Risk Factor Analysis of Lymph Node Metastasis for Rectal Neuroendocrine Tumors: Who Needs a Radical Resection in Rectal Neuroendocrine Tumors Sized 1-2 cm?

BACKGROUND: Rectal neuroendocrine tumors (NETs) have malignant potential, and lymph node (LN) or distant metastases can occur; however, treatment of NETs 1-2 cm in size is controversial. OBJECTIVE: This study aimed to identify predictive factors for LN metastasis and prognostic factors for recurrence of rectal NETs, especially tumors 1‒2 cm in size. METHODS: Between October 2004 and November 2020, 453 patients underwent endoscopic or surgical treatment for rectal NETs in Seoul National University Hospital. The data on these patients were prospectively collected in our database and reviewed retrospectively. In cases of local excision, we evaluated LN metastasis with radiologic imaging, including computed tomography or magnetic resonance imaging before treatment and during the follow-up periods. RESULTS: LN metastasis was observed in 40 patients (8.8%). A higher rate of LN metastasis was observed in larger-sized tumors, advanced T stage, lymphovascular invasion (LVI), perineural invasion (PNI), and high tumor grade. In multivariable analysis, the significant risk factors for LN metastasis were tumor size (1 ≤ size < 2 cm: hazard ratio [HR] 64.07; size ≥2 cm: HR 102.37, p < 0.001) and tumor grade (G2: HR 3.63, p = 0.034; G3: HR 5.09, p = 0.044). In multivariable analysis for tumors 1-2 cm in size, the risk factor for LN metastasis was tumor grade (G2: HR 6.34, p = 0.013). CONCLUSIONS: Tumor grade and size are important predictive factors for LN metastasis. In NETs 2 cm in size, tumor grade is also important for LN metastasis, and radical resection should be considered.

A 3 mm Port Reduces Postoperative Pain After Laparoscopic Colon Cancer Surgery: A Case-control Matched Study.

BACKGROUND: Recently, smaller-size trocars and instruments have been developed for laparoscopic colon cancer surgery; however, their effectiveness and safety have not been elucidated. This study aimed to investigate whether 3 mm trocars and instruments have benefits compared with conventional trocars and instruments. PATIENTS AND METHODS: Patients with colon cancer who underwent laparoscopic anterior resection or right hemicolectomy were included. Patients who underwent combined resections of other organs and those with conversion to open surgery were excluded. In the 3 mm group, three 5 mm trocars were replaced by 3 mm trocars. The numeric rating scale (NRS) immediately postoperatively at 24, 48, and 72 hours, respectively, after surgery and the use of additional analgesics and perioperative outcomes were analyzed. Case-control matched analysis was used to reduce bias according to the type of surgery. RESULTS: A total of 207 patients (conventional: n = 158, 3 mm: n = 49) were included. Before matching, NRS 48 hours postoperatively ( P = 0.049), proportion of patients using additional intravenous (IV) analgesics ( P = 0.007), postoperative hospital stay ( P < 0.001), and blood loss ( P < 0.001) were lower in the 3 mm group. In multivariable analysis, trocar type significantly impacted the proportion of patients using additional IV analgesics (odds ratio: 0.330; 95% CI: 0.153-0.712; P = 0.005). After case-control matching, NRS immediately postoperatively ( P = 0.015) and 24 hours postsurgery ( P = 0.043), patients using additional IV analgesics ( P = 0.019), postoperative hospital stay ( P = 0.010), intraoperative blood loss ( P < 0.001), and postoperative complication rate ( P = 0.028) were significantly lower in the 3 mm group compared with the 5 mm group. CONCLUSIONS: The use of 3 mm trocars and instruments in laparoscopic colon cancer surgery can effectively reduce postoperative pain while maintaining perioperative safety.

Effects of tacrolimus intrapatient variability and CYP3A5 polymorphism on the outcomes of pediatric kidney transplantation.

BACKGROUND: The intrapatient variability (IPV) of tacrolimus (Tac) is associated with the long-term outcome of kidney transplantation. The CYP3A single-nucleotide polymorphism (SNP) may affect the IPV of Tac. We investigated the impact of IPV and genetic polymorphism in pediatric patients who received kidney transplantation. METHODS: A total of 202 pediatric renal transplant recipients from 2000 to 2016 were analyzed retrospectively. The IPV was calculated between 6 and 12 months after surgery. Among these patients, CYP3A5 polymorphism was analyzed in 67 patients. RESULTS: The group with high IPV had a significantly higher rate of de novo donor-specific human leukocyte antigen antibodies (dnDSA) development (35.7% vs. 16.7%, p = .003). The high IPV group also had a higher incidence of T-cell-mediated rejection (TCMR; p < .001). The high IPV had no significant influence on Epstein-Barr virus, cytomegalovirus, and BK virus viremia but was associated with the incidence of posttransplant lymphoproliferative disorders (p = .003). Overall, the graft survival rate was inferior in the high IPV group (p < .001). The CYP3A5 SNPs did not significantly affect the IPV of Tac. In the CYP3A5 expressor group, however, the IPV was significantly associated with the TCMR-free survival rate (p < .001). CONCLUSION: The IPV of Tac had a significant impact on dnDSA development, occurrence of acute TCMR, and graft failure in pediatric patients who received renal transplantation. CYP3A5 expressors with high IPV of Tac showed worse outcomes, while the CYP3A5 polymorphism had no impact on IPV of Tac.

The Impact of Expanded National Health Insurance Coverage of Dentures and Dental Implants on Dental Care Utilization among Older Adults in South Korea: A Study Based on the Korean Health Panel Survey.

In South Korea, the National Health Insurance Service (NHIS) began its coverage of dentures and dental implants for older people in 2012 and 2014, respectively. This study aimed to investigate the impact of these policies on dental care utilization among people aged 65 years or older according to their sociodemographic characteristics. Data were collected from the Korea Health Panel Survey (KHP; years 2012 and 2015). The statistical significance of the relationships between sociodemographic characteristics and the use of outpatient dental care, denture, and dental implant were analyzed. Results showed an increase of 5.7%, 1.4%, and 2.8% in the use of outpatient dental care, denture, and dental implant, respectively, over the course of three years. Including dentures increased its use by 2.5-3.7 times among people aged 70 years or older. Including dental implants alleviated the disparities among older adults based on age groups and duration of education, except those among uneducated people; however, it caused inequity according to household income. Some Korean older adults remain neglected from the benefits of the expanded NHIS. Therefore, older adults' access to dental care should be enhanced by the implementation of policies to promote oral health care utilization, dental prosthetic services, and older adults' insurance coverage.

Changes in oral health indicators due to implementation of the National Health Insurance Services coverage for first molar dental sealant for children and adolescents in South Korea.

BACKGROUND: In South Korea, dental sealant was included in the National Health Insurance Services (NHIS) coverage for the first molar for ages 6-14 in December 2009. The second molar was included in 2012, and the age of insurance coverage was extended to under 18 in 2013. This study aimed to verify the effectiveness of an NHIS dental sealant coverage policy for children and adolescents by comparing the changes in first molar oral health indicators before and after policy implementation. METHODS: The Korea National Health and Nutrition Examination Survey data were analyzed; the fourth period (2007-2009) provided data for before and the sixth period (2013-2015) provided data for after policy implementation. The proportion of individuals with first-molar sealant, decay-missing-filled first molar permanent teeth, and single crowns in the group aged 11-20 years were calculated. Data were analyzed using chi-square for complex samples and the complex samples general linear model. In addition, complex-sample logistic regression analysis was performed to confirm the association between factors. RESULTS: Compared with non-beneficiaries, among policy beneficiaries, sealant ownership increased by 7.7% (from 27.8 to 35.5, P < 0.001), and the number of permanent teeth with sealant per capita increased by approximately 0.4 to 0.8 (P < 0.001). The proportion of individuals with decay-missing-filled permanent teeth decreased by 9.1% (from 68.4 to 59.3, P < 0.001), and the average decay-missing-filled permanent teeth index per person decreased by approximately 2.0 to 1.5 (P < 0.001). The rate of single-crown holders decreased by 2.7% (from 8.7 to 6.0, P > 0.05), and the average single-crown index decreased by approximately 0.11 to 0.08 per person(P > 0.05). The number of sealants increased with age and household income (P < 0.001). The mother's education level affected sealant experience (P < 0.05). The caries rate was higher in females and older respondents (P < 0.001). CONCLUSIONS: The sealant covered by NHIS contributed to decreasing dental caries in Korea. However, policies that can reduce oral health inequality should also be considered, and a follow-up study is required for long-term sealant maintenance in Korea.

Renal transplantation in patients with an augmentation cystoplasty.

Background: The effects of renal transplantation in patients with augmentation cystoplasty are still controversial. We retrospectively analyzed nine patients who underwent renal transplantation after augmentation cystoplasty. Methods: A total of nine patients who underwent augmentation cystoplasty prior to renal transplantation between January 1990 and May 2020 were reviewed. Basic information on augmentation cystoplasty, transplant procedures, and long-term outcomes of renal transplantation were analyzed. Results: The bowel segments utilized for augmentation cystoplasty were the stomach in two patients (one patient needed revision using the ileum), the ileum in four patients, the ileocolic pouch in one patient, the sigmoid in one patient, and the ureter in one patient. All the cystoplasties were performed prior to renal transplantation. The mean follow-up period after transplantation was 161 months (range, 2-341 months). Two patients had an episode of acute rejection each; however, their graft functions were well-maintained. Five patients had recurrent urinary tract infections, and three of these patients progressed to allograft failure. One patient died from bladder cancer with a functioning graft. Five of nine patients showed well-maintained graft function. Conclusions: Renal transplantation after bladder augmentation surgery is a major operation requiring a high level of surgical skill. Based on our long-term experiences, we recommend diligent postoperative monitoring for urinary tract infections, optimal catheter use, and use of appropriate antibiotic prophylaxis to avoid severe complications.

The impact of national health insurance coverage on pit and fissure sealing experience.

INTRODUCTION: The purpose of this study was to review the change of supplied amount of oral pit and fissure sealing (PFS) in urban and rural areas of South Korea after including PFS into the list of treatments covered by the National Health Insurance (NHI), and to check whether there is a difference in supplied amount in areas where the dental treatment accessibility is different based on the data of the Korean National Health and Nutritional Examination Survey (KNHANES). METHODS: The KNHANES data year used for 'before coverage' was 2007, and that of 'after coverage' was 2012. Data analysis was done using STATA software. RESULTS: Areas were classified as urban or rural. Reduction of out-of-pocket expenses, according to the NHI coverage PFS experience of children aged 6-14 years, increased from 28.7% before coverage to 34.9% after coverage. PFS experience of children aged 6-14 years in the urban area was increased from 29.2% before coverage to 35.6% after coverage. The increase in rural areas was from 27.2% before coverage to 31.5% after coverage. CONCLUSIONS: Although PFS supplying was increased after inclusion in NHI coverage, it is still insufficient to reduce the decayed, missing, filled teeth index effectively. To reduce inequality, supply of PFS in rural area by community oral health program should be strengthened. And also, waiving out-of-pocket money for PFS in NHI should be considered.

Cytoplasmic pro-apoptotic function of the tumor suppressor p73 is mediated through a modified mode of recognition of the anti-apoptotic regulator Bcl-XL.

In response to genotoxic stress, the tumor suppressor protein p73 induces apoptosis and cell cycle arrest. Despite extensive studies on p73-mediated apoptosis, little is known about the cytoplasmic apoptotic function of p73. Here, using H1299 lung cancer cells and diverse biochemical approaches, including colony formation, DNA fragmentation, GST pulldown, and apoptosis assays along with NMR spectroscopy, we show that p73 induces transcription-independent apoptosis via its transactivation domain (TAD) through a mitochondrial pathway and that this apoptosis is mediated by the interaction between p73-TAD and the anti-apoptotic protein B-cell lymphoma-extra large (Bcl-XL or BCL2L1). This binding disrupted an interaction between Bcl-XL and the pro-apoptotic protein BH3-interacting domain death agonist (Bid). In particular, we found that a 16-mer p73-TAD peptide motif (p73-TAD16) mediates transcription-independent apoptosis, accompanied by cytochrome c release from the mitochondria, by interacting with Bcl-XL Interestingly, the structure of the Bcl-XL-p73-TAD16 peptide complex revealed a novel mechanism of Bcl-XL recognition by p73-TAD. We observed that the α-helical p73-TAD16 peptide binds to a noncanonical site in Bcl-XL, comprising the BH1, BH2, and BH3 domains in an orientation opposite to those of pro-apoptotic BH3 peptides. Taken together, our results indicate that the cytoplasmic apoptotic function of p73 is mediated through a noncanonical mode of Bcl-XL recognition. This finding sheds light on a critical transcription-independent, p73-mediated mechanism for apoptosis induction, which has potential implications for anticancer therapy.

Association of meal frequency with metabolic syndrome in Korean adults: from the Korea National Health and Nutrition Examination Survey (KNHANES).

BACKGROUND: Although previous studies have established a close relationship between caloric intake and metabolic syndrome, there is limited research exploring the impact of meal frequency adjusted by caloric intake on metabolic syndrome (MetS). OBJECTIVE: To evaluate the association of meal frequency and MetS after adjusting for confounding factors including caloric intake in Korean men and women. METHODS: We analyzed the national representative data of a total 12,389 adults (5171 men, 7218 women) from the Korean National Health and Nutrition Examination Survey (KNHANES) 2010-2012. Subjects were categorized as eating 3 meals/day (MF3) or 2 or fewer meals/day (MF ≤ 2). Daily caloric intake was calculated using CAN-Pro 4.0 (The Korean Nutrition Society, Seoul, Korea). RESULTS: The prevalence of components of MetS differed significantly according to meal frequency in both men and women. In an unadjusted analysis, the prevalence of MetS in women was significantly higher in the MF3 group than the MF ≤ 2 group (27.5% vs. 17.8%, P < 0.001), whereas the prevalence of MetS in men did not differ between the MF3 and MF ≤ 2 groups (24.6% vs. 22.7%, P = 0.281). However, after adjusting for age, caloric intake, smoking status, alcohol consumption, physical activity, income, and education level, men in the MF ≤ 2 group had an increased risk of metabolic syndrome compared to men in the MF3 group (OR = 1.37, 95%, CI = 1.12-1.67). On the other hand, meal frequency did not affect the risk of metabolic syndrome in women after adjusting for confounding factors including caloric intake (OR = 1.09, 95%, CI = 0.90-1.31). CONCLUSIONS: This study suggests that lower meal frequency adjusted for caloric intake, physical activity, age, smoking, alcohol, income, and education may be associated with increased risk of MetS in Korean men.

Skeletal overgrowth syndrome caused by overexpression of C-type natriuretic peptide in a girl with balanced chromosomal translocation, t(1;2)(q41;q37.1).

Chromosomal translocation of 2q37.1 just distal to the NPPC gene coding for C-type natriuretic peptide (CNP) and subsequent overproduction of CNP have been reported to cause a skeletal overgrowth syndrome. Loeys-Dietz syndrome (LDS) is one of marfanoid overgrowth syndromes, of which subtype IV is caused by haploinsufficiency of transforming growth factor beta 2 (TGFB2). We report on a girl with clinical phenotypes of overgrowth syndrome, including long and slim body habitus, macrodactyly of the big toe, scoliosis, ankle valgus deformity, coxa valga, slipped capital femoral epiphysis, and aortic root dilatation. Karyotyping revealed a balanced chromosomal translocation between 1q41 and 2q37.1, and the breakpoints could be mapped by targeted resequencing analysis. On chromosome 2q37.1, the translocation took place 200,365 bp downstream of NPPC, and serum level of the amino terminal of CNP was elevated. The contralateral site of translocation on chromosome 1q41 disrupted TGFB2 gene, presumed to cause its haploinsufficiency. This case supports the concept that NPPC is overexpressed because of the loss of a specific negative regulatory control in the normal chromosomal location, and demonstrates the effectiveness of targeted resequencing in the mapping of breakpoints.

HAX1 regulates E3 ubiquitin ligase activity of cIAPs by promoting their dimerization.

HS-1-associated protein X-1 (HAX1) is a multi-functional protein which was first identified as a Hematopoietic cell specific Lyn Substrate 1 (HS1)-binding protein. Although the roles of HAX1 in apoptosis have been unraveled and HAX1 has been proposed to be involved in several diseases, additional roles of HAX1 are still being identified. Here, we demonstrated that HAX1 directly interacted with cellular Inhibitor of Apoptosis Proteins (cIAPs), ubiquitin E3 ligases which regulate the abundance of cellular proteins, via ubiquitin-dependent proteasomal degradation. We showed that HAX1 promotes auto-ubiquitination and degradation of cIAPs by facilitating the intermolecular homodimerization of RING finger domain. Moreover, HAX1 regulates the non-canonical Nuclear Factor-κB (NF-κB) signaling pathway by modulating the stability of NF-κB-Inducing Kinase (NIK), which is one of the substrates of cIAPs. Taken together, these results unveil a novel role of HAX1 in the non-canonical NF-κB pathway, and provide an important clue that HAX1 is a potential therapeutic target for the treatment of cancer.

Monochorionic dizygotic twins with discordant sex and confined blood chimerism.

UNLABELLED: Monochorionic (MC) pregnancy in humans is usually considered to be associated only with monozygotic twinning. However, several reports have revealed that dizygotic (DZ) twins can also share a chorion during pregnancy. A chimera is defined as an organism that contains different cells derived from two or more distinct zygotes. As artificial reproductive techniques develop, it can be predicted that the occurrence of MC DZ twins will increase, and DNA-fingerprinting methods, such as short tandem repeat (STR) analysis, will be essential for their accurate diagnosis. We report the first Korean case of MC DZ twins with blood chimerism, 46,XX/46,XY, as a consequence of in vitro fertilization/embryo transfer. The clinical phenotypes of the twins' genitalia were complete female and male, respectively. Monochorionicity was confirmed by pathological analysis of the placenta after delivery. The dizygosity and confined blood chimerism of the twins were confirmed by STR analysis using their peripheral lymphocytes and skin fibroblasts. The confined blood chimerism of the twins can be considered similar to the status of the hematopoietic system in patients after allogenic bone marrow transplantation. CONCLUSION: When MC twins with discordant sex are expected during pregnancy, it is important to consider the possibility of DZ twins showing normal sexual development, especially in twins who were fertilized using artificial reproductive techniques.

A unique phenotype of 2q24.3-2q32.1 duplication: early infantile epileptic encephalopathy without mesomelic dysplasia.

The voltage-gated sodium channel genes and HOXD genes are clustered on chromosome 2q, and duplication of this region is associated with 2 clinical phenotypes: early-onset epilepsy and mesomelic dysplasia Kantaputra type, respectively. We report a case involving 2q24.3-2q32.1 duplication encompassing both the voltage-gated sodium channel and HOXD gene clusters, which were detected by a comparative genomic hybridization array. The associated clinical features were early-infantile-onset epilepsy, hypoplastic left heart syndrome, and global developmental delay. However, no features of mesomelic dysplasia were found. A fluorescent in situ hybridization study showed that the noncontiguous insertion of the duplicated chromosome 2q segment into chromosome 6q was inherited from the father, who has a balanced insertional translocation. The unique genotype-phenotype correlation in the present case suggests that dosage-sensitive effects might apply only to the voltage-gated sodium channel genes.

Co-chaperone CHIP associates with mutant Cu/Zn-superoxide dismutase proteins linked to familial amyotrophic lateral sclerosis and promotes their degradation by proteasomes.

Although the ubiquitin-proteasome system and the molecular chaperones are implicated to play an important role in pathogenesis of familial amyotrophic lateral sclerosis (FALS) caused by mutations in Cu/Zn-superoxide dismutase (SOD1), the mechanism underlying the causes of this fatal disease is still poorly understood. Here we found that co-chaperone CHIP (carboxyl terminus of Hsc70-interacting protein), together with molecular chaperones Hsc70/Hsp70 and Hsp90, associates with FALS-linked mutant SOD1 proteins in cultured human cells. S5a subunit of 26S proteasomes, which recognizes polyubiquitylated proteins, also interacts with mutant SOD1 proteins. Over-expression of CHIP leads to the reduction in cellular levels of mutant SOD1 as well as the suppression of cytotoxicity induced by mutant SOD1. Unusually, rather than increasing the level of poly-ubiquitylated SOD1, over-expressed CHIP alters the ubiquitylation pattern of mutant SOD1 proteins. Both down-regulation and ubiquitylation of mutant SOD1 are greatly reduced by a mutant CHIP protein lacking U-box domain. Taken together, these results suggest that co-chaperone CHIP, possibly with another E3 ligase(s), modulates the ubiquitylation of mutant SOD1 and renders them more susceptible for proteasomal degradation.