Response to Nivolumab and Ipilimumab in Microsatellite Instability-High (MSI-H) Cervical Carcinoma with Acquired Resistance to Pembrolizumab: A Case Report and Literature Review.

As the use of immune checkpoint inhibitors (ICIs) in treating a variety of cancer types has increased in recent years, so too have the number of reports on patients acquiring resistance to these therapies. Overcoming acquired resistance to immunotherapy remains an important need in the field of immuno-oncology. Herein, we present a case that suggests sequential administration of combination immunotherapy may be beneficial to advanced cervical cancer patients exhibiting acquired resistance to mono-immunotherapy. The patient's tumor is microsatellite instability-high (MSI-H), which is an important biomarker in predicting ICI response. Results from recent interim prospective studies using combination immunotherapy (eg, nivolumab and ipilimumab) with anti-PD-1 plus anti-CTLA-4 inhibitor following progression on anti-PD-1 inhibitors (eg, nivolumab) have shown anti-tumor activity in patients with advanced melanoma and metastatic urothelial carcinoma. We also introduce retrospective studies and case reports/case series of dual checkpoint inhibition with anti-PD-1 inhibitor plus anti-CTLA-4 inhibitor after progression on prior anti-PD/PD-L1 monotherapy. To date, there has been no prospective study on the use of combined anti-PD-1 and anti-CTLA-4 therapy at the time of progression on anti-PD-1 therapy in patients with MSI-H tumors or advanced cervical cancer. In this report, we provide evidence that supports future investigations into such treatments.

Association between Second-hand Smoke Exposure and Urinary NNAL Level in Korean Adolescents.

BACKGROUND: The 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) is a metabolite of tobacco-specific lung carcinogen that can be found in both smokers and non-smokers. Particularly, NNAL levels of children with a history of exposure to second-hand smoke (SHS) are higher than those of adults. Thus, we aimed to investigate the association between SHS exposure and urine NNAL levels in Korean adolescents. METHODS: This cross-sectional study used data from the Korea National Health and Nutrition Examination Survey VII. Overall, 648 never-smoking adolescents (425 boys and 223 girls) aged 12 to 18 were included in this study. Logistic regression analyses identified the relationship between SHS exposure and elevated urine NNAL levels. RESULTS: The mean urine NNAL levels of the no exposure and exposure group in boys were 1.39 and 2.26 ng/mL, respectively, whereas they were 1.01 and 2.45 ng/mL in girls, respectively (P < 0.001). Among the adolescents exposed to SHS, the confounder-adjusted odds ratio (95% confidence intervals) for elevated urine NNAL levels according to exposure area as overall, home, and public area were 2.68 (1.58-4.53), 31.02 (9.46-101.74), and 1.89 (1.12-3.17) in boys; and 6.50 (3.22-13.11), 20.09 (7.08-57.04), and 3.94 (1.98-7.77) in girls, respectively. CONCLUSION: SHS exposure was significantly associated with elevated urine NNAL levels in Korean adolescents, particularly in female adolescents and in those with home exposure. These findings remind us of the need to protect adolescents from SHS.

Dental trauma trends in emergency care:a comparative analysis before, during, and after COVID-19.

Objectives: This analysis details the characteristics of dental trauma in South Korea during the coronavirus disease 2019 (COVID-19) (DC) pandemic and compares them in patients before and after COVID-19 (BC and AC, respectively). Materials and Methods: Data were collected from medical records of patients who visited Seoul National University Bundang Hospital's Emergency Dental Care Center during three 12-month periods: BC, DC, and AC (BC from March 1, 2019 to February 29, 2020; DC from March 1, 2020 to February 28, 2021; AC from March 1, 2022 to February 28, 2023). A retrospective review was conducted to investigate patient age, sex, time of visit, cause, and diagnosis. The study included 1,544 patients: 660 BC, 374 DC, and 510 AC. Results: Significant difference in age and sex was not observed among the three periods; 1-9 years of age was the largest group (38.3% in BC, 29.6% in DC, and 27.8% in AC), and the percentage of male patients was greater than of female patients (male proportion as 63.5% in BC, 67.4% in DC, and 64.9% in AC). The number of patients generally peaked at a Saturday night in spring (for BC: May, Saturday, 18:00-19:59; for DC: March, Saturday, 18:00-19:59; for AC: April as the second most (October as the most peaked), Saturday, 20:00-21:59). The primary etiology of the dental trauma was identical in the three periods: falls, followed by sports. The most frequent diagnosis was laceration, followed by tooth avulsion and jaw fracture. Conclusion: Significant differences were not found between the characteristics and patterns of dental trauma in the BC, DC, and AC periods. However, due to the pandemic and social distancing, activities decreased and associated dental trauma-related incidents declined.

Papillary thyroid cancer immune phenotypes via tumor-infiltrating lymphocyte spatial analysis.

Standard-of-care treatment options provide an excellent prognosis for papillary thyroid cancers (PTCs); however, approximately 10% of cases are advanced PTCs, resulting in less than 50% 5-year survival rates. Understanding the tumor microenvironment is essential for understanding cancer progression and investigating potential biomarkers for treatment, such as immunotherapy. Our study focused on tumor-infiltrating lymphocytes (TILs), which are the main effectors of antitumor immunity and related to the mechanism of immunotherapy. Using an artificial intelligence model, we analyzed the density of intratumoral and peritumoral TILs in the pathologic slides of The Cancer Genome Atlas PTC cohort. Tumors were classified into three immune phenotypes (IPs) based on the spatial distribution of TILs: immune-desert (48%), immune-excluded (34%), and inflamed (18%). Immune-desert IP was mostly characterized by RAS mutations, high thyroid differentiation score, and low antitumor immune response. Immune-excluded IP predominantly consisted of BRAF V600E-mutated tumors and had a higher rate of lymph node metastasis. Inflamed IP was characterized by a high antitumor immune response, as demonstrated by a high cytolytic score, immune-related cell infiltrations, expression of immunomodulatory molecules (including immunotherapy target molecules), and enrichment of immune-related pathways. This study is the first to investigate IP classification using TILs in PTC through a tissue-based approach. Each IP had unique immune and genomic profiles. Further studies are warranted to assess the predictive value of IP classification in advanced PTC patients treated with immunotherapy.

Exposure to Secondhand Smoke and a Tobacco-Specific Carcinogen in Non-Smokers.

BACKGROUND: The International Agency for Research on Cancer classifies 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (NNAL) as a known carcinogen. This study aimed to investigate the association between exposure to secondhand smoke (SHS) and NNAL concentrations in non-smokers. METHODS: This was a cross-sectional study based on data from the 2016 to 2018 Korea National Health and Nutrition Examination Survey. Urine NNAL concentrations were categorized into tertiles of 3,615 study participants who were non-smokers. All sampling and weight variables were stratified, and analyses to account for the complex sampling design were conducted. RESULTS: The overall, male, and female percentages of SHS exposure among non-smokers were 22.4%, 29.2%, and 20.4%, respectively. The geometric means of urine NNAL concentrations were 1.896±0.098 pg/mL and 1.094±0.028 pg/mL in the SHS exposure and non-exposure groups, respectively. After adjusting for confounding variables, in the total group, the geometric mean of urine NNAL concentrations was significantly higher in the SHS exposure group than in the SHS non-exposure group (adjusted P-value <0.001). Compared with the non-exposure group, the adjusted odds ratios (95% confidence intervals) for the highest NNAL tertile group of overall SHS exposure in the total, men, and women groups were 2.44 (1.95-3.05), 1.65 (1.08-2.53), and 2.73 (2.11-3.52), respectively, after full adjustment. CONCLUSION: The urine NNAL concentration in the SHS exposure group was significantly higher than that in the non-exposure group. Exposure to SHS was associated with a higher risk of elevated urine NNAL concentrations in non-smokers.

Increased Omega-3 Fatty Acid Intake Is Inversely Associated with Subclinical Inflammation in Healthy Elderly Men, Based on the 2015-2018 Korean National Health and Nutrition Examination Survey.

(1) Background: Subclinical inflammation as a risk factor of cardiovascular diseases was clinically measured using C-reactive protein (CRP) level. (2) Methods: This study was cross-sectionally designed based the 2015-2018 Korean National Health and Nutrition Examination Survey (KNHANES). The ratio of daily omega-3 fatty acids to energy intake (ω3FA ratio) was classified into four quartile groups (Q1, <0.3%; Q2, 0.3%-<0.6%; Q3, 0.6%-<1.0%; and Q4, ≥1.0% in both sexes). Logistic regression analysis was conducted to investigate the association between the ω3FA ratio and subclinical inflammation defined as CRP levels ≥3 mg/dL. (3) Results: The ω3FA ratio in subjects without and with subclinical inflammation was 0.8% and 0.7% in men (p-value = 0.001), and 0.8% and 0.8% in women (p-value = 0.491), respectively. The prevalence of subclinical inflammation in males decreased with increasing quartile of ω3FA ratio (12.9%, 9.6%, 7.4%, and 7.7%, p-value = 0.033), while female prevalence was not significant among quartile groups. Compared to Q1, odds ratios (95% confidence intervals) for subclinical inflammation of Q2, Q3, and Q4 were 0.740 (0.465-1.177), 0.564 (0.341-0.930), and 0.549 (0.317-0.953) in males, and 1.066 (0.653-1.741), 1.105 (0.600-1.718), and 0.934 (0.556-1.571) in females after full adjustment. (4) Conclusion: The ω3FA ratio is associated with subclinical inflammation in men.

Beneficial Effects of a Specially Designed Home Meal Replacement on Cardiometabolic Parameters in Individuals with Obesity: Preliminary Results of a Randomized Controlled Clinical Trial.

We aimed to investigate if a home meal replacement (HMR), designed with a low ω-6/ω-3 fatty acid ratio, improves cardiometabolic parameters, including metabolic syndrome (MetS) in obese individuals. We conducted a monocentric, controlled, randomized crossover trial. The HMR contains higher protein and fat content, lower carbohydrate content, and a lower ω6FA/ω3FA ratio than the regular diet. Sixty-four participants were randomized into two groups and switched to the other group following a 4-week intervention. While subjects in the HMR group were provided three HMRs daily, those in the control group were requested to maintain their regular dietary pattern. We conducted paired t-tests, repeated measures analysis of variance, and McNemar tests before and after the intervention. Body mass index (BMI) and weight were lower in the HMR group after adjusting for age, sex, and total energy intake and significantly changed in the between-group differences. The waist circumference, systolic blood pressure, triglycerides, triglyceride-glucose index, and triglyceride to high-density lipoprotein cholesterol ratio were reduced in the HMR group (all p < 0.05). The percentage of subjects with MetS significantly decreased from 39.1% at baseline to 28.1% post-intervention (p = 0.035). Using the HMR for 4 weeks reduced the BMI, weight, and MetS prevalence in individuals with obesity. This trial was registered at clinicaltrials.gov (NCT04552574).

Increased Omega-3 Fatty Acid Intake is Inversely Associated with Sarcopenic Obesity in Women but not in Men, Based on the 2014-2018 Korean National Health and Nutrition Examination Survey.

(1) Background: Omega-3 fatty acids (ω3FAs) are known to improve protein anabolism, increase the sensitivity to anabolic stimuli, decrease lipogenesis, and stimulate lipid oxidation. We aim to investigate whether ω3FAs are associated with the prevalence of sarcopenic obesity (SO). (2) Methods: Data were obtained from the 2014-2018 Korean National Health and Nutrition Examination Survey. The ratio of daily ω3FA intake to energy intake (ω3FA ratio) was categorized into four quartile groups. (3) Results: The prevalence of SO from Q1 to Q4 was 8.9%, 11.3%, 11.0%, and 9.8% respectively, in men and 17.4%, 14.0%, 13.9%, and 10.1% respectively, in women. The ω3FA ratio in individuals with and without SO were 1.0% and 0.9% in men (p-value = 0.271) respectively, and 0.8% and 1.0% in women (p-value = 0.017), respectively. Compared with Q1, odds ratios (95% confidence intervals) of Q2, Q3, and Q4 of ω3FA ratios were 1.563 (0.802-3.047), 1.246 (0.611-2.542), and 0.924 (0.458-1.864) respectively, in men and 0.663 (0.379-1.160), 0.640 (0.372-1.102), and 0.246 (0.113-0.534) respectively, in women, after fully adjusting for confounding factors. (4) Conclusions: The ω3FA ratio was significantly higher in older females without SO than in older females with SO. The ω3FA ratio was associated with the prevalence of SO in elderly females.

Primary Prevention of Cardiocerebrovascular Diseases and Related Deaths According to Statin Type.

(1) Background: Statin is the mainstay of treatment for the primary prevention of atherosclerotic cardiocerebrovascular diseases (CCVDs) in adults with hypercholesterolemia. This study aims to investigate the differences in effect on primary composite outcomes (CCVDs and CCVD-related deaths) among five statins in hypercholesterolemic individuals. (2) Methods: This retrospective study is based on the Korean National Health Insurance Service-National Health Screening Cohort. Participants, aged 40 to 69 years at baseline, were categorized into five statin-treated groups (pitavastatin, atorvastatin, rosuvastatin, simvastatin, and pravastatin) and two untreated groups (untreated hypercholesterolemia and no hypercholesterolemia). (3) Results: A total of 161,583 individuals was included. The median follow-up period was 8.2 years. Compared with the pitavastatin group, the hazard ratios (HRs; 95% confidence intervals (CIs)) for CCVDs and CCVD-related deaths of the atorvastatin, rosuvastatin, simvastatin, pravastatin, untreated hypercholesterolemia, and no-hypercholesterolemia groups were 0.969 (0.567-1.657), 0.988 (0.533-1.832), 0.862 (0.490-1.518), 0.906 (0.326-2.515), 2.665 (1.556-4.562), and 0.656 (0.388-1.110), respectively, in men and 1.124 (0.632-1.999), 1.119 (0.582-2.152), 1.324 (0.730-2.400), 1.023 (0.330-3.171), 2.650 (1.476-4.758), and 0.921 (0.522-1.625), respectively, in women, after being fully adjusted. (4) Conclusions: No significant differences among the five statins were observed, but there was an increased risk in untreated hypercholesterolemic individuals, for CCVDs and CCVDs-related deaths in individuals with hypercholesterolemia of either sex.

The preventive effect of Se-methylselenocysteine on γ-radiation-induced oxidative stress in rat lungs.

We investigated the preventive effect of Se-methylselenocysteine (MSC) administration on γ-radiation (whole body irradiation, single 10-Gy dose)-induced oxidative damage in rat lungs. Rats were pretreated with MSC (0.75mg/rat/day) for 1 week before γ-irradiation. The MSC pretreatment prevented the irradiation-induced increase in lipid peroxidation and the concomitant decrease in cellular glutathione content. The prevention of irradiation-induced oxidative damage in MSC-pretreated rat lungs appeared to be associated with increased antioxidant capacity, particularly in the glutathione system. The 1-week MSC treatment resulted in an increase in glutathione peroxidase, glutathione reductase, and glucose 6-phosphate dehydrogenase activities, which are involved in glutathione redox cycling. An increase in catalase activity was also observed in the rat lungs. Additionally, a significantly increased level of nuclear factor erythroid 2-related factor 2 (Nrf2) was exhibited in the MSC-treated rat lungs. Heme oxygenase 1, glutathione S-transferase pi, and peroxiredoxin 1, which are known target proteins of Nrf2, were also increased in MSC-treated lungs. These results implicate Nrf2 signaling in the MSC-induced activation of the antioxidant system.