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.

Are self-test kits still relevant post COVID-19 pandemic? Qualitative study on working adults' perceptions.

BACKGROUND: Other than self-isolation measures, self-testing is likely to reduce the transmission of COVID-19 and may become a valuable approach in future outbreaks of infectious diseases. This study delves into the perceptions and experiences of working adults who utilised COVID-19 self-test kits in Singapore during the post-pandemic period. METHODS: Employing a qualitative descriptive design, in-depth interviews were conducted with 40 working adults from diverse occupations, with a median age of 35 years. Thematic analysis of transcribed interviews was carried out by two independent qualitative research-trained researchers. RESULTS: Facilitators included personal motivations like safeguarding vulnerable individuals and the convenience of user-friendly self-test kits. Proximal environmental factors encompassed situations involving close contacts and large gatherings, while distal factors involved workplace regulations, public health campaigns, mass media influence, and trust in authorised kits. Nonetheless, barriers include discomfort, cost, uncertainty about proper technique, and evolving testing requirements. Positive test results prompted participants to notify contacts and self-isolate, whereas negative results encouraged a return to normalcy. Participants recommend sustained testing for new variants and vulnerable groups, though some view it as unnecessary due to pandemic normalisation. CONCLUSIONS: Self-testing emerged as a social phenomenon influenced by societal obligations and relationships across multiple levels. Effective communication strategies may play a role in fostering trust and ensuring that working adults sustain the practice of self-testing; therefore, further research is needed to explore their potential impact. Such efforts could be valuable for maintaining vigilance and achieving effective disease control in the post-COVID-19 pandemic landscape.

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.

A Systematic Review on the Effectiveness of Systems-Based Practice Curricula in Health Professions Education.

This systematic review aims to evaluate the effectiveness of systems-based practice (SBP) curricula from the perspective of health professions students and workers. A total of 8468 citations were sourced from six electronic databases and manual searches conducted independently by two researchers, of which 44 studies were eventually included. A meta-analysis using a random effects model and a meta-synthesis using the thematic synthesis approach were conducted. Most studies targeted medical students, residents, and resident physicians from various clinical specialties. Almost half of all studies focused on didactic or knowledge-based interventions to teach SBP. About a third of all studies measured non-self-evaluated knowledge change, clinical abilities, and clinical outcomes. Both meta-analysis and meta-synthesis results revealed positive outcomes of increased knowledge of SBP, increased recognition of SBP as a core competency in one's profession, and increased application of SBP knowledge in one's profession. Meta-synthesis results also revealed negative outcomes at the institutional and teacher/health professions level. This review highlights the importance of SBP education and supports the effectiveness of SBP curricula. There is a need to address the negative outcomes at the institutional and teacher/health professions level. Moreover, future studies could investigate the integration of self-assessment outcomes with comparison to some external standard.

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.

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.

Correlates, motivating factors, and barriers of engaging in regular self-reflection among public health students in higher education-A mixed methods approach.

Despite the wide implementation of self-reflection in higher education, the body of literature has predominantly focused on students from the clinical health sciences rather than public health. The objective of this study was to evaluate the correlates as well as to explore the motivating factors and barriers of engaging in regular self-reflection among public health students in higher education. We used a mixed methods approach (explanatory sequential design), comprising a cross-sectional survey (quantitative phase) followed by in-depth interviews (qualitative phase). We evaluated the association between reflection frequency as well as the perceptions and facilitators in reflection using the modified Breslow-Cox proportional hazards regression model. Prevalence ratio (PR) was generated. Thematic data analysis was carried out to analyse the qualitative data. Quantitative findings revealed being a regular reflector was positively associated with being more motivated to learn when one applied self-reflection (adjusted PR 1.60, 95% CI 1.17-2.20), the perception of being more prepared for a public health career in the future (adjusted PR 1.28, 95% CI 1.02-1.60), as well as being given enough opportunities to carry out self-reflection in the public health modules (adjusted PR 1.24, 95% CI 1.05-1.45). Qualitative findings revealed most students started their self-reflection mainly due to extrinsic factors such as institutional support, social support, teacher influence and environmental influence. Of these, the most prominent was teacher influence, indicating that they are key agents in promoting self-reflection. Students expressed that it would be important to cultivate intrinsic motivation to sustain their practice of self-reflection along the learning journey such as for the development of career-related professional skills. Other than intrinsic motivation, environmental influences were also important to promote continual reflection among students such as the availability of ample opportunities. Prominent barriers to address included external student factors such as the imbalanced power relationship between teacher and student, and internal student factors such as the perception that self-reflection was too cumbersome and time consuming.

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.

Effectiveness of a Cluster Randomized Controlled Trial Involving Community-Based Intervention for Older Adults With Type 2 Diabetes Mellitus in Singapore.

PURPOSE: The purpose of the study was to investigate the effectiveness of a community-based intervention on improving knowledge about diabetes, self-care behaviors, and glycemic control among older adults with type 2 diabetes mellitus (T2DM) in Singapore, a country in Asia with a high prevalence of diabetes. METHODS: A 3-arm cluster randomized controlled trial involving community-dwelling older adults ages 55 to 99 with T2DM was conducted. Intervention group 1 and 2 participants received a 12-session intervention program designed to teach knowledge and practical skills in diabetes self-care with psychological techniques for behavioral change like problem solving, goal setting, and motivational interviewing. In addition, intervention group 2 participants received a glucometer and a supply of accessories each. The control group received routine care from their health care providers. RESULTS: Compared to the control group, intervention group 2 reported an increase in medication adherence and self-monitoring of blood glucose (SMBG) at 3-month follow-up and increased knowledge about diabetes and self-care behavior in general diet control at 6-month follow-up. CONCLUSIONS: The community-based intervention should be extended to more older adults with T2DM in the community. Glucometers and accessories could be provided at subsidized rates or be made free contingent on older adults' income status to overcome the barrier of performing SMBG.

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.

Exploring the Perspective of Diabetes, Diabetes Self-Management, and Quality of Life Among Older Adults With Type 2 Diabetes: A Qualitative Study Before and During the COVID-19 Pandemic.

PURPOSE: The purpose of the study was to explore the perspective and impact of diabetes, diabetes self-management, and quality of life (QoL) among older adults with Type 2 diabetes (T2DM) before and during the COVID-19 pandemic to better inform T2DM self-management interventions. METHODS: A qualitative descriptive approach with focus group discussions (n = 5 sessions with 5-6 older adults per session) and in-depth interviews (n = 15) was conducted with community-dwelling older adults with T2DM. RESULTS: Five themes emerged. The definition of diabetes carries negative connotations, QoL is defined in terms of biopsychosocial health, diabetes self-management refers to the ability to adhere to medical advice and lifestyle changes, the QoL of older adults is differentially affected by COVID-19 measures, and important aspects of diabetes self-management activities are impacted by COVID-19 measures. CONCLUSIONS: Understanding older adults' perspectives on diabetes, diabetes self-management, and QoL provided insights into the facilitators and barriers to diabetes self-management practices before and during the COVID-19 pandemic. Findings inform the need for greater bottom-up initiatives and the need for a multipronged approach that considers the intra- and interpersonal and current policy factors to encourage diabetes self-management behaviors, especially during the COVID-19 era.

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.

Sociodemographic characteristics associated with self-care and quality of life among community-dwelling older adults with type 2 diabetes.

AIMS: To assess how well community-dwelling older adults in Singapore were coping with their diabetes, and the sociodemographic characteristics that were associated with their level of coping. METHODS: This was a cross-sectional study involving 257 older adults. Multiple regression was used to assess the associations between various sociodemographic characteristics and coping measures of present quality of life and level of self-care. RESULTS: Older adults mainly sought care in the primary care setting. They were not coping well given their mean scores for diabetes-dependent quality of life and the self-care index were -3.57 and 3.55 respectively. Compared to those with post-secondary education, individuals who had no formal (adjusted B -0.92, p 0.003), primary level (adjusted B -0.76, p < 0.001) and secondary level (adjusted B -0.50, p < 0.02) education reported lower present quality of life. Those with prior lowest skill level occupations were less likely to consume a healthy diet per week than those with prior highest skill level occupations (adjusted B -1.48, p 0.004). CONCLUSIONS: There should be provision of diabetes self-care interventions targeting older adults in Singapore especially for those with lower education and work skill levels. As the first line of contacts, primary care providers should advocate for diabetes self-care and develop community-based interventions for these priority groups.

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.