Gene-specific somatic epigenetic mosaicism of FDFT1 underlies a non-hereditary localized form of porokeratosis.

Porokeratosis is a clonal keratinization disorder characterized by solitary, linearly arranged, or generally distributed multiple skin lesions. Previous studies showed that genetic alterations in MVK, PMVK, MVD, or FDPS-genes in the mevalonate pathway-cause hereditary porokeratosis, with skin lesions harboring germline and lesion-specific somatic variants on opposite alleles. Here, we identified non-hereditary porokeratosis associated with epigenetic silencing of FDFT1, another gene in the mevalonate pathway. Skin lesions of the generalized form had germline and lesion-specific somatic variants on opposite alleles in FDFT1, representing FDFT1-associated hereditary porokeratosis identified in this study. Conversely, lesions of the solitary or linearly arranged localized form had somatic bi-allelic promoter hypermethylation or mono-allelic promoter hypermethylation with somatic genetic alterations on opposite alleles in FDFT1, indicating non-hereditary porokeratosis. FDFT1 localization was uniformly diminished within the lesions, and lesion-derived keratinocytes showed cholesterol dependence for cell growth and altered expression of genes related to cell-cycle and epidermal development, confirming that lesions form by clonal expansion of FDFT1-deficient keratinocytes. In some individuals with the localized form, gene-specific promoter hypermethylation of FDFT1 was detected in morphologically normal epidermis adjacent to methylation-related lesions but not distal to these lesions, suggesting that asymptomatic somatic epigenetic mosaicism of FDFT1 predisposes certain skin areas to the disease. Finally, consistent with its genetic etiology, topical statin treatment ameliorated lesions in FDFT1-deficient porokeratosis. In conclusion, we identified bi-allelic genetic and/or epigenetic alterations of FDFT1 as a cause of porokeratosis and shed light on the pathogenesis of skin mosaicism involving clonal expansion of epigenetically altered cells.

Bone loss over time and risk of osteoporosis in advanced pancreatic cancer.

BACKGROUND: Pancreatic cancer has a high risk of developing osteoporosis. However, the impact of osteoporosis has not been well-studied. This study aimed to evaluate bone loss over time and risk of osteoporosis in patients with advanced pancreatic cancer. METHODS: We retrospectively examined consecutive patients with unresectable pancreatic cancer who had evaluable computed tomography before treatment and at 1-year follow-up. Bone mineral density at the first lumbar vertebra was measured on computed tomography, and osteoporosis was defined as bone mineral density < 135 Hounsfield units. The prevalence and risk factors for osteoporosis, changes in bone mineral density over time and incidence of bone fractures were analyzed. RESULTS: Three hundred eighty patients were included. Osteoporosis was associated with older age, female sex, low body mass index and poor performance status at baseline. A consistent decrease in bone mineral density was observed over time regardless of age, sex or disease status, resulting in an increase in the prevalence of osteoporosis over time (47% at baseline, 79% at 1 year, 88% at 2 years, 89% at 3 years, 95% at 4 years and 100% at 5 years). Changes in bone mineral density from baseline were greater in patients with locally-advanced pancreatic cancer, in those who received modified FOLFIRINOX or S-IROX for more than 3 months, and in those who received radiation therapy. Incident fractures developed in 45 patients (12%) during follow-up. CONCLUSIONS: Osteoporosis and osteoporotic fractures were highly prevalent in patients with advanced pancreatic cancer. This study highlights the importance of screening for osteoporosis in such patients.

Early versus delayed EUS-guided drainage for postoperative pancreatic fluid collections: a systematic review and meta-analysis.

BACKGROUND: Postoperative pancreatic fluid collections (POPFCs) are common adverse events (AEs) after pancreatic surgery and may need interventions. Endoscopic ultrasound (EUS)-guided drainage for POPFCs is increasingly reported, but its appropriate timing has not been fully elucidated. The aim of this meta-analysis was to evaluate treatment outcomes of POPFCs according to the timing of EUS-guided drainage. METHODS: Using PubMed, Embase, Web of Science, and the Cochrane database, we identified clinical studies published until December 2022 with data comparing outcomes of early and delayed EUS-guided drainage for POPFCs. We pooled data on AEs, mortality, and technical and clinical success rates, using the random-effects model. RESULTS: From 1415 papers identified in the initial literature search, we identified 6 retrospective studies, including 128 and 107 patients undergoing early and delayed EUS-guided drainage for POPFCs. The threshold of early and delayed drainage ranged from 14 to 30 days. Distal pancreatectomy was the major cause of POPFCs, ranging from 44 to 100%. The pooled odds ratio (OR) for AEs was 0.81 (95% confidence interval [CI] 0.40-1.64, P = 0.55) comparing early to delayed drainage. There was no procedure-related mortality. Technical success was achieved in all cases and a pooled OR of clinical success was 0.60 (95% CI 0.20-1.83, P = 0.37). CONCLUSION: POPFCs can be managed by early EUS-guided drainage without an increase in AEs.

TOKYO criteria 2024 for the assessment of clinical outcomes of endoscopic biliary drainage.

The consensus-based TOKYO criteria were proposed as a standardized reporting system for endoscopic transpapillary biliary drainage. The primary objective was to address issues arising from the inconsistent reporting of stent outcomes across studies, which has complicated the comparability and interpretation of study results. However, the original TOKYO criteria were not readily applicable to recent modalities of endoscopic biliary drainage such as biliary drainage based on endoscopic ultrasound or device-assisted endoscopy. There are increasing opportunities for managing hilar biliary obstruction and benign biliary strictures through endoscopic drainage. Biliary ablation has been introduced to manage benign and malignant biliary strictures. In addition, the prolonged survival times of cancer patients have increased the importance of evaluating overall outcomes during the period requiring endoscopic biliary drainage rather than solely focusing on the patency of the initial stent. Recognizing these unmet needs, a committee has been established within the Japan Gastroenterological Endoscopy Society to revise the TOKYO criteria for current clinical practice. The revised criteria propose not only common reporting items for endoscopic biliary drainage overall, but also items specific to various conditions and interventions. The term "stent-demanding time" has been defined to encompass the entire duration of endoscopic biliary drainage, during which the overall stent-related outcomes are evaluated. The revised TOKYO criteria 2024 are expected to facilitate the design and reporting of clinical studies, providing a goal-oriented approach to the evaluation of endoscopic biliary drainage.

Serum DUPAN-2 could be an Alternative Biological Marker for CA19-9 Nonsecretors with Pancreatic Cancer.

OBJECTIVE: This study investigates the use of serum DUPAN-2 in predicting the PC progression in CA19-9 nonsecretors. BACKGROUND: Although we previously reported that serum CA19-9 >500U/ mL is a poor prognostic factor and an indication for enhanced neoadjuvant treatment, there is not a biomarker surrogate that equivalently predicts prognosis for CA19-9 nonsecretors. METHODS: We evaluated consecutive PC patients who underwent pancreatectomy from 2005 to 2019. All patients were categorized as either nonsecretor or secretor (CA19-9 ≤ or >2.0U/mL). RESULTS: Of the 984 resected PC patients, 94 (9.6%) were nonsecretors and 890 (90.4%) were secretors. The baseline characteristics were not statistically different between the 2 groups except for the level of DUPAN-2 (720 vs. 100U/mL, P < 0.001). Survival curves after resection were similar between the 2 groups (29.4 months vs. 31.3 months, P = 0.900). Survival curves of patients with DUPAN-2 >2000U/mL in the nonsecretors and patients with CA19-9 >500U/mL in the secretors were nearly equivalent as well (hazard ratio 2.08 vs. 1.89). In the multivariate analysis, DUPAN-2 >2000U/mL (hazard ratio 2.53, P = 0.010) was identified as independent prognostic factor after resection. CONCLUSION: DUPAN-2 >2000U/mL in CA19-9 nonsecretors can be an unfavorable factor that corresponds to CA19-9 >500U/mL in CA19-9 secretors which is an indicator for enhanced neoadjuvant treatment. The current results shed light on the subset of nonsecretors with poor prognosis that were traditionally categorized in a group with a more favorable prognosis group.

Identification of α-ionone, nootkatone, and their derivatives as TGR5 agonists.

TGR5 is a G-protein-coupled receptor that is activated by bile acids. The activation of TGR5 in brown adipose tissue (BAT) increases energy expenditure by increasing the expression level of thermogenesis-related genes, such as peroxisome proliferator-activated receptor-gamma coactivator 1-alpha, uncoupling protein 1, and type II iodothyronine deiodinase. Therefore, TGR5 is a potential drug target in treating obesity and associated metabolic disorders. In this study, we identified the aroma compounds α-ionone and nootkatone as well as their derivatives as TGR5 agonists by using the luciferase reporter assay system. These compounds had little effect on the activity of the farnesoid X receptor, a nuclear receptor activated by bile acids. Mice fed 0.2% α-ionone containing high-fat diet (HFD) increased the thermogenesis-related gene expression level in BAT and suppressed weight gain compared with mice fed a normal HFD. These findings indicate that aromatic compounds with TGR5 agonist activity are promising chemicals to prevent obesity.

Clinical Efficacy of Neoadjuvant Chemotherapy with Gemcitabine plus S-1 for Resectable Pancreatic Ductal Adenocarcinoma Compared with Upfront Surgery.

BACKGROUND: The efficacy of neoadjuvant chemotherapy with gemcitabine plus S-1 (NAC-GS) in the prognosis of patients with resectable pancreatic ductal adenocarcinoma (PDAC) has been reported. NAC-GS is now assumed to be a standard regimen for resectable PDAC in Japan. However, the reason for this improvement in prognosis remains unclear. METHODS: In 2019, we introduced NAC-GS for resectable PDAC. From 2015 to 2021, 340 patients were diagnosed with resectable PDAC (anatomical and biological [carbohydrate antigen (CA) 19-9 < 500 U/mL]) and were divided according to the treatment period (upfront surgery [UPS] group, 2015-2019, n = 241; NAC-GS group, 2019-2021, n = 80). We used "intention-to-treat" analysis to compare the clinical outcomes of NAC-GS to those of UPS. RESULTS: Of the 80 patients with NAC-GS, 75 (93.8%) completed two cycles of NAC-GS, and the resection rate of the NAC-GS group was comparable to that of the UPS group (92.5 vs. 91.3%, P = 0.73). The R0 resection rate was significantly higher in the NAC-GS group than in the UPS group (91.3 vs. 82.6%, P = 0.04), even though the surgical burden was smaller. Progression-free survival tended to be better (hazard ratio [HR] = 0.70, P = 0.06), and overall survival was significantly better in the NAC-GS group than in the UPS group (HR 0.55, P = 0.02). CONCLUSIONS: NAC-GS provided improvements in microscopic invasion leading to a high R0 rate and smooth administration and completion of adjuvant therapy, which might lead to an improved prognosis in patients with resectable PDAC.

A prospective multicenter phase II study of FOLFIRINOX as a first-line treatment for patients with advanced and recurrent biliary tract cancer.

Given the promising activity and tolerability of FOLFIRINOX as a second-line treatment for advanced biliary tract cancer (BTC), it can be an attractive first-line treatment option as well. This is a single-arm, open-label, multicenter phase II study to evaluate the safety and efficacy of FOLFIRINOX as a first-line treatment for patients with advanced BTC. Primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), tumor response and safety. This study defined primary endpoint might be met when the lower limit value of 80% confidence interval [CI] of the median PFS ≥ 6.0 months. Between June 2016 and March 2020, 35 BTC patients (21 intrahepatic, 10 extrahepatic, 2 gallbladder, 2 ampulla) including 26 unresectable and 9 recurrent disease were enrolled. After a median follow-up of 13.9 months, the median PFS and OS were 7.4 (80% CI, 5.5-7.5) and 14.7 (80% CI, 11.8-15.7) months, respectively. Complete response was achieved in 1 (2.9%) and partial response in 10 (28.6%), giving an objective response rate of 31.4% and disease control rate of 74.3%. Major grade 3-4 adverse events included neutropenia (54.3%), leukopenia (34.4%), febrile neutropenia (17.1%), thrombocytopenia (8.6%), cholangitis (8.6%), anemia, nausea, diarrhea, and peripheral sensory neuropathy (2.9% each). FOLFIRINOX was well tolerable in patients with advanced BTC, however, this study did not meet the primary endpoint to conduct a phase III trial. Thus, further explorations are required to find a subset of patients and/or certain clinical scenario which might be beneficial from FOLFIRINOX.

GC-MS analysis of exhaled gas for fine detection of inflammatory diseases.

Exhaled gas analysis is a non-invasive test ideal for continuous monitoring of biological metabolic information. We analyzed the exhaled gas of patients with inflammatory diseases for trace gas components that could serve as biomarkers that enable early detection of inflammatory diseases and assessment of treatment efficacy. Furthermore, we examined the clinical potential of this method. We enrolled 34 patients with inflammatory disease and 69 healthy participants. Volatile components from exhaled gas were collected and analyzed by a gas chromatography-mass spectrometry system, and the data were examined for gender, age, inflammatory markers, and changes in markers before and after treatment. The data were tested for statistical significance through discriminant analysis by Volcano plot, Analysis of variance test, principal component analysis, and cluster analysis comparing healthy and patient groups. There were no significant differences in the trace components of exhaled gas by gender or age. However, we found differences in some components of the exhaled gas between healthy and untreated patients. In addition, after treatment, gas patterns including the patient-specific components changed to a state closer to the inflammation-free status. We identified trace components in the exhaled gas of patients with inflammatory diseases and found that some of these regressed after treatment.

Prognostic impact of osteosarcopenia in patients with advanced pancreatic cancer receiving gemcitabine plus nab-paclitaxel.

BACKGROUND: Osteosarcopenia, defined as the combination of osteoporosis and sarcopenia, has recently gained attention as a novel prognostic factor for survival in patients with cancer. This study aimed to evaluate the prognostic impact of osteosarcopenia in metastatic pancreatic cancer (PC). METHODS: We retrospectively investigated consecutive metastatic PC patients receiving first-line gemcitabine plus nab-paclitaxel (GnP). Skeletal muscle index at the third lumbar vertebra and bone mineral density at the first lumbar vertebra were measured using pretreatment computed tomography. Treatment outcomes of osteosarcopenia and non-osteosarcopenia groups were compared and analyzed. Multivariate analysis was performed to identify variables associated with survival. RESULTS: Among 313 patients, osteosarcopenia was present in 59 patients (19%). The osteosarcopenia group was associated with older age, higher proportion of females, worse performance status, and higher modified Glasgow prognostic scores (mGPS). Response rates to chemotherapy, progression-free survival (3.5 months vs. 6.4 months, p < 0.001), and overall survival (5.6 months vs. 13.0 months, p < 0.001) were significantly better in the non-osteosarcopenia group. Osteosarcopenia, performance status of 1-2, mGPS score of 1-2, carcinoembryonic antigen ≥10 ng/mL, and carbohydrate antigen 19-9 ≥ 1000 IU/mL were identified as independent factors predicting shorter survival. Grade 3 or higher anemia and febrile neutropenia occurred more frequently in the osteosarcopenia group. CONCLUSIONS: Osteosarcopenia was associated with poor survival in metastatic PC treated with first-line GnP. Screening for osteosarcopenia may be helpful for better management of metastatic PC.

"Conversion surgery" for locally advanced pancreatic cancer: A position paper by the study group at the joint meeting of the International Association of Pancreatology (IAP) & Japan Pancreas Society (JPS) 2022.

Locally advanced pancreatic cancer (LAPC), which progresses locally and surrounds major vessels, has historically been deemed unresectable. Surgery alone failed to provide curative resection and improve overall survival. With the advancements in treatment, reports have shown favorable results in LAPC after undergoing successful chemotherapy therapy or chemoradiation therapy followed by surgical resection, so-called "conversion surgery", at experienced high-volume centers. However, recognizing significant regional and institutional disparities in the management of LAPC, an international consensus meeting on conversion surgery for LAPC was held during the Joint Congress of the 26th Meeting of the International Association of Pancreatology (IAP) and the 53rd Annual Meeting of Japan Pancreas Society (JPS) in Kyoto in July 2022. During the meeting, presenters reported the current best multidisciplinary practices for LAPC, including preoperative modalities, best systemic treatment regimens and durations, procedures of conversion surgery with or without vascular resections, biomarkers, and genetic studies. It was unanimously agreed among the experts in this meeting that "cancer biology is surpassing locoregional anatomical resectability" in the era of effective multiagent treatment. The biology of pancreatic cancer has yet to be further elucidated, and we believe it is essential to improve the treatment outcomes of LAPC patients through continued efforts from each institution and more international collaboration. This article summarizes the agreement during the discussion amongst the experts in the meeting. We hope that this will serve as a foundation for future international collaboration and recommendations for future guidelines.

Synthesis and properties of a novel modified nucleic acid, 2'-N-methanesulfonyl-2'-amino-locked nucleic acid.

2'-Amino-locked nucleic acid has a functionalizable nitrogen atom at the 2'-position of its furanose ring that can provide desired properties to a nucleic acid as a scaffold. In this study, we synthesized a novel nucleic acid, 2'-N-methanesulfonyl-2'-amino-locked nucleic acid (ALNA[Ms]) and conducted comparative studies on the physical and pharmacological properties of the ALNA[Ms] and on conventional nucleic acids, such as 2'-methylamino-LNA (ALNA[Me]), which is a classical 2'-amino-LNA derivative, and also on 2',4'-BNA/LNA (LNA). ALNA[Ms] oligomers exhibited binding affinities for the complementary RNA strand that are similar to those of conventional nucleic acids. Four types of ALNA[Ms] nucleosides exhibited no genotoxicity in bacterial reverse mutation assays. The knockdown abilities of Malat1 RNA using the Matat1 antisense oligonucleotide (ASO) containing ALNA[Ms] were higher than those of ALNA[Me] and were closer to those of LNA. Furthermore, the ASO containing ALNA[Ms] showed different tissue tropism from that containing LNA. ALNA[Ms] exhibited biological activities that were distinct from conventional constrained nucleic acids, suggesting the possibility that ALNA[Ms] can serve as novel modified nucleic acids in oligonucleotide therapeutics.

Recent prevalence and characteristics of patients with hepatitis delta virus in Hokkaido, Japan.

AIM: Although hepatitis delta virus (HDV) coinfection with hepatitis B virus (HBV) is a global health concern, the global prevalence of HDV infections remains unknown due to insufficient data in many countries. In Japan, HDV prevalence has not been updated for over 20 years. We aimed to investigate the recent prevalence of HDV infections in Japan. METHODS: We screened 1264 consecutive patients with HBV infection at Hokkaido University Hospital between 2006 and 2022. Patients' serums were preserved and subsequently tested for HDV antibody (immunoglobulin-G). Available clinical information was collected and analyzed. We compared the changes in liver fibrosis using the Fibrosis-4 (FIB-4) index between propensity-matched patients with and without the evidence of anti-HDV antibodies and corrected for baseline FIB-4 index, nucleoside/nucleotide analog treatment, alcohol intake, sex, HIV coinfection, liver cirrhosis, and age. RESULTS: After excluding patients without properly stored serums and those lacking appropriate clinical information, 601 patients with HBV were included. Of these, 1.7% of patients had detectable anti-HDV antibodies. Patients with anti-HDV antibody serum positivity had a significantly higher prevalence of liver cirrhosis, significantly lower prothrombin time, and a higher prevalence of HIV coinfection than those who demonstrated serum anti-HDV antibody negativity. A propensity-matched longitudinal analysis revealed that liver fibrosis (FIB-4 index) progressed more rapidly in patients with positive results for anti-HDV antibody tests. CONCLUSIONS: The recent prevalence of HDV infections in Japanese patients with HBV was 1.7% (10/601). These patients experienced rapid liver fibrosis progression, highlighting the importance of routine HDV testing.

Hepatitis C virus eradication by direct-acting antivirals causes a simultaneous increase in the prevalence of fatty liver and hyper low-density lipoprotein cholesterolemia without an increase in body weight.

AIM: Hepatitis C virus (HCV) infection has been reported to cause liver steatosis. Thus, eradicating HCV with direct-acting antivirals (DAAs) is expected to reduce liver steatosis. We aimed to clarify long-term changes in the prevalence of fatty liver and hyper-low-density lipoprotein (LDL) cholesterolemia and their associations in patients who achieve successful HCV eradication using DAAs. METHODS: This retrospective study included patients with HCV who achieved sustained virologic response after interferon-free DAA and analyzed the changes in the prevalence of fatty liver diagnosed with controlled attenuation parameter (CAP), hyper-LDL cholesterolemia, and their relationships at baseline (n = 100) and 24 weeks (SVR24, n = 100), 96 weeks (SVR96, n = 100), and 144 weeks (SVR144, n = 90) after DAA. RESULTS: In 100 participants, the prevalence of fatty liver (19% vs. 32%, p = 0.0349) and hyper-LDL cholesterolemia (6% vs. 15%, p = 0.0379) significantly increased without changes in body weight at SVR96. Median total cholesterol, low-density lipoprotein cholesterol (LDL-C), and small-dense-LDL (sdLDL) levels and CAP values were significantly greater at SVR24, SVR96, and SVR144 than at baseline. Baseline CAP values and changes in CAP values were significantly negatively correlated at every observation point: r = -0.5305, p < 0.0001 at SVR24; r = -0.3617, p = 0.0005 at SVR96; and r = -0.4735, p < 0.0001 at SVR144. A similar relationship was observed in cholesterol levels. Unlike at baseline, CAP values were significantly positively correlated with LDL-C and sdLDL-C levels at all observation points after DAAs. CONCLUSIONS: Direct-acting antivirals may cause an increased prevalence of fatty liver accompanying hyper-LDL cholesterolemia without increased body weight. As post-SVR liver steatosis could cause HCC, careful follow-up may be required.

The impact of osteosarcopenia in patients with unresectable or recurrent biliary tract cancer receiving palliative chemotherapy.

BACKGROUND: Osteosarcopenia is a newly described syndrome that has been reported to be associated with worse outcomes in various types of cancer. However, its impact on survival in biliary tract cancer remains unclear. This study evaluated the impact of osteosarcopenia on survival in patients with unresectable or recurrent biliary tract cancer. METHODS: A total of 306 patients with unresectable or recurrent biliary tract cancer who initiated chemotherapy at our institution between 2015 and 2021 were retrospectively investigated. Skeletal muscle index and bone mineral density were measured using pretreatment cross-sectional computed tomography images. Baseline characteristics and survival outcomes were compared between patients with osteosarcopenia and those without. The Cox proportional hazards regression model was used to identify factors associated with survival. RESULTS: Osteosarcopenia was present in 66 patients (22%) and was associated with older age (74 vs. 69 years, P < 0.001) and female sex (58 vs. 37%, P = 0.003). Patients with osteosarcopenia tended to have worse performance status (P = 0.098), higher modified Glasgow prognostic score (P = 0.082), higher neutrophil to lymphocyte ratio (P = 0.058) and were significantly less likely to receive combination chemotherapy (68 vs. 80%, P = 0.044) than those without. Osteosarcopenia was associated with reduced survival (8.9 vs. 14.0 months, P < 0.001) and was identified as an independent factor predicting shorter survival in multivariate analysis. CONCLUSIONS: Osteosarcopenia was associated with poor survival in unresectable or recurrent biliary tract cancer treated with chemotherapy. This study highlights the potential importance of screening for osteosarcopenia in patients with biliary tract cancer.

Outcomes of lung oligometastasis in pancreatic cancer.

OBJECTIVE: Pancreatic cancer with lung oligometastasis may have favourable overall survival. The aim of this study was to evaluate outcomes of pancreatic cancer with lung oligometastases including both synchronous and metachronous metastases. METHODS: Consecutive pancreatic cancer patients with lung metastasis treated at our institution between February 2015 and December 2021 were identified from our prospectively maintained database. Clinical characteristics and outcomes were compared and analysed according to the extent of lung metastases. Predictors for overall survival were analysed using the Cox proportional hazards model. RESULTS: A totoal of 171 patients were included (oligometastasis/polymetastasis/multi-organ metastasis: 34/50/87). Patients with oligometastases were more likely to undergo surgical resection (41% vs. 0% vs. 2%) and showed a longer median overall survival (41.3 vs. 17.6 vs. 13.1 months) compared with those with other types of metastases. Oligometastasis (hazard ratio, 0.43; 95% confidence interval, 0.24-0.76; P = 0.004) was identified as an independent factor predicting favourable overall survival in patients with lung-only metastasis. Disease status (synchronous vs. metachronous) was not associated with survival in patients with oligometastasis (29.4 vs. 41.3 months, P = 0.527) and polymetastasis (17.9 vs. 16.7 months, P = 0.545). Selected patients who underwent surgical resection showed a median overall survival of 52.7 months. CONCLUSIONS: Patients with lung oligometastases presented a favourable prognosis. Surgical resection in selected patients was associated with a long median overall survival.

Long-term outcomes of duckbill-type anti-reflux metal stents versus conventional covered metal stents in reinterventions after covered biliary metal stent dysfunction in unresectable pancreatic cancer.

BACKGROUND: The use of duckbill-type anti-reflux metal stents (DMS) in reinterventions after covered metal stent (CMS) dysfunction has been reported in patients with distal malignant biliary obstruction (MBO). However, the superiority of DMS over conventional CMS (c-CMS) has not been established. Therefore, we conducted this retrospective study to evaluate the long-term efficacy and safety of DMS as a second stent in comparison with c-CMS. METHODS: We investigated consecutive patients with distal MBO due to unresectable pancreatic cancer who underwent reintervention after dysfunction of initial biliary CMS at our institution. We compared causes of recurrent biliary obstruction (RBO), time to RBO (TRBO), adverse events (AEs), and reintervention rates of DMS and c-CMS in this stenting. RESULTS: A total of 76 patients were included (DMS 41 and c-CMS 35). While overall RBO rates were similar between the two groups (46% vs. 63%, p = 0.172), RBO due to non-occlusion cholangitis tended to be less frequent in the DMS group than in the c-CMS group (2% vs. 14%, p = 0.089). Median TRBO was significantly longer in the DMS group (286 days vs. 112 days, p = 0.029). DMS was identified as the only significant risk factor for TRBO (hazard ratio, 0.52; p = 0.044). Overall AE rates were significantly lower in the DMS group (2% vs. 23%, p = 0.010), with non-occlusion cholangitis being the most common AE in the c-CMS group. Endoscopic reintervention was successfully performed in all patients in both groups, despite failed stent removal in 15% of patients in DMS group. CONCLUSIONS: DMS was associated with a significantly longer TRBO and lower rate of AEs compared with c-CMS in reinterventions after initial CMS dysfunction. DMS may be preferable to c-CMS as a second stent after biliary CMS dysfunction.

Outcomes after partially covered self-expandable metal stent placement for recurrent duodenal obstruction.

BACKGROUND: Outcomes of partially covered self-expandable metal stents (SEMS) as an additional stent after recurrent duodenal obstruction (RDO) have not been elucidated. In this study, we compared outcomes of partially covered and uncovered SEMS placement after RDO in patients with malignant duodenal obstruction and explored factors affecting re-recurrent obstruction and overall survival in this population. METHODS: We conducted a retrospective study of patients undergoing SEMS placement for RDO at a cancer institute in Japan from July 2014 to June 2021. Clinical variables and outcomes of patients undergoing partially covered and uncovered SEMS placement were compared. RESULTS: Sixty-one patients underwent SEMS placement after RDO, for which the COMVI stent was used in 38 cases and uncovered stents were used in 23 cases. Stent ingrowth was the most common cause of RDO (51.4%). Stent migration only occurred after partially covered stent placement (20% vs. 0%, p = 0.018). Choice of SEMS had no impact on time to re-RDO (median 2.8 vs. 4.1 months, p = 0.776) or overall survival (median 2.6 vs. 2.4 months, p = 0.703). Median overall survival was longer in patients receiving chemotherapy after second stenting (4.6 vs. 1.8 months, p < 0.001) and shorter in those with early RDO, regardless of the SEMS used. Use of the partially covered stent had no impact on survival or time to RDO. CONCLUSIONS: While outcomes after partially covered SEMS placement for RDO were not significantly different from uncovered SEMS, migration remains a concern when they are used as a second stent. Chemotherapy after second stenting was associated with longer overall survival but not with longer time to re-RDO.

Dietary protein intake and all-cause mortality: results from The Kawasaki Aging and Wellbeing Project.

BACKGROUND: Increased protein intake has been recommended to prevent sarcopenia/frailty, reports on the quantity and quality of protein intake needed and the associated prognosis, particularly in the aging population of Asia, are limited. In this study, we aimed to investigate the relationship between protein intake and mortality in Japanese individuals, aged 85 years and older. METHODS: The data were obtained from The Kawasaki Aging and Wellbeing Project, which is a prospective cohort study of older adults aged between 85 and 89 years with no physical disability at baseline. Of the 1,026 adults in the cohort, 833 were included in the analysis, after excluding those who had not completed a brief, self-administered diet history questionnaire or those who scored less than 24 on the Mini-Mental State Examination. The participants were grouped into quartiles based on protein intake: Q1 (protein < 14.7, %Energy), Q2 (14.7 ≤ protein < 16.7, %Energy), Q3 (16.7 ≤ protein < 19.1, %Energy), and Q4 (≥ 19.1, %Energy). Multivariate Cox proportional hazards models were utilized to evaluate the association between protein intake and all-cause mortality. Kaplan-Meier survival curves were employed to investigate the relationship between protein intake and all-cause mortality. RESULTS: The mean protein intake of our study population was 17.0% of total energy. Animal protein intake, particularly fish intake, increased significantly along with total protein intake. The study had an average observation period of 1,218 days and recorded 89 deaths. After adjusting for age, sex, skeletal muscle mass index, cardiovascular disease, cancer, education, and serum albumin levels, a lower risk of all-cause mortality was observed in the highest protein intake (Q4) group than in the lowest protein intake (Q1) group (hazard ratio: 0.44, 95% confidence interval: 0.22-0.90, p-value: 0.020). CONCLUSION: Protein intake is associated with a reduced risk of all-cause mortality in older adults (aged ≥ 85 years) who engage in independent activities of daily living. This association may impact all-cause mortality independent of muscle mass.

A case of severe respiratory failure due to interstitial pneumonia successfully bridged to lung transplantation from a brain-dead donor using 109-day veno-arterial extracorporeal membrane oxygenation.

In Japan, successful cases of a bridge to lung transplantation (BTT) by extracorporeal membrane oxygenation (ECMO) are rare. We present the case of a man in his thirties, diagnosed with interstitial pneumonia 6 years prior and registered for lung transplant 1 year prior due to disease progression despite treatment. Due to the patient's worsening respiratory failure, he was transferred to our hospital for BTT by ECMO. Since long-term management was expected and pulmonary hypertension was present, veno-arterial (V-A) ECMO was conducted using the right atrial blood outflow via the right internal jugular vein and right axillary artery inflow via a vascular graft. After tracheostomy, he was managed as "Awake ECMO". In addition, interprofessional collaboration such as physiotherapist rehabilitation, nurses, and liaison teams prevented muscle weakness and supported the mental aspect. We were able to minimize complications such as severe infections and bleeding. A compatible brain-dead donor was found on day 108 after introducing ECMO, and the patient was transferred to a transplant facility on day 109. The peripheral upper V-A ECMO is one of the configurations suitable for long-term BTT management.