non-DP Group Research Articles

6376 Wnt/beta-catenin Pathway is Associated with Cell Proliferation in Growth Hormone-producing Pituitary Tumors

Abstract Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. M. Fujimura: None. T. Atsumi: None. Objective: It has been well recognized that the Wnt/β-catenin pathway regulates cell proliferation, and that translocation of β-catenin from the cytoplasm to the nucleus promotes cell proliferation. There have been, however, limited reports on the Wnt/β-catenin pathway in growth hormone-producing pituitary tumors (GHomas), and we aimed to investigate the impact of the Wnt/β-catenin pathway on cell proliferation in GHomas. Methods: We performed three types of experiments with patient pathological specimens, disease model cell lines, and primary culture of GHoma cells. 1.The intracellular localization of β-catenin was evaluated using immunofluorescence staining of pathological specimens from GHoma patients and subsequently its association with clinical data was analyzed. 2.The Wnt/β-catenin inhibitor iCRT14 was administered to rat GHoma cells GH1, using the WST-1 assay to measure cell viability and real-time PCR to assess GH and cell cycle genes expression. 3. The Wnt/β-catenin inhibitor iCRT14 was added to cultured cells obtained from GHoma patients to evaluate cell viability and gene expression. Results: 1. Samples from 26 cases (42%) exhibited strong dot-like expression of β-catenin in the nucleus (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). Tumors in the DP group had a larger size than non-DP group (diameters 18.3±9.2 vs. 13.4±7.4 mm, p<0.05), and the postoperative remission rate was lower (23 vs. 50%, p<0.05). 2. Viability evaluation using WST-1 assay showed a maximum decrease of 25%. Gene expression showed concentration-dependent reduction in GH gene expression by up to 40% (p<0.05) and cyclin D1 gene up to 50% (p<0.05) following iCRT14 administration. 3. Among 6 cases, 3 showed a tendency toward cell growth inhibition, and 4 showed a tendency toward decreased cyclin D1 gene expression. Conclusion: It is suggested that the Wnt/β-catenin pathway is activated in the DP group because of the nucleus accumulation of β-catenin, and given the larger tumor size and lower postoperative remission rate in DP group, the Wnt/β-catenin pathway may stimulate cell proliferation in GHomas. In addition, cyclin D1-mediated effects were considered. Wnt/β-catenin pathway could play a role in GHomas growth, therefore this pathway would be a potential therapeutic target for treating affected patients. Presentation: 6/3/2024

Defecation Symptoms in Relation to Stool Consistency Significantly Reflect the Dyssynergic Pattern in High-resolution Anorectal Manometry in Constipated Patients.

To evaluate the usefulness of a 2-week patient-completed bowel habit and symptom diary as a screening tool for disordered rectoanal coordination (DRC). DRC is an important subgroup of chronic constipation that benefits from biofeedback treatment. Diagnosis of DRC requires a dyssynergic pattern (DP) of attempted defecation in high-resolution anorectal manometry (HRAM) and at least 1 other positive standardized examination, such as the balloon expulsion test or defecography. However, HRAM is generally limited to tertiary gastroenterology centres and finding tools for selecting patients for referral for further investigations would be of clinical value. Retrospective data from HRAM and a 2-week patient-completed bowel habit and symptom diary from 99 chronically constipated patients were analyzed. Fifty-seven percent of the patients had a DP pattern during HRAM. In the DP group, 76% of bowel movements with loose or normal stool resulted in a sense of incomplete evacuation compared with 55% of the non-DP group ( P =0.004). Straining and sensation of incomplete evacuation with the loose stool were significantly more common in the DP group ( P =0.032). Hard stool was a discriminator for non-DP ( P =0.044). Multiple logistic regression including incomplete evacuation and normal stool predicted DP with a sensitivity of 82% and a specificity of 50%. The sensation of incomplete evacuation with loose or normal stool could be a potential discriminator in favor of DP in chronically constipated patients. The bowel habit and symptom diary may be a useful tool for stratifying constipated patients for further investigation of suspected DRC.

THU044 The Subcellular Localization Of β-Catenin Is Associated With Tumor Size And The Surgical Remission Rate In Growth Hormone-producing Pituitary Adenomas

Abstract Disclosure: S. Kuwabara: None. H. Kameda: None. H. Nomoto: None. K. Cho: None. A. Nakamura: None. Y. Ishi: None. H. Motegi: None. F. Miki: None. H. Miyoshi: None. T. Atsumi: None. The Wnt/β-catenin pathway is the best understood Wnt signaling pathway and controls cell proliferation. In the presence of Wnt, the translocation of β-catenin from the cytoplasm to the nucleus leads to pathway activation. It has been reported that the nuclear accumulation of β-catenin is associated with Ki-67 expression in pituitary adenomas and that the invasiveness of growth hormone (GH)-producing pituitary adenomas is associated with β-catenin expression. We aimed to clarify the effects of the Wnt/β-catenin pathway in GH-producing pituitary adenomas. We performed immunofluorescence staining using antibodies against GH and β-catenin in pathological samples of pituitary adenoma from 62 patients with acromegaly who underwent pituitary surgery at our hospital between January 2008 and December 2021. We also obtained clinical data for the patients, including the results of endocrine testing, and evaluated the relationships of key indices with the intracellular localization of β-catenin. Samples from 26 cases (42%) showed strong punctate expression of β-catenin in the nuclei (dot pattern (DP) group), and samples from 36 cases (58%) showed β-catenin expression in the cytoplasm or cell membrane (non-DP group). There were no differences in the sex, age, GH concentration, or insulin-like growth factor I (IGF-1) SD scores of the two groups, but the DP group had larger tumors (diameters 18±8 vs. 13±7 mm) and a higher prevalence of macroadenomas (77% vs. 53%). In the DP group, a paradoxical preoperative GH response (an increase of ≥30% of the basal concentration) to 75-g oral glucose tolerance testing was more frequent (46 vs. 22%, p<0.05) and postoperative remission was less frequent (23% vs. 50%, p<0.05). Accordingly, the Wnt/β-catenin pathway appears to be more active in the DP group. The larger tumors and lower postoperative remission rate of the DP group suggest that the Wnt/β-catenin pathway may influence tumor growth. Wnt/β-catenin pathway could play a major role in GH-producing pituitary tumor growth, therefore this pathway would be a potential therapeutic target in the affected patients. Presentation: Thursday, June 15, 2023

Blood Krebs von den Lungen-6 levels predict treatment response to antifibrotic therapy in patients with idiopathic pulmonary fibrosis

Antifibrotic therapy can slow disease progression (DP) in patients with idiopathic pulmonary fibrosis (IPF). However, the prognostic biomarkers for DP in patients with IPF receiving antifibrotic therapy have not been identified. Therefore, we aimed to evaluate the prognostic efficacy of serum Krebs von den Lungen-6 (KL-6) for DP in patients with IPF receiving antifibrotic therapy. The clinical data of 188 patients with IPF who initiated antifibrotic therapy at three tertiary hospitals was retrospectively analyzed. DP was defined as a relative decline in forced vital capacity (FVC) ≥ 10%, diffusing capacity for carbon monoxide ≥ 15%, acute exacerbation, or deaths during 6 months after antifibrotic therapy. The mean age of patients was 68.9 years, 77.7% were male, and DP occurred in 43 patients (22.9%) during follow-up (median, 7.6 months; interquartile range, 6.2-9.8 months). There was no difference in baseline KL-6 levels between the DP and no-DP groups; however, among patients with high baseline KL-6 levels (≥ 500 U/mL), changes in KL-6 levels over 1 month were higher in the DP group than those in the non-DP group, and higher relative changes in KL-6 over 1 month were independently associated with DP (odds ratio, 1.043; 95% confidence interval 1.005-1.084) in the multivariable logistic analysis adjusted for age and FVC. In the receiver operating characteristic curve analysis, the 1-month change in KL-6 was also useful for predicting DP (area under the curve = 0.707; P < 0.012). Our data suggest that the relative change in KL-6 over 1 month might be useful for predicting DP in patients with IPF receiving antifibrotic therapy when baseline KL6 is high.

Postoperative Outcomes of Distal Pancreatectomy for Retroperitoneal Sarcoma Abutting the Pancreas in the Left Upper Quadrant.

BackgroundEn bloc resection of the tumor with adjacent organs is recommended for localized retroperitoneal sarcoma (RPS). However, resection of the pancreas is controversial because it may cause serious complications, such as pancreatic fistula or bleeding. Thus, we evaluated the outcomes of distal pancreatectomy (DP) in pancreas-abutting RPS of the left upper quadrant (LUQ).MethodsWe retrospectively reviewed all consecutive patients who underwent surgery for RPS between September 2001 and April 2020. We selected 150 patients with all or part of their tumor located in the LUQ on preoperative computed tomography. Eighty-six patients who had tumors abutting the pancreas were finally enrolled in our study.ResultsFifty-three patients (53/86; 61.6%) were included in the non-DP group, and 33 patients (33/86; 38.4%) were included in the DP group. Total postoperative complications and complication rates for those Clavien–Dindo grade 3 or higher were similar between the non-DP group and DP group (p = 0.290 and p = 0.550). In the DP group, grade B pancreatic fistulae occurred in 18.2% (6/33) of patients, but grade C pancreatic fistulae were absent, and microscopic pancreatic invasion was noted in 42.4% (14/33) of patients. During multivariate analysis, microscopic pancreatic invasion was deemed a risk factor for local recurrence (p = 0.029). However, there were no significant differences on preoperative computed tomography findings between the pancreatic invasion and non-invasion groups.ConclusionDP is a reasonable procedure for pancreas-abutting RPS located at the LUQ when both complications and complete resection are considered.

Penumbra volume predicts unfavorable outcome in patients with acute minor stroke or transient ischemic attack.

A subgroup of patients with acute minor stroke (AMS) or transient ischemic attack (TIA) become disabled due to disease progression (DP) or recurrent stroke within 3 months. The aim of this article is to identify the risk factors for DP in AMS/TIA patients. In the literature, no studies focused on computed tomography perfusion (CTP) in AMS/TIA patients at the acute stage. This retrospective study included patients with AMS or TIA (onset of symptoms ≤4.5 hours, baseline National Institutes of Health Stroke Scale [NIHSS] score of 0-4). DP was defined as a deterioration of NIHSS score of ≥2 points during hospitalization or modified Ranking Scale ≥2 at 3-month follow-up. Clinical data and imaging results were retrieved and measured for statistical analysis. From 2011 to 2017, total 135 patients were eligible for further analysis: 28 patients (20.7%, DP group) and 107 patients (79.3%, non-DP group). The DP group had significantly higher larger penumbra volumes (p = 0.028). In univariate model of the logistic regression, patients with the following risk factors tended to have unfavorable outcome: female gender, higher HbA1c, chronic kidney disease stage ≥3b, intracranial atherosclerosis, and penumbra volume were associated unfavorable outcome, but larger deadcore volume was not. In further multivariate analysis, only penumbra volume >5 cm (p = 0.049, odds ratio [OR] = 3.21, 95% CI: 1.00-10.27) had the statistical significance. The cut-point value of the penumbra volume for unfavorable outcome in AMS/TIA patients was 4.73 cm. One fifth of the AMS/TIA patients had unfavorable outcome at 90 days. In CTP performed within 4.5 hours after the onset of AMS/TIA, the penumbra volume (>5 cm) was a significant risk factor for DP, and the cut-point value was 4.73 cm. Further studies could be designed to involve this subgroup of patients for more aggressive treatment.

Impact of Distal Protection with Filter-Type Device on Long-term Outcome after Percutaneous Coronary Intervention for Acute Myocardial Infarction: Clinical Results with Filtrap®.

Aim: Although distal embolization during percutaneous coronary intervention (PCI) for acute myocardial infarction (AMI) deteriorates cardiac function, whether distal protection (DP) can improve prognosis is still controversial. We investigated whether a filter-type DP device, Filtrap®, could improve long-term outcomes after PCI for AMI.Method: We studied 164 patients (130 men, mean age: 65.7 years) who underwent PCI. Patients were divided into two groups based on the use of Filtrap®. The occurrence of congestive heart failure (CHF) and major adverse cardiac events (MACE) defined as cardiac death, recurrent AMI, and target vessel revascularization were compared.Result: Between DP (n = 53, 41 men, mean age: 65.5 years) and non-DP (n = 111, 89 men, mean age: 65.8 years) groups, although there was significantly greater plaque area in the DP group than in the non-DP group, there were no significant differences in coronary reperfusion flow after PCI. Interestingly, patients with CHF in the non-DP group exhibited a higher CK level than those in the DP group. During a 2-year follow-up period, cumulative CHF was significantly lower in the DP group than in the non-DP group (log-rank p = 0.018), and there was no significant difference in the MACE rate (log-rank p = 0.238). The use of DP device could not predict MACE, but could predict CHF by multivariate analysis (odds ratio = 0.099, 95% CI: 0.02–0.42, p = 0.005).Conclusion: These results demonstrate that favorable clinical outcomes could be achieved by the filter-type DP device in AMI, particularly in patients with CHF.

Impact of phrenic nerve paralysis on the surgical outcome of intercostal nerve transfer.

Brachial plexus injuries (BPI) can be complicated by diaphragmatic paralysis (DP). This study determined the influence of DP on biceps brachii (BB) recovery after intercostal nerve transfer (ICNT) for BPI and investigated the respiratory complications of ICNT. The study included 100 patients, 84 showing no DP in preoperative and early postoperative chest radiographic images (non-DP group) and 16 with DP that persisted for over one year after surgery (DP group). The postoperative reinnervation time did not differ between groups. BB strength one year after surgery was lower in the DP group than non-DP group (p = 0.0007). No differences were observed 2-3 years after surgery. In the DP group, four patients had respiratory symptoms that affected daily activities and their outcomes deteriorated (p = 0.04). Phrenic nerve transfer should not be combined with ICNT in patients with poor respiratory function because of the high incidence of respiratory complications.

Neuroimmunological function in parents of children suffering from cancer

The main aim of this study is to evaluate the relationship between depression and immunological function in parents of children with cancer. Thirty-two parents participated in the study. The parents completed the following assessments: a list of major stressful events in a Hemato-Oncology ward, beck depression inventory II (BDI-II), posttraumatic diagnostic scale (PDS) and quality of life (QOL) questionnaire. A single blood sample was drawn from parents for evaluation of cortisol levels and lymphocyte cell subgroups. The parents were divided into two groups: Those who suffered from depression as defined by BDI-II cutoff score of 14 (depressed parents (DP), n = 7), and non-depressed parents (non-DP, n = 25). In parents of children with cancer the DP group had statistically significantly higher stressful event scores, dysfunction scores (from the PDS) and CD8 percentage compared to the non-DP group. QOL, CD4 percentage and CD4/CD8 ratio were significantly lower in the DP group. The BDI scores significantly positively correlated with events and dysfunctional scores, and significantly negatively correlated with QOL scores and CD4/CD8 ratio. High psychiatric morbidity was found in parents of children with cancer. The findings of altered immunity in DP provide further evidence that the physiological response to stress and depression may alter immune functions.

Association of the UCP-1 single nucleotide polymorphism A-3826G with the dampness-phlegm pattern among Korean stroke patients

BackgroundPatients with stroke have various syndromes and symptoms. Through pattern identification (PI), traditional Korean medicine (TKM) classifies the several syndromes and symptoms of stroke patients into five categories: Fire-heat (FH), Dampness-phlegm (DP), Yin-deficiency (YD), Qi-deficiency (QD) and Blood-stasis (BS). DP has been associated with obesity and hyperlipidemia. Uncoupling protein-1 (UCP-1), which plays a major role in thermogenesis and energy expenditure can increase the risk of obesity and can be related metabolic disorders. In this study, we elucidated the association of three polymorphisms located in the UCP-1 promoter and coding region with DP among Korean stroke patients.Methods1,593 patients with cerebral infarction (583/DP, 1,010/non-DP) and 587 normal subjects were enrolled. The genotypes A-3826G, G-1766A and Ala64Thr (G+1068A) for each subject were determined by polymerase chain reaction with TaqMan probes and five percent of subjects were re-genotyped by sequencing method to confirm the accuracy of genotyping. The results were analyzed using a multiple logistic regression model to evaluate the genetic associations: the UCP-1polymorphisms of normal versus those of DP subjects and those of normal versus those of non-DP subjects.ResultsA significantly higher percentage of subjects in the DP group possessed the A-3826G G allele than the A allele (OR=1.508, p=0.006). Furthermore, the number of subjects with the GG type of A-1766G was significantly lower in the non-DP group than the normal group in the recessive model (OR=0.606, p=0.042). In addition, an analysis of the relationship among 2 SNPs of UCP-1 and lipid serum concentration showed that the serum level of HDL cholesterol was significantly higher in subjects with the A-3826G G allele in the normal group (p=0.032). Serum triglyceride and HDL cholesterol were also associated with the A-1766G variant in the recessive model (p=0.002, p=0.046).ConclusionsThese results suggest that that the A-3826G and A-1766G UCP-1 polymorphisms, which are related to obesity, might be candidate genetic markers for the DP pattern in the TKM diagnosis system.

Distal Protection During Primary Coronary Intervention Can Preserve the Index of Microcirculatory Resistance in Patients With Acute Anterior ST-Segment Elevation Myocardial Infarction

The objective of this study was to investigate whether a distal protection (DP) device can preserve the index of microcirculatory resistance (IMR) after primary percutaneous coronary intervention (PCI) in patients with anterior ST-segment elevation myocardial infarction (STEMI). The study group of 36 consecutive patients with anterior STEMI were randomized into 2 groups of primary PCI with or without DP: stenting without DP (non-DP group, n = 17) and with DP (DP group, n = 19). The DP in all cases was Filtrap (Nipro, Japan). Following final coronary angiography after successful PCI, IMR was measured using PressureWire™ Certus (St Jude Medical, USA) at maximal hyperemia. The averaged IMR of the 36 patients with STEMI after primary PCI was 31.6U. The IMR in the DP group was significantly lower than that in the non-DP group (26.6 ± 25.8U vs. 37.2 ± 23.2U, P = 0.03242). DP as an adjunctive therapy of PCI for acute anterior STEMI may have beneficial effects on myocardial microcirculation because of preservation of IMR.

Socioeconomic inequalities and mortality among disability pensioners in Norway – a population-based cohort study

Background: The study assessed the mortality related to disability pension (DP) status in Norway during 1990-96 and investigated whether socioeconomic factors explained the increased mortality. Methods: A 10% random sample of the Norwegian population aged 30-59 years, 73,420 women and 75,500 men, were followed-up with respect to death or emigration in 1990-96. DP-status, age, gender, educational level and mean income before inclusion were used as explanatory variables in Cox’ regression analysis with death as endpoint. The analyses were stratified for gender and separately for persons who had obtained DP before 1985 (early) and in 1985-1989 (late). Results: The majority of persons with DP had only basic education and belonged to the lowest income level. Among the women 6.2% in the DP-group died during follow-up compared to 1.2% of those in the non-DP group. The corresponding percentages for men were 14.5% and 2.3%. The age-adjusted hazard ratios (HRs) were 3.5 and 2.5 for women with early and late DP, and 4.3 and 3.3 among men. After adjustment for socioeconomic variables, the HRs were 2.9 and 2.2 for women, and 2.2 and 1.9 for men. Conclusions: Nearly half of the excess mortality related to DP-status was explained by low socioeconomic status among the men. Among women, HR related to DP was not significantly reduced after the adjustments for socioeconomic variables. These findings indicate a strong impact of the medical factors underlying the DP decision, especially among women, but also an important role of the socioeconomic factors related to DP status.

Mortality among disability pensioners in Norway and Sweden 1990—96: Comparative prospective cohort study

The aim of the study was to assess excess mortality related to disability pension (DP) status and DP diagnoses in Norway and Sweden during 1990-96. Representative samples of the population aged 30-59 years, without DP at baseline 1 January 1990, 71,293 women and 76,928 men from Norway, and 68,181 women and 71,950 men from Sweden, were followed up during 1990-96. Granting of DP, DP diagnosis, age and gender were explanatory variables in Cox proportional hazards analysis with death from all causes as the outcome variable. Among women, 10.4% in Sweden and 7.1% in Norway obtained DP, as compared to 7.5% and 5.6% of the men. In Sweden, 66% of female and 49% of male DP recipients had musculoskeletal diagnoses, as compared to 40% and 27% in Norway. In Sweden, 3.0% of the women and 6.1% of the men with DP died, as compared to 4.6% and 8.5% in Norway. Hazard ratios (HRs) for women with DP vs. the non-DP group were 3.2 (95% confidence interval (CI)=2.7-3.8) in Sweden, and 4.9 (95% CI=4.1-5.7) in Norway. Among men with DP, there was no difference in mortality rate between the countries. HRs for men with musculoskeletal diagnoses vs. the non-DP group were 1.5 (95% CI= 1.1-2.0) in Norway and 1.4 (95% CI= 1.1-1.8) in Sweden. In both countries, the mortality rate among female disability pensioners with musculoskeletal diagnoses was not increased. The study confirmed an increased mortality rate among disability pensioners, except for women with musculoskeletal diagnoses. The mortality pattern related to DP diagnoses was similar in the two countries. A high frequency of musculoskeletal DP diagnoses among women with DP in Sweden explained a lower mortality rate as compared to Norway.

Detection of embolic particles with the Doppler guide wire during coronary intervention in patients with acute myocardial infarction: Efficacy of distal protection device

We investigated whether embolic particles could be detected as high-intensity transient signals (HITS) with a Doppler guide wire during percutaneous coronary intervention (PCI) in patients with acute myocardial infarction (AMI) We also assessed whether these signals could be reduced using a distal protection (DP) device.Embolization of thrombi and plaque components to the microcirculation is a major complication of PCI in patients with AMI. Embolic particles running in the cerebral artery are detected as HITS by transcranial Doppler ultrasound.We prospectively studied 16 consecutive patients with AMI who underwent direct PCI within 24 h after the onset of symptoms. A PercuSurge GuardWire (MedtronicAVE, Santa Rosa, California) was used as the DP device. Eight patients were randomly assigned to the non-DP group, and the remaining eight were assigned to the DP group. Coronary flow velocity was recorded continuously from before the first balloon inflation to after balloon deflation.All patients in the non-DP group had HITS detected (12 +/- 9 counts) within five consecutive beats (4 +/- 1 beat) after balloon deflation, but none were detected in any of the patients in the DP group.The Doppler guide wire can be used to visually detect and count emboli as HITS, and the DP device is effective for prevention of distal embolization.

Antiarrhythmic Efficacy of Dipyridamole in Treatment of Reperfusion Arrhythmias

Intracellular calcium overload is believed to play an important role in development of reperfusion arrhythmias. Dipyridamole, an inhibitor of cellular uptake of adenosine, may prevent or terminate reperfusion arrhythmias by reducing intracellular calcium overload. First, we tested for a preventive effect of dipyridamole. Sixty-one patients who underwent primary PTCA for treatment of acute anterior wall myocardial infarction were enrolled in this prospective study. Patients were divided into dipyridamole (DP) and nondipyridamole (non-DP) groups. The 2 groups had similar baseline characteristics. In the DP group, dipyridamole 0.5 mg/kg was infused intravenously for 3 minutes immediately before reperfusion during primary PTCA. Arrhythmias after reperfusion were analyzed from continuous ECG recordings. None of the patients in the DP group (n=23) had accelerated idioventricular rhythms (AIVR) or ventricular tachycardia (VT). In contrast, 7 (18.4%) had AIVR and 3 (7.9%) had VT in the non-DP group (n=38; P<0.01). Second, we tested for a termination effect of dipyridamole. Dipyridamole 0.5 mg/kg was infused intravenously while continuous ECG recordings were obtained in 9 patients who had either sustained AIVR (n=7) or sustained VT (n=2) after reperfusion of occluded coronary artery. Arrhythmias were terminated in all patients. These results indicate that administration of dipyridamole can prevent and terminate reperfusion arrhythmias such as AIVR and VT. cAMP-mediated triggered activity may, at least in part, be responsible for reperfusion-induced AIVR and VT.