across the spectrum of early-stage lung adenocarcinoma. SIGNIFICANCE: Analysis of a spectrum of subsolid pulmonary nodules by single-cell RNA sequencing provides insights into the immune regulation and cell-cell interactions in the tumor microenvironment during early lung tumor development.

Multi-organ landscape of therapy-resistant melanoma.

Metastasis and failure of present-day therapies represent the most common causes of mortality in patients with cutaneous melanoma. To identify the underlying genetic and transcriptomic landscapes, in this study we analyzed multi-organ metastases and tumor-adjacent tissues from 11 rapid autopsies after treatment with MAPK inhibitor (MAPKi) and/or immune checkpoint blockade (ICB) and death due to acquired resistance. Either treatment elicits shared genetic alterations that suggest immune-evasive, cross-therapy resistance mechanisms. Large, non-clustered deletions, inversions and inter-chromosomal translocations dominate rearrangements. Analyzing data from separate melanoma cohorts including 345 therapy-naive patients and 35 patients with patient-matched pre-treatment and post-acquired resistance tumor samples, we performed cross-cohort analyses to identify MAPKi and ICB as respective contributors to gene amplifications and deletions enriched in autopsy versus therapy-naive tumors. In the autopsy cohort, private/late mutations and structural variants display shifted mutational and rearrangement signatures, with MAPKi specifically selecting for signatures of defective homologous-recombination, mismatch and base-excision repair. Transcriptomic signatures and crosstalks with tumor-adjacent macroenvironments nominated organ-specific adaptive pathways. An immune-desert, CD8+-macrophage-biased archetype, T-cell exhaustion and type-2 immunity characterized the immune contexture. This multi-organ analysis of therapy-resistant melanoma presents preliminary insights with potential to improve therapeutic strategies.

Tumor heterogeneity in VHL drives metastasis in clear cell renal cell carcinoma.

Loss of function of the von Hippel-Lindau (VHL) tumor suppressor gene is a hallmark of clear cell renal cell carcinoma (ccRCC). The importance of heterogeneity in the loss of this tumor suppressor has been under reported. To study the impact of intratumoral VHL heterogeneity observed in human ccRCC, we engineered VHL gene deletion in four RCC models, including a new primary tumor cell line derived from an aggressive metastatic case. The VHL gene-deleted (VHL-KO) cells underwent epithelial-to-mesenchymal transition (EMT) and exhibited increased motility but diminished proliferation and tumorigenicity compared to the parental VHL-expressing (VHL+) cells. Renal tumors with either VHL+ or VHL-KO cells alone exhibit minimal metastatic potential. Combined tumors displayed rampant lung metastases, highlighting a novel cooperative metastatic mechanism. The poorly proliferative VHL-KO cells stimulated the proliferation, EMT, and motility of neighboring VHL+ cells. Periostin (POSTN), a soluble protein overexpressed and secreted by VHL non-expressing (VHL-) cells, promoted metastasis by enhancing the motility of VHL-WT cells and facilitating tumor cell vascular escape. Genetic deletion or antibody blockade of POSTN dramatically suppressed lung metastases in our preclinical models. This work supports a new strategy to halt the progression of ccRCC by disrupting the critical metastatic crosstalk between heterogeneous cell populations within a tumor.

Impact of an Interactive Health Corner Using the Culinary Education Approach in Promoting Long-Term Dietary Changes among Patients Who Seek Public Primary Care Services.

An unhealthy diet is a major risk factor for chronic diseases. Although nutrition education and cooking demonstrations have resulted in favourable dietary changes, it is unclear whether this is sustainable for longer periods. This study aims to evaluate the long-term impact of a nutrition-led cooking intervention using the culinary education approach on dietary patterns based on My Healthy Plate (MHP). This was a quasi-experimental study involving patients who sought public primary care services in two polyclinics (mean age 59.3 years old). A self-administered survey was done at baseline, 6 months, and 1 year for both the intervention and the comparison groups. Participants in the intervention group were exposed to the health corner, which provided nutrition education and cooking demonstrations using the culinary education approach. A total of 216 participants completed the study at 1 year with a follow-up rate of 86%. Adjusted risk ratios (aRR) were obtained from negative binomial regression. Compared with the comparison group, participants in the intervention group were more likely to report adhering to the requirements of MHP at 6 months (aRR 1.83, 95% CI 1.12-2.99) and 1 year (aRR 1.54, 95% CI 1.10-2.16). Participants in the intervention group were less likely to add salt or sauces to food at 6 months (aRR 0.29, 95% CI 0.12-0.75) and 1 year (aRR 0.21, 95% CI 0.07-0.61) and more likely to remove fat when eating meat at 1 year (aRR 0.30, 95% CI 0.13-0.67) than the comparison group. The interventions at the health corner had a positive impact in helping patients achieve MHP recommendations, not adding salt and sauces to their food, and removing animal fat before eating. There is potential for expanding this initiative to improve healthy eating practices in other polyclinics.

Esophageal squamous cell carcinoma and adenocarcinoma in Malaysia - Pooled data from upper gastrointestinal centers in a multiethnic Asian population.

BACKGROUND: Esophageal cancer is the sixth leading cause of cancer death worldwide with considerable geographical histological variation There is a paucity of data in esophageal cancer in demographics, histology, and survival among the multi-ethnic Malaysian population. This paper is a review of esophageal cancer epidemiology and survival among esophageal cancer patients from data collected by the Malaysian Upper Gastrointestinal Surgical Society. METHODS: This is a multicenter retrospective observational study of esophageal cancer patients from six upper gastrointestinal surgical centers in Malaysia between 2005 and 2019. Patient characteristics, histological type and stage were compared and survival analyzed. RESULTS: There were 820 patients with esophageal cancer included, where 442 (53.9 %) cases had squamous cell carcinoma (SCC) and 378 (46.1 %) had adenocarcinomas (AC). Malays were the predominant ethnicity with AC (66.7 %) while Indians were the ethnic majority (74.6 %) with SCC. Majority of patients (56.8 %) presented as stage IV disease. Overall, the 1-, 3-, and 5-years' survival were 35.8 %, 13.8 % and 11.0 %, respectively. Surgical resection with curative intent yielded the best 5-year survival (29.4 %). Intervention in stage IV AC yielded superior survival when compared to SCC (median survival, 7.9 months vs 4.8 months; p, 0.018) Our series demonstrated an increase in AC to SCC over the last 15 years. CONCLUSIONS: There was an ethnic preponderance seen between different histology in this region, not previously discussed. An increase in AC was observed over the last 15 years. Late diagnosis seen in most patients imparts poor prognosis as curative surgery affords the best outcome.

Effect of protein supplementation on fat-free mass among upper gastrointestinal surgical patients: A review of compliance.

BACKGROUND & AIMS: There is minimal data regarding the long-term effects of targeted daily protein intake and its role in nutritional restoration. This study aims to evaluate the effect of protein supplementation among upper gastrointestinal (GI) surgical patients, reviewing the effect on muscle mass and hand grip strength. METHODS: The records of 223 upper GI surgical patients from September 2017 to June 2021 were retrospectively reviewed. Protein intake was categorised based on average daily protein intake (0.8g-1.2 g/kg/day vs. more than 1.2 g/kg/day), depending on compliance to the institution target of 1.2g-1.5 g/kg/day. Hand grip strength and body composition including weight, Body Mass Index (BMI), Fat-Free Mass (FFM), and Fat Mass (FM) were measured. Paired t-tests and independent t-tests were used to analyse the effects of different levels of protein intake on hand grip strength and body composition. RESULTS: Among the 223 patients included, 84 subjects had benign upper GI pathology and 139 subjects had malignant upper GI pathology, with mean follow-up duration of 52.3 (SD,42.10) weeks and 39.3 (SD,35.11) respectively. Patients with malignant pathology who consumed more than 1.2 g/kg/day of protein had increased hand-grip strength and preservation of FFM, while those who consumed 0.8g-1.2 g/kg/day of protein had deteriorating hand grip strength and significant FFM reduction (p = 0.004). Patients with benign pathology showed significant improvement in hand-grip strength (p < 0.001) and increase in FFM (p < 0.001) with higher protein intake. CONCLUSION: Protein supplementation is paramount in nutrition recovery and muscle mass restoration among upper gastrointestinal surgical patients. Protein intake of at least 1.2 g/kg/day was especially important among patients with malignancy to preserve muscle mass and strength.

Post Laparoscopy Pain Reduction Project I (POLYPREP I): intraperitoneal normal saline instillation-a randomised controlled trial.

OBJECTIVES: To evaluate the effect of intraperitoneal normal saline instillation (INSI) of 15 mL/kg body weight on postoperative pain after a gynaecological laparoscopic procedure. DESIGN: Randomised controlled trial. SETTING: University Hospital in Kuala Lumpur, Malaysia. PARTICIPANTS: Patients aged 18-55 years, with American Society of Anaesthesiologists (ASA) classification I-II, scheduled for an elective gynaecological laparoscopic procedure for a benign cause. INTERVENTION: The patients were randomly allocated to two groups. In the intervention group, 15 mL/kg body weight of normal saline was instilled intraperitoneally, while the control group received the conventional combination of open laparoscopic trocar valves with gentle abdominal pressure to remove the retained carbon dioxide. MAIN OUTCOME MEASURES: The outcomes measured were the mean pain scores for shoulder and upper abdominal pain at 24 h, 48 h, and 72 h postoperatively. RESULTS: A total of 68 women completed the study, including 34 women in each group. There was no difference in the shoulder pain score at 24 h, 48 h, and 72 h postoperatively. However, a significant improvement in the upper abdominal pain score after 48 h (95% confidence interval [CI] 0.34-1.52, p = 0.019) and 72 h (95% CI 0.19-0.26, p = 0.007) postoperatively were observed. CONCLUSIONS: INSI of 15 mL/kg body weight does not lower postoperative shoulder pain compared to no fluid instillation. A modest pain score improvement was observed in the upper abdominal area at 48 h and 72 h after surgery. An INSI of up to 30 mL/kg body weight may be required to eliminate shoulder pain. Care must be taken before administering a higher amount of INSI, considering the potential risk of peritoneal adhesions. Clinical registration ISRCTN Identifier: 87898051 (Date: 26 June 2019) https://doi.org/10.1186/ISRCTN87898051.

Response and recurrence correlates in individuals treated with neoadjuvant anti-PD-1 therapy for resectable oral cavity squamous cell carcinoma.

Neoadjuvant PD-1 blockade may be efficacious in some individuals with high-risk, resectable oral cavity head and neck cancer. To explore correlates of response patterns to neoadjuvant nivolumab treatment and post-surgical recurrences, we analyzed longitudinal tumor and blood samples in a cohort of 12 individuals displaying 33% responsiveness. Pretreatment tumor-based detection of FLT4 mutations and PTEN signature enrichment favors response, and high tumor mutational burden improves recurrence-free survival. In contrast, preexisting and/or acquired mutations (in CDKN2A, YAP1, or JAK2) correlate with innate resistance and/or tumor recurrence. Immunologically, tumor response after therapy entails T cell receptor repertoire diversification in peripheral blood and intratumoral expansion of preexisting T cell clones. A high ratio of regulatory T to T helper 17 cells in pretreatment blood predicts low T cell receptor repertoire diversity in pretreatment blood, a low cytolytic T cell signature in pretreatment tumors, and innate resistance. Our study provides a molecular framework to advance neoadjuvant anti-PD-1 therapy for individuals with resectable head and neck cancer.

Genotoxic Treatment Enhances Immune Response in a Genetic Model of Lung Cancer.

Recent advances in immunotherapy have reshaped the clinical management of lung cancer, and immune checkpoint inhibitors (ICIs) are now first-line treatment for advanced lung cancer. However, the majority of patients do not respond to ICIs as single agents, and many develop resistance after initial responses. Therefore, there is urgent need to improve the current ICI strategies. Murine models currently available for pre-clinical studies have serious limitations for evaluating novel immunotherapies. GEMMs are reliable and predictable models driven by oncogenic mutations mirroring those found in cancer patients. However, they lack the mutational burden of human cancers and thus do not elicit proper immune surveillance. Carcinogen-induced models are characterized by mutational burden that more closely resembles human cancer, but they often require extremely long experimental times with inconsistent results. Here, we present a hybrid model in which genetically engineered mice are exposed to the carcinogen N-Methyl-N-Nitrosourea (MNU) to increase tumor mutational burden (TMB), induce early-stage immune responses, and enhance susceptibility to ICIs. We anticipate that this model will be useful for pre-clinical evaluation of novel immunotherapies.

Pinch-off syndrome from a chemoport catheter successfully managed with endovascular retrieval.

INTRODUCTION AND IMPORTANCE: A totally implantable venous access device (TIVAD), also referred to as 'chemoport', is frequently used for oncology patients. Chemoport insertion via the subclavian vein access may compress the catheter between the first rib and the clavicle, resulting in pinch-off syndrome (POS). The sequela includes catheter transection and subsequent embolization. It is a rare complication with incidence reported to be 1.1-5.0% and can lead to a devastating outcomes. CASE PRESENTATION: 50-year-old male had his chemoport inserted for adjuvant chemotherapy 3 years ago. During the removal, remaining half of the distal catheter was not found. There was no difficulties during the removal. Chest xray revealed that the fractured catheter had embolized to the right ventricle. Further history taking, he did experienced occasional palpitation and chest discomfort for the past six months. Electrocardiogram and cardiac enzymes were normal. Urgent removal of the fractured catheter via the percutaneous endovascular approach, under fluoroscopic guidance by an experience interventional radiologist was done. The procedure was successful without any complication. Patient made an uneventful recovery. He was discharged the following day, and was well during his 3rd month follow up. CONCLUSION: Early detection and preventive measures can be done to prevent pinch-off syndrome. Unrecognized POS can result in fatal complications such as cardiac arrhythmia and septic embolization. Retrieval via the percutaneous endovascular approach provide excellent outcome in the case of embolized fractured catheter.

Inhibition of Granulocytic Myeloid-Derived Suppressor Cells Overcomes Resistance to Immune Checkpoint Inhibition in LKB1-Deficient Non-Small Cell Lung Cancer.

LKB1 inactivating mutations are commonly observed in patients with KRAS-mutant non-small cell lung cancer (NSCLC). Although treatment of NSCLC with immune checkpoint inhibitors (ICI) has resulted in improved overall survival in a subset of patients, studies have revealed that co-occurring KRAS/LKB1 mutations drive primary resistance to ICIs in NSCLC. Effective therapeutic options that overcome ICI resistance in LKB1-mutant NSCLC are limited. Here, we report that loss of LKB1 results in increased secretion of the C-X-C motif (CXC) chemokines with an NH2-terminal Glu-Leu-Arg (ELR) motif in premalignant and cancerous cells, as well as in genetically engineered murine models (GEMM) of NSCLC. Heightened levels of ELR+ CXC chemokines in LKB1-deficient murine models of NSCLC positively correlated with increased abundance of granulocytic myeloid-derived suppressor cells (G-MDSC) locally within the tumor microenvironment and systemically in peripheral blood and spleen. Depletion of G-MDSCs with antibody or functional inhibition via all-trans-retinoic acid (ATRA) led to enhanced antitumor T-cell responses and sensitized LKB1-deficent murine tumors to PD-1 blockade. Combination therapy with anti-PD-1 and ATRA improved local and systemic T-cell proliferation and generated tumor-specific immunity. Our findings implicate ELR+ CXC chemokine-mediated enrichment of G-MDSCs as a potential mediator of immunosuppression in LKB1-deficient NSCLC and provide a rationale for using ATRA in combination with anti-PD-1 therapy in patients with LKB1-deficient NSCLC refractory to ICIs. SIGNIFICANCE: These findings show that accumulation of myeloid-derived suppressor cells in LKB1-deficient non-small cell lung cancer can be overcome via treatment with all-trans-retinoic acid, sensitizing tumors to immunotherapy.

Novel Kras-mutant murine models of non-small cell lung cancer possessing co-occurring oncogenic mutations and increased tumor mutational burden.

Conditional genetically engineered mouse models (GEMMs) of non-small cell lung cancer (NSCLC) harbor common oncogenic driver mutations of the disease, but in contrast to human NSCLC these models possess low tumor mutational burden (TMB). As a result, these models often lack tumor antigens that can elicit host adaptive immune responses, which limits their utility in immunotherapy studies. Here, we establish Kras-mutant murine models of NSCLC bearing the common driver mutations associated with the disease and increased TMB, by in vitro exposure of cell lines derived from GEMMs of NSCLC [KrasG12D (K), KrasG12DTp53-/-(KP), KrasG12DTp53+/-Lkb1-/- (KPL)] to the alkylating agent N-methyl-N-nitrosourea (MNU). Increasing the TMB enhanced host anti-tumor T cell responses and improved anti-PD-1 efficacy in syngeneic models across all genetic backgrounds. However, limited anti-PD-1 efficacy was observed in the KPL cell lines with increased TMB, which possessed a distinct immunosuppressed tumor microenvironment (TME) primarily composed of granulocytic myeloid-derived suppressor cells (G-MDSCs). This KPL phenotype is consistent with findings in human KRAS-mutant NSCLC where LKB1 loss is a driver of primary resistance to PD-1 blockade. In summary, these novel Kras-mutant NSCLC murine models with known driver mutations and increased TMB have distinct TMEs and recapitulate the therapeutic vulnerabilities of human NSCLC. We anticipate that these immunogenic models will facilitate the development of innovative immunotherapies in NSCLC.

Lung Cancer and Immunity Markers.

An in-depth understanding of lung cancer biology and mechanisms of tumor progression has facilitated significant advances in the treatment of lung cancer. There remains a pressing need for the development of innovative approaches to detect and intercept lung cancer at its earliest stage of development. Recent advances in genomics, computational biology, and innovative technologies offer unique opportunities to identify the immune landscape in the tumor microenvironment associated with early-stage lung carcinogenesis, and provide further insight in the mechanism of lung cancer evolution. This review will highlight the concept of immunoediting and focus on recent studies assessing immune changes and biomarkers in pulmonary premalignancy and early-stage non-small cell lung cancer. A protumor immune response hallmarked by an increase in checkpoint inhibition and inhibitory immune cells and a simultaneous reduction in antitumor immune response have been correlated with tumor progression. The potential systemic biomarkers associated with early lung cancer will be highlighted along with current clinical efforts for lung cancer interception. Research focusing on the development of novel strategies for cancer interception prior to the progression to advanced stages will potentially lead to a paradigm shift in the treatment of lung cancer and have a major impact on clinical outcomes.See all articles in this CEBP Focus section, "NCI Early Detection Research Network: Making Cancer Detection Possible."

Safety Evaluation of Human Cord-Lining Epithelial Stem Cells Transplantation for Liver Regeneration in a Porcine Model.

We investigated the safety of using umbilical cord-lining stem cells for liver regeneration and tested a novel method for stem cell delivery. Stem cells are known by their ability to repair damaged tissues and have the potential to be used as regenerative therapies. The umbilical cord's outer lining membrane is known to be a promising source of multipotent stem cells and can be cultivated in an epithelial cell growth medium to produce cell populations which possess the properties of both epithelial cells and embryonic stem cells-termed cord-lining epithelial cells (CLEC). Hepatocytes are epithelial cells of the liver and their proliferation upon injury is the main mechanism in restoring the liver. Earlier studies conducted showed CLEC can be differentiated into functioning hepatocyte-like cells (HLC) and can survive in immunologically competent specimens. In this study, we chose a porcine model to investigate CLEC as a treatment modality for liver failure. We selected 16 immune competent Yorkshire-Dutch Landrace pigs, with a mean weight of 40.5 kg, for this study. We performed a 50% hepatectomy to simulate the liver insufficient disease model. After the surgery, four pigs were transplanted with a saline scaffold while seven pigs were transplanted with a HLC scaffold. Five pigs died on the surgical table and were omitted from the study analysis. This study addressed the safety of transplanting human CLEC in a large animal model. The transplant interfaces were evaluated and no signs of cellular rejection were observed in both groups.

Health education and communication needs among primary care patients with prediabetes in Singapore: A mixed methods approach.

AIMS: To assess factors associated with ever receiving prediabetes education, and to explore the health education and communication needs among primary care patients with prediabetes in Singapore. METHODS: A mixed methods study, consisting of a cross-sectional survey involving 433 patients with prediabetes aged 21-79, and in-depth interviews (IDIs) with 48. Multivariable regression was used to analyse the survey results, while thematic analysis was used to analyse the IDIs. RESULTS: The prevalence of ever receiving prediabetes education was 26.6%. This was positively associated with school education, impaired glucose tolerance, number of co-morbidities, having family or peer with diabetes, having support to reduce diabetes risk, confidence to self-manage prediabetes, and negatively associated with age. A common reason among those not receiving such education was not being referred by doctors. The preferred content of health communication messages were to focus on risk and prevention of diabetes, health and family, and to avoid the term 'prediabetes' in messages. The top 2 preferred education components were healthy eating and physical activity, and the most desired setting was the community centre. CONCLUSIONS: More efforts are needed to increase the take-up rate of prediabetes education. Polyclinic healthcare professionals could provide preliminary advice, and subsequently refer patients to community-based programmes or resources.

High-intensity sequencing reveals the sources of plasma circulating cell-free DNA variants.

Accurate identification of tumor-derived somatic variants in plasma circulating cell-free DNA (cfDNA) requires understanding of the various biological compartments contributing to the cfDNA pool. We sought to define the technical feasibility of a high-intensity sequencing assay of cfDNA and matched white blood cell DNA covering a large genomic region (508 genes; 2 megabases; >60,000× raw depth) in a prospective study of 124 patients with metastatic cancer, with contemporaneous matched tumor tissue biopsies, and 47 controls without cancer. The assay displayed high sensitivity and specificity, allowing for de novo detection of tumor-derived mutations and inference of tumor mutational burden, microsatellite instability, mutational signatures and sources of somatic mutations identified in cfDNA. The vast majority of cfDNA mutations (81.6% in controls and 53.2% in patients with cancer) had features consistent with clonal hematopoiesis. This cfDNA sequencing approach revealed that clonal hematopoiesis constitutes a pervasive biological phenomenon, emphasizing the importance of matched cfDNA-white blood cell sequencing for accurate variant interpretation.

Facilitators and barriers of human papillomavirus vaccine uptake in young females 18-26 years old in Singapore: A qualitative study.

BACKGROUND: Around 70% of cervical cancers are caused by Types 16 and 18 of human papillomavirus (HPV). Vaccines against HPV have been shown to be safe and effective in preventing HPV and cervical cancer. OBJECTIVE: To explore the facilitators and barriers of HPV vaccination in young females aged 18-26 years in Singapore, and to describe their recommended strategies to improve the uptake of HPV vaccination. DESIGN: Qualitative, descriptive design guided by the socio-ecological model. PARTICIPANTS: Young women studying in National University of Singapore (NUS), aged 18-26 (N = 40). Purposive sampling was used to recruit participants from various socio-economic levels and faculties, both vaccinated against HPV and unvaccinated. METHODS: In-depth interviews (IDIs) and focus group discussions (FGDs) were conducted with the participants. IDIs and FGDs were transcribed and coded using NVIVO software. Thematic data analysis was performed using an inductive approach. RESULTS: Barriers to HPV vaccination included lack of awareness, lack of perceived risk for cervical cancer, cost, lack of parental support, inconvenience of getting the vaccination, stigma associated with connection with sexual activity, and concern regarding safety. Facilitators include parental encouragement, protection of one's health, lack of logistical barriers, and perceived safety and efficacy of the vaccine. Participants recommended increasing awareness of HPV vaccination and cervical cancer, reducing cost of vaccination and making the vaccine compulsory to increase vaccine uptake. CONCLUSION: Barriers and facilitators exist at different levels to influence vaccine uptake. Public education on cervical cancer and the vaccine should be stepped up to increase public awareness. A school-based national vaccination programme was proposed by the target group to increase the rate of uptake of HPV vaccination in Singapore.