Real-world effectiveness of CDK4/6 inhibitors on patients with HR+/HER2- advanced breast cancer in South Korea, focusing on underrepresented patients.

OBJECTIVE: We assessed the real-world effectiveness of cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors as first-line treatments in postmenopausal patients with HR+/HER2- advanced breast cancer, focusing on younger (<45 years) and older (>78 years) populations not considered in clinical trials. METHODS: We analyzed nationwide claims data from the Health Insurance Review and Assessment Service between November 2016 and February 2021. In this retrospective cohort study, patients using CDK4/6 inhibitors and aromatase inhibitors were selected and grouped by age as follows: 45-78 years (trial-enrolled), <45 years (younger), and >78 years (older). We estimated the median real-world progression-free survival (rwPFS) and overall survival (OS) using the Kaplan-Meier method. We conducted Cox regression analysis using a sub-distribution hazard model to evaluate risk factors (age, history of prior systemic treatment, presence of metastasis, comorbidity index, and type of provider) and estimated hazard ratios (HR). RESULTS: Among the 2,830 patients who received CDK4/6 inhibitors as first-line therapy, we identified 358 (12.65%) younger and 148 (5.23%) older underrepresented patients. The younger patient group (50.84%) had the highest rate of prior systemic therapy, followed by the trial-enrolled (25.39%) and older patient groups (8.11%). The median rwPFS was shorter in the older group (19.30 months) than those in the younger and the trial-enrolled age groups (30.33 and 34.53 months, respectively; p = .002). The HR of older age for death was 1.59 (95% confidence interval (CI) = 1.24-2.03). For rwPFS, the HR of prior systemic therapy was 1.19 (95% CI = 1.04-1.37). CONCLUSIONS: The younger age group, which was underrepresented in the trial, did not show a significant difference in risk compared with the enrolled age group. However, the older age group, which was also underrepresented in the trial, faces a risk of mortality but not progression. Patients who fall outside the specified age groups for the clinical trial can still expect the same level of effectiveness in terms of progression.

Concomitant Use of Proton Pump Inhibitors and Palbociclib Among Patients With Breast Cancer.

Importance: Proton pump inhibitors (PPIs) are commonly used drugs to relieve gastrointestinal tract symptoms, but their acid-inhibitory action negatively affects the bioavailability and clinical outcomes of orally administered concomitant drugs. Objective: To identify the clinical outcomes of patients with advanced breast cancer who concomitantly use PPIs and palbociclib. Design, Setting, and Participants: This retrospective cohort study used nationwide claims data between November 1, 2016, and July 31, 2021, in South Korea. Patients with breast cancer receiving palbociclib between November 1, 2017, and July 31, 2020, were identified. Patients whose prescriptions for palbociclib and PPI overlapped by at least 33% were classified into a concomitant PPI group. Patients who never received PPI during the palbociclib treatment period were classified into a nonconcomitant PPI group. Patients were selected through 1:3 propensity score matching for analyses. Exposures: Concomitant use of PPIs with palbociclib. Main Outcomes and Measures: Time to progression and death. These outcomes were presented as progression-free survival (PFS) and overall survival (OS) and were analyzed using the Kaplan-Meier method and log-rank test. Cox proportional hazards regression was used to estimate the hazard ratio (HR) of concomitant PPI use associated with clinical PFS and/or OS. Results: A total of 344 women were included in the concomitant PPI group and 966 in the nonconcomitant PPI group. Among 1310 patients identified after matching, 1108 (84.6%) were older than 50 years; 1111 (84.8%) were treated with letrozole and anastrozole (endocrine sensitive); and 199 (15.2%) were treated with fulvestrant (endocrine resistant). The median clinical PFS in the concomitant PPI group was shorter than that of the nonconcomitant PPI group (25.3 [95% CI, 19.6-33.0] vs 39.8 [95% CI, 34.9 to not applicable] months; P < .001), and the HR was 1.76 (95% CI, 1.46-2.13). Concomitant use of PPI was also associated with shorter OS (HR, 2.71 [95% CI, 2.07-3.53]). Both clinical PFS and OS in the concomitant PPI group were consistently poor in patients receiving endocrine-sensitive and endocrine-resistant treatment. Conclusions and Relevance: These findings suggest that concomitant use of PPIs with palbociclib may hinder the complete therapeutic benefits of palbociclib in patients with breast cancer.

Vaginal Cuff Dehiscence and a Guideline to Determine Treatment Strategy.

In this retrospective study, our aim was to investigate a novel treatment strategy guideline for vaginal cuff dehiscence after hysterectomy based on the mode of operation and time of occurrence in patients who underwent hysterectomy at Severance Hospital between July 2013 and February 2019. We analyzed the characteristics of 53 cases of vaginal cuff dehiscence according to the mode of hysterectomy and time of occurrence. Out of a total of 6530 hysterectomy cases, 53 were identified as vaginal cuff dehiscence (0.81%; 95% confidence interval: 0.4-1.6%). The incidence of dehiscence after minimally invasive hysterectomy was significantly higher in patients with benign diseases, while malignant disease was associated with a higher risk of dehiscence after transabdominal hysterectomy (p = 0.011). The time of occurrence varied significantly based on menopausal status, with dehiscence occurring relatively earlier in pre-menopausal women compared to post-menopausal women (93.1% vs. 33.3%, respectively; p = 0.031). Surgical repair was more frequently required in cases of late-onset vaginal cuff dehiscence (≥8 weeks) compared to those with early-onset dehiscence (95.8% vs. 51.7%, respectively; p < 0.001). Patient-specific factors, such as age, menopausal status, and cause of operation, may influence the timing and severity of vaginal cuff dehiscence and evisceration. Therefore, a guideline may be indicated for the treatment of potentially emergent complications after hysterectomy.

Clinical Relevance of Vaginal Cuff Dehiscence after Minimally Invasive versus Open Hysterectomy.

This study aimed to evaluate the clinical relevance of vaginal cuff dehiscence following a hysterectomy. Data were prospectively collected from all patients who underwent hysterectomies at a tertiary academic medical center between 2014 and 2018. The incidence and clinical factors of vaginal cuff dehiscence after minimally invasive versus open hysterectomy were compared. Vaginal cuff dehiscence occurred in 1.0% (95% confidence interval [95% CI], 0.7-1.3%) of women who underwent either form of hysterectomy. Among those who underwent open (n = 1458), laparoscopic (n = 3191), and robot-assisted (n = 423) hysterectomies, vaginal cuff dehiscence occurred in 15 (1.0%), 33 (1.0%), and 3 (0.7%) cases, respectively. No significant differences in cuff dehiscence occurrence were identified in patients who underwent various modes of hysterectomies. A multivariate logistic regression model was created using the variables indication for surgery and body mass index. Both variables were identified as independent risk factors for vaginal cuff dehiscence (odds ratio [OR]: 2.74; 95% CI, 1.51-4.98 and OR: 2.20; 95% CI, 1.09-4.41, respectively). The incidence of vaginal cuff dehiscence was exceedingly low in patients who underwent various modes of hysterectomies. The risk of cuff dehiscence was predominantly influenced by surgical indications and obesity. Thus, the different modes of hysterectomy do not influence the risk of vaginal cuff dehiscence.

The effect of heteroscedasticity on the prediction efficiency of genome-wide polygenic score for body mass index.

Globally, more than 1.9 billion adults are overweight. Thus, obesity is a serious public health issue. Moreover, obesity is a major risk factor for diabetes mellitus, coronary heart disease, and cardiovascular disease. Recently, GWAS examining obesity and body mass index (BMI) have increasingly unveiled many aspects of the genetic architecture of obesity and BMI. Information on genome-wide genetic variants has been used to estimate the genome-wide polygenic score (GPS) for a personalized prediction of obesity. However, the prediction power of GPS is affected by various factors, including the unequal variance in the distribution of a phenotype, known as heteroscedasticity. Here, we calculated a GPS for BMI using LDpred2, which was based on the BMI GWAS summary statistics from a European meta-analysis. Then, we tested the GPS in 354,761 European samples from the UK Biobank and found an effective prediction power of the GPS on BMI. To study a change in the variance of BMI, we investigated the heteroscedasticity of BMI across the GPS via graphical and statistical methods. We also studied the homoscedastic samples for BMI compared to the heteroscedastic sample, randomly selecting samples with various standard deviations of BMI residuals. Further, we examined the effect of the genetic interaction of GPS with environment (GPS×E) on the heteroscedasticity of BMI. We observed the changing variance (i.e., heteroscedasticity) of BMI along the GPS. The heteroscedasticity of BMI was confirmed by both the Breusch-Pagan test and the Score test. Compared to the heteroscedastic sample, the homoscedastic samples from small standard deviation of BMI residuals showed a decreased heteroscedasticity and an improved prediction accuracy, suggesting a quantitatively negative correlation between the phenotypic heteroscedasticity and the prediction accuracy of GPS. To further test the effects of the GPS×E on heteroscedasticity, first we tested the genetic interactions of the GPS with 21 environments and found 8 significant GPS×E interactions on BMI. However, the heteroscedasticity of BMI was not ameliorated after adjusting for the GPS×E interactions. Taken together, our findings suggest that the heteroscedasticity of BMI exists along the GPS and is not affected by the GPS×E interaction.

Dietary Diversity during Early Infancy Increases Microbial Diversity and Prevents Egg Allergy in High-Risk Infants.

We aimed to investigate associations of dietary diversity (DD) with gut microbial diversity and the development of hen's egg allergy (HEA) in infants. We enrolled 68 infants in a high-risk group and 32 infants in a control group based on a family history of allergic diseases. All infants were followed from birth until 12 months of age. We collected infant feeding data, and DD was defined using 3 measures: the World Health Organization definition of minimum DD, food group diversity, and food allergen diversity. Gut microbiome profiles and expression of cytokines were evaluated by bacterial 16S rRNA sequencing and real-time reverse transcriptase-polymerase chain reaction. High DD scores at 3 and 4 months were associated with a lower risk of developing HEA in the high-risk group, but not in the control group. In the high-risk group, high DD scores at 3, 4, and 5 months of age were associated with an increase in Chao1 index at 6 months. We found that the gene expression of IL-4, IL-5, IL-6, and IL-8 were higher among infants who had lower DD scores compared to those who had higher DD scores in high-risk infants. Additionally, high-risk infants with a higher FAD score at 5 months of age showed a reduced gene expression of IL-13. Increasing DD within 6 months of life may increase gut microbial diversity, and thus reduce the development of HEA in infants with a family history of allergic diseases.

Value-Based Pricing and Budget Impact Analysis for Multi-Indication Drugs: A Case Study of Immunotherapies.

We aimed to calculate the value-based price of each indication and compare the drug price and budget impact among value-based pricing (VBP) scenarios, using immunotherapy as a case. Atezolizumab, nivolumab, and pembrolizumab prices were estimated for VBP scenarios, namely indication value-based pricing (IBP), IBP with refund, and weighted-average pricing (WAP). To estimate the value-based price of each indication, cost-effectiveness analyses were conducted by setting the incremental cost-effectiveness ratio of the first reimbursed indication to the threshold. The budget impact for each scenario was compared with that of the pricing system in Korea (which has a 4.75% price reduction). The value-based prices of non-reimbursed indications were lower for atezolizumab and higher for nivolumab than those for the reimbursed indication. The drug price fluctuations were the largest in IBP, varying between 28.56-328.81% of the current list price. The net price of the non-reimbursed indications decreased from 0% to 71.44% in IBP with refund, and the budget impact was the lowest among VBPs. Although the fluctuation in the budget impact in WAP was smaller than IBP, higher drug prices were identified for low-value indications. In conclusion, IBP with refund is a viable method for multi-indication drugs, because it has minimal drug price and budget impact changes.

The quality of non-alcoholic fatty liver disease information resources for patients on the internet in Korea.

BACKGROUND/AIMS: Many patients uses the internet to obtain information about their diseases. However, there is increasing concern regarding the quality of internet information. Thus, we aimed to systematically evaluate the quality of websites containing educational information about non-alcoholic fatty liver disease (NAFLD) in Korea. METHODS: Naver, Daum, and Google search engines were searched using the term "non-alcoholic fatty liver disease" in Korean. Two reviewers independently evaluated website quality using the quality evaluation instrument (QEI), which awarded websites scores for specific information on various aspects of NAFLD, as well as a five-point Likert scale (1-5), the DISCERN instrument, and a global quality scale (GQS). RESULTS: Forty-seven websites met the inclusion criteria. We found that the quality of the internet information about NAFLD is generally poor. The mean QEI score with standard deviation was 10.31 ± 5.09 (range, 4 to 22), with only 17% of websites scoring higher than 10 points. The median GQS of the websites was 2.0, with no website achieving a score of 4 or 5. The QEI score was highly associated with the GQS score (r = 0.74, p < 0.01). For each DISCERN question from question 1 to question 15, the mean score was less than 3. CONCLUSION: Overall, the internet health information for patients regarding NAFLD is poor and in need of much improvement. There is a need for institutional support, qualitative regulation of internet information, and development of an accreditation system to provide patients with internet health information of appropriate quality.

Co-existence of relapsing polychondritis and Crohn disease treated successfully with infliximab.

Relapsing polychondritis (RP) is a rare, progressive immune-mediated systemic inflammatory disease of unknown etiology, characterized by recurrent inflammation of cartilaginous structures. Approximately 30% of RP cases are associated with other autoimmune diseases. However, the co-occurrence of RP and Crohn disease (CD) has rarely been reported. Herein, we present a 35-year-old woman diagnosed with RP and CD, who was refractory to initial conventional medications, including azathioprine and glucocorticoid, but who subsequently responded to infliximab (IFX). For both diseases, remission was sustained with IFX. There has been no previous report regarding the successful treatment of co-existing RP and CD with IFX.

Prevalence of lung cancer in patients with interstitial lung disease is higher than in those with chronic obstructive pulmonary disease.

We aimed to explore lung cancer prevalence in interstitial lung disease (ILD) patients with or without connective tissue disorder (CTD) and idiopathic pulmonary fibrosis (IPF) in comparison with chronic obstructive pulmonary disorder (COPD).We evaluated lung cancer prevalence associated with ILD and IPF using Korean Health Insurance Review and Assessment Service (HIRA) data from January to December 2011. This database (HIRA-NPS-2011-0001) was sampled using random sampling of outpatients; 1,375,842 sample cases were collected, and 670,258 (age ≥ 40 ys) were evaluated. Patients with ILDs, IPF, CTD, or COPD were identified using the International Classification of Disease-10 diagnostic codes.Lung cancer prevalence rates per 100,000 persons for the sample population and those with ILD, IPF, CTD-ILD, and COPD were 420, 7334, 7404, 7272, and 4721, respectively. Lung cancer prevalence was significantly higher in those with ILD than in those with COPD (P < .01).More attention should be paid to lung cancer development in those with ILD as well as COPD.

A primary gastric synovial sarcoma: A case report and literature review.

RATIONALE: When a gastric spindle cell tumor is observed, the possibility of synovial carcinoma, besides common mesenchymal tumor, should also be considered. PRESENTING CONCERNS OF THE PATIENT: The patient is a 51-year-old American woman who underwent medical check-up at a general hospital. Upper endoscopy showed a 2-cm sized mass covered with intact mucosa, and a central depression located on the posterior wall of the mid body. Biopsy of the mass showed focal atypical cells proliferation in mucosa on hematoxylin & eosin (H&E) staining. Endoscopic ultrasound showed a 17-mm homogenously hypoechoic mass within the submucosal layer. INTERVENTIONS: After diagnostic endoscopic submucosal dissection was performed, H&E and immunohistochemical staining showed synovial sarcoma (SS). To confirm the diagnosis, reverse transcriptase-polymerase chain reaction was performed, revealing a chimeric transcript of the SYT-SSX1 fusion gene. The diagnosis of primary gastric SS was confirmed because no evidence of possible primary lesions or metastatic lesions was observed. Therefore, the patient underwent distal gastrectomy. OUTCOMES: After surgery, the surgical specimen demonstrated no residual tumor cells. The patient received no adjuvant therapy, and there has been no evidence of local recurrence or distant metastasis for 2 months after the operation. LESSONS: When gastric subepithelial tumor is suspicious, we should also consider gastric SS.

Risk factors associated with provoked pulmonary embolism.

BACKGROUND/AIMS: This study aimed to investigate the risk factors associated with provoked pulmonary embolism (PE). METHODS: This retrospective cohort study included 237 patients with PE. Patients that had transient risk factors at diagnosis were classified as having provoked PE, with the remaining patients being classified as having unprovoked PE. The baseline clinical characteristics and factors associated with coagulation were compared. We evaluated the risk factors associated with provoked PE. RESULTS: Of the 237 PE patients, 73 (30.8%) had provoked PE. The rate of respiratory failure and infection, as well as the disseminated intravascular coagulation score and ratio of right ventricular diameter to left ventricular diameter were significantly higher in patients with provoked PE than in those with unprovoked PE. The protein and activity levels associated with coagulation, including protein C antigen, protein S antigen, protein S activity, anti-thrombin III antigen, and factor VIII, were significantly lower in patients with provoked PE than in those with unprovoked PE. Multivariate analysis showed that infection (odds ratio [OR], 3.2; 95% confidence interval [CI], 1.4 to 7.4) and protein S activity (OR, 0.97; 95% CI, 0.95 to 0.99) were significantly associated with provoked PE. CONCLUSIONS: Protein S activity and presence of infection were important factors associated with provoked PE. We should pay attention to the presence of infection in patients with provoked PE.

Involvement of PI3K and PKA pathways in mouse tongue epithelial differentiation.

In mice, tongue epithelial differentiation is mainly regulated by the interactions among various signalling molecules including Fgf signalling pathways. However, the subsequent signalling modulations for epithelial maturation, initiated by Fgf signalling, remain to be elucidated. Therefore, we employed an in vitro tongue organ cultivation system along with the applications of various pharmacological inhibitors against the intracellular signalling molecules of Fgf signalling pathways, including H89, LY294002, PD98059, and U0126. Following treatments with LY294002 and H89, inhibitors for PI3K and PKA, respectively, the decreased thickness of the tongue epithelium was observed along with the alteration in cell proliferative and apoptotic patterns. Meanwhile, cultivated tongues treated with MEK inhibitor U0126 or PD98059 showed significantly decreased cell proliferation in the tongue epithelium and the mesenchyme. Based on these results, we suggest that the tongue epithelium is differentiated into multiple epithelial cell layers via the PI3K and PKA pathways in tissue-specific manner during the epithelial-mesenchymal interactions.

Erratum: Does the Mean Arterial Pressure Influence Mortality Rate in Patients with Acute Hypoxemic Respiratory Failure under Mechanical Ventilation?

[This corrects the article on p. 85 in vol. 78, PMID: 25861341.].

Does the Mean Arterial Pressure Influence Mortality Rate in Patients with Acute Hypoxemic Respiratory Failure under Mechanical Ventilation?

BACKGROUND: In sepsis patients, target mean arterial pressures (MAPs) greater than 65 mm Hg are recommended. However, there is no such recommendation for patients receiving mechanical ventilation. We aimed to evaluate the influence of MAP over the first 24 hours after intensive care unit (ICU) admission on the mortality rate at 60 days post-admission in patients showing acute hypoxemic respiratory failure under mechanical ventilation. METHODS: This prospective, multicenter study included 22 ICUs and compared the mortality and clinical outcomes in patients showing acute hypoxemic respiratory failure with high (75-90 mm Hg) and low (65-74.9 mm Hg) MAPs over the first 24 hours of admission to the ICU. RESULTS: Of the 844 patients with acute hypoxemic respiratory failure, 338 had a sustained MAP of 65-90 mm Hg over the first 24 hours of admission to the ICU. At 60 days, the mortality rates in the low (26.2%) and high (24.5%) MAP groups were not significantly different. The ICU days, hospital days, and 60-day mortality rate did not differ between the groups. CONCLUSION: In the first 24 hours of ICU admission, MAP range between 65 and 90 mm Hg in patients with acute hypoxemic respiratory failure under mechanical ventilation may not cause significantly differences in 60-day mortality.

Isolated cervical lymph node sarcoidosis presenting in an asymptomatic neck mass: a case report.

Sarcoidosis, a systemic granulomatous disease of unknown etiology. The presentation of sarcoidal granuloma in neck nodes without typical manifestations of systemic sarcoidosis is difficult to diagnose. We describe the case of a 37-year-old woman with an increasing mass on the right side of neck. The excisional biopsy from the neck mass showed noncaseating epithelioid cell granuloma of the lymph nodes. No evidence of mycobacterial or fungal infection was noted. Thoracic evaluations did not show enlargement of mediastinal lymph nodes or parenchymal abnormalities. Immunohistochemistry showed abundant expression of tumor necrosis factor-α in the granuloma. However, transforming growth factor-ß was not expressed, although interleukin-1ß was focally expressed. These immunohistochemical findings supported characterization of the granuloma and the diagnosis of sarcoidosis. Sarcoidosis can present with cervical lymph node enlargement without mediastinal or lung abnormality. Immunohistochemistry may support the diagnosis of sarcoidosis and characterization of granuloma.

Reciprocal interactions of Fgf10/Fgfr2b modulate the mouse tongue epithelial differentiation.

The molecular mechanisms for epithelial differentiation have been studied by observing skin development in embryogenesis, but the early signaling modulations involved in tongue epithelial differentiation are not completely understood. Based on the gene expression patterns of the Fgf signaling molecules and previous results from Fgf10 and Fgfr2b knockout mice, it was hypothesized that there would be fundamental signaling interactions through the epithelial Fgfr2b and its mesenchymal ligand Fgf10 to regulate tongue epithelium differentiation. To elucidate these reciprocal interactions in tongue epithelial differentiation, this study employed an in vitro tongue organ culture system with antisense-oligodeoxynucleotides (AS-ODNs) and recombinant protein-soaked bead implantation for the loss-of-function and gain-of-function studies. Functional analysis of Fgf signaling revealed precise reciprocal interactions, which showed that mesenchymal Fgf10 rather than Fgf7 modulates tongue epithelial differentiation via Fgfr2b in a temporal- and spatial-specific manner.

Feasibility of ultrasound-guided posterior approach for interscalene catheter placement during arthroscopic shoulder surgery.

BACKGROUND: Continuous interscalene block has been known to improve postoperative analgesia after arthroscopic shoulder surgery. This was a prospective study investigating the ultrasound-guided posterior approach for placement of an interscalene catheter, clinical efficacy and complications after placement of the catheter. METHODS: Forty-two patients undergoing elective arthroscopic shoulder surgery were included in this study and an interscalene catheter was inserted under the guidance of ultrasound with posterior approach. With the inplane approach, the 17 G Tuohy needle was advanced until the tip was placed between the C5 and C6 nerve roots. After a bolus injection of 20 ml of 0.2% ropivacaine, a catheter was threaded and secured. A continuous infusion of ropivacaine 0.2% 4 ml/hr with patient-controlled 5 ml boluses every hour was used over 2 days. Difficulties in placement of the catheter, clinical efficacy of analgesia and complications were recorded. All patients were monitored for 48 hours and examined by the surgeon for complications within 2 weeks of hospital discharge. RESULTS: Easy placement of the catheter was achieved in 100% of the patients and the success rate of catheter placement during the 48 hr period was 92.9%. Postoperative analgesia was effective in 88.1% of the patients in the post anesthetic care unit. The major complications included nausea (7.1%), vomiting (4.8%), dyspnea (4.8%) and unintended vascular punctures (2.4%). Other complications such as neurologic deficits and local infection around the puncture site did not occur. CONCLUSIONS: The ultrasound-guided interscalene block with a posterior approach is associated with a success high rate in placement of the interscalene catheter and a low rate of complications. However, the small sample size limits us to draw definite conclusions. Therefore, a well-designed randomized controlled trial is required to confirm our preliminary study.

Shh and ROCK1 modulate the dynamic epithelial morphogenesis in circumvallate papilla development.

In rodents, a circumvallate papilla (CVP) develops with dynamic changes in epithelial morphogenesis during early tongue development. Molecular and cellular studies of CVP development revealed that there would be two different mechanisms in the apex and the trench wall forming regions with specific expression patterns of Wnt11 and Shh. Molecular interactions were examined using in vitro organ culture with over-expression of Shh, important signalling molecules and various inhibitors revealed that there are two significant different mechanisms in CVP formation by Wnt11 and Shh expressions. Wnt, a well known key molecule to initiate taste papillae, would govern Rho activation and cytoskeleton formation in the apex epithelium of CVP. In contrast, Shh regulates the cell proliferation to differentiate taste buds and to invaginate the epithelium for development of von Ebner's gland (VEG). Based on these results, we suggest that these different molecular signalling cascades of Wnt11 and Shh would play crucial roles in specific morphogenesis and pattern formation of CVP during early mouse embryo development.