Prognostic and diagnostic effects of high serum midkine levels in patients with hepatocellular carcinoma.

Midkine (MK) is a soluble cytokine, and its serum levels strongly correspond to protein expression levels in tumors. The present study aimed to clarify the clinicopathological and prognostic significance of serum MK (s-MK) in patients with hepatocellular carcinoma (HCC). Serum samples were obtained before surgery from 123 patients with HCC who had undergone surgery between January 2012 and December 2020. The receiver operating characteristic curve revealed that the best cut-off value for s-MK in differentiating HCC from healthy cases was 426 pg/ml. The clinicopathological variables and overall survival of patients were compared between the s-MK-positive group and s-MK-negative group. The sensitivity, specificity and accuracy of s-MK were 82.1, 97.4 and 88.0%, respectively. An s-MK-positive status was significantly associated with the number of tumors (≥2). The positivity rate of s-MK was significantly higher compared with that of α-fetoprotein and protein-induced by vitamin K absence-II. In total, only 28% of the patients were positive for s-MK. The s-MK-positive group showed significantly worse overall survival compared with the s-MK-negative group. Moreover, multivariate analysis revealed that an s-MK-positive status was independently associated with poor prognosis. s-MK was useful in detecting early HCC. The findings of this study indicated that the s-MK-positive status is associated with the number of tumors and can act as an independent prognostic risk factor.

Safety of laparoscopic liver resection for high-risk patients.

BACKGROUND/PURPOSE: To investigate the safety of laparoscopic liver resections (LLRs) for high-risk patients (HRs) with preoperative comorbidities affecting the heart, lungs, kidneys, glucose tolerance, and central nervous system. METHODS: This retrospective study included 585 patients who had undergone total hepatectomies from 2006 to 2020. Among them, 239 patients underwent LLRs, and 349 underwent open liver resections (OLRs). The safety and validity of LLRs were analyzed by comparing outcomes and preoperative records between HRs and nonhigh-risk patients (nHRs). HRs were defined as patients with any type of chronic heart disease rated New York Heart Association II or higher, chronic obstructive pulmonary disease rated stage III or higher, chronic kidney disease rated stage III or higher, insulin-dependent diabetes mellitus, or cerebrovascular disease with neurological sequelae. RESULTS: A total of 117 LLRs (49.0%) were performed in HRs, and there were more patients with ASA class III or higher than nHRs. Complications of Clavien-Dindo classification grade 3b or higher were not observed in HRs and in only one nHR. Furthermore, no postoperative exacerbations of the five HRs factors were observed in either group. CONCLUSIONS: Rigorous assessment of surgical indications and perioperative management can promote safe LLRs, even in HRs with comorbidities.

The Outcome of Conversion to Hand-Assisted Laparoscopic Surgery in Laparoscopic Liver Resection.

BACKGROUND: Hand-assisted laparoscopic surgery (HALS) is known as a useful option. However, the outcome and predictor of conversion to HALS in laparoscopic liver resection (LLR) are unclear. METHODS: Data from consecutive patients who planned pure LLR between 2011 and 2020 were retrospectively reviewed. Univariate and multivariate analyses were performed and compared pure LLR, HALS, and converted open liver resection (OLR). RESULTS: Among the 169 LLRs, conversion to HALS was performed in 19 (11.2%) and conversion to OLR in 16 (9.5%). The most frequent reasons for conversion to HALS were failure to progress (11 cases). Subsequently, bleeding (3 cases), severe adhesion (2 cases), and oncological factors (2 cases) were the reasons. In the multivariable analysis, the tumor located in segments 7 or 8 (p = 0.002) was evaluated as a predictor of conversion to HALS. Pure LLR and HALS were associated with less blood loss than conversion to OLR (p = 0.005 and p = 0.014, respectively). However, there was no significant difference in operation time, hospital stay, or severe complications. CONCLUSIONS: The predictor of conversion to HALS was a tumor located in segments 7 or 8. The outcome of conversion to HALS was not inferior to pure LLR in terms of bleeding, operation time, hospital stay, or severe complication.

[Surgical Resection as Local Therapy for Sister Mary Joseph's Nodule Due to Pancreatic Tail Cancer].

We experienced a case of resection of a metastatic umbilical tumor(Sister Mary Joseph's nodule: SMJN)derived from a pancreatic tail carcinoma. The patient was a 70-year-old woman. She visited her previous doctor with a chief complaint of lower abdominal pain and came to our hospital due to suspicion of pancreatic tail cancer. She was found to have metastases to multiple organs which was unresectable by surgery. After chemotherapy up to the second-line of treatment, she was diagnosed to have progressive disease. The decision was made to provide the best supportive care for the patient. Thereafter, the patient developed SMJN. She had hemorrhage from the tumor accompanied by body movement, and her activity of daily living became impaired. She had difficulty controlling the bleeding despite repeated hemostatic treatment at the outpatient clinic and at her home. However, she required frequent blood transfusions for her severe anemia. Therefore, we performed a resection of the SMJN to control bleeding and to relieve her symptoms. She had a good postoperative course and was discharged on the fifth postoperative day. Due to deterioration of her general condition, she expired on the 59th day after surgery. However, the patient was able to live at home without bleeding or pain by the umbilical tumor. The local resection was considered to be useful as a palliative surgical treatment for SMJN.

Liver stiffness and arterial stiffness/abnormal central hemodynamics in the early stage of heart failure.

BACKGROUND: It remains to be clarified whether liver stiffness is a direct risk factor for heart failure (HF) or whether its association with HF is mediated by vascular damage. We conducted cross-sectional and prospective longitudinal studies to examine whether fibrosis 4 score (FIB-4 score) is directly associated with the serum NT-pro-BNP levels or the association is mediated by arterial stiffness and/or abnormal central hemodynamics. METHODS AND RESULTS: In 3040 health Japanese subjects with serum NT-pro-BNP levels < 125 pg/ml, the FIB-4 score was calculated, and the serum NT-pro-BNP levels, brachial-ankle pulse wave (baPWV) velocity and radial augmentation index (rAI) were measured. These parameters were measured again after a 3-year interval in 2135 subjects. Multivariate linear regression analysis demonstrated a significant cross-sectional association of the FIB-4 scores with the log-transformed the serum NT-pro-BNP levels (beta = 0.08, p < 0.01), but not with the baPWV or rAI. The change of serum NT-pro BNP levels during the study period was significantly higher in subjects with increase of the FIB-4 score during the study period (8.2 ±â€¯22.5 pg/ml) than that in those with decrease/no change (5.4 ±â€¯22.3 pg/ml) (p < 0.05). CONCLUSION: Liver stiffness may have a significant direct association with the development of HF from the early stage, without the mediation of arterial stiffness and/or abnormal central hemodynamics. Therefore, the FIB-4 score appears to serve as a direct risk factor for HF from the early stage, and its association with HF may not be mediated by vascular damages.

Involvement of Arterial Stiffness and Inflammation in Hyperuricemia-Related Development of Hypertension.

This study analyzed repeated measurement data to clarify the longitudinal associations between hyperuricemia and the risk factors for the development of hypertension (ie, increased arterial stiffness, renal dysfunction, and inflammation), and then examined whether these risk factors show longitudinal associations with the development of hypertension. In 3274 Japanese men without hypertension, the brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum uric acid and CRP (C-reactive protein) levels were measured annually over an 8-year period. Of these, 474 subjects developed hypertension by the end of the study period. Mixed model linear regression analysis revealed a significant longitudinal association of hyperuricemia with increase of the brachial-ankle pulse wave velocity (estimate=5.50, P=0.04), decrease of the estimated glomerular filtration rate (estimate=-2.02, P<0.01), and elevation of the CRP (estimate=0.08×10-1, P=0.02). Hyperuricemia at the study baseline was associated with a significant odds ratio for the development of hypertension by the end of the study period. After adjustments for covariates, the brachial-ankle pulse wave velocity (estimate=0.51×10-2, P<0.01) and CRP (estimate=1.91, P=0.03), but not estimated glomerular filtration rate, were found to show independent longitudinal associations with the new onset of hypertension. In Japanese men without hypertension, hyperuricemia may have a longitudinal association with the development of hypertension, and increased arterials stiffness and inflammation may be involved in the risk of development of hypertension associated with hyperuricemia.

Effect of Wave Reflection and Arterial Stiffness on the Risk of Development of Hypertension in Japanese Men.

BACKGROUND: We conducted analyses of repeated-measures data to examine whether pressure wave reflection acts additively or synergistically with arterial stiffness in the pathogenesis of hypertension. METHODS AND RESULTS: In 3172 middle-aged (42±9 years) healthy Japanese men without hypertension at the study baseline, systolic and diastolic blood pressures, brachial-ankle pulse wave velocity, and radial augmentation index were measured annually during a 9-year study period. Of these, 474 participants (15%) developed hypertension by the end of the study period. Binary logistic regression analysis demonstrated significant individual odds ratios for both baseline brachial-ankle pulse wave velocity and radial augmentation index for the development of hypertension. The rate of onset of hypertension during the study period was highest in the participant group with high values for both brachial-ankle pulse wave velocity and radial augmentation index at study baseline (262 of 965 participants: 27%). The generalized estimating equation analysis revealed that both radial augmentation index (estimate=0.06, SE=0.03, P=0.05) and brachial-ankle pulse wave velocity (estimate=0.07×10-1, SE=0.02×10-1, P<0.01) showed significant longitudinal association with new onset of hypertension, with no significant interaction. CONCLUSIONS: In Japanese men, abnormal wave reflection and increased arterial stiffness may be additively associated with the risk of new onset of hypertension. Abnormal wave reflection and elevated central blood pressure may be longitudinally associated with increase in arterial stiffness, and this longitudinal association may be a mechanism underlying the additive effect of these 2 variables on the risk of new onset of hypertension.

The Contribution of Inflammation to the Development of Hypertension Mediated by Increased Arterial Stiffness.

BACKGROUND: The mechanisms underlying the possible contribution of chronic inflammation to the development of hypertension remain unclear. We examined the longitudinal association of inflammation with the progression of vascular and/or renal abnormalities in the development of hypertension. METHODS AND RESULTS: In 3274 middle-aged Japanese men without hypertension at the study baseline, brachial-ankle pulse wave velocity, blood pressure, estimated glomerular filtration rate, and serum CRP (C reactive protein) levels were measured annually during a 9-year period. During this study period, 474 participants (14.5%) developed hypertension. Analysis of the repeated-measures data revealed that sustained elevation of serum CRP levels was associated with a longitudinal increase of the brachial-ankle pulse wave velocity. A linear mixed model analysis revealed that higher log-transformed serum CRP values (log CRP) at each measurement were associated with a higher annual increase of the brachial-ankle pulse wave velocity (estimate=32.553±11.635 cm/s per log CRP, P=0.018), and that higher values of the brachial-ankle pulse wave velocity at each measurement were associated with a higher annual elevation of blood pressure (estimate=0.025±0.002 mm Hg per log CRP, P<0.001). CONCLUSIONS: In middle-aged Japanese men without hypertension at study baseline, long-term active inflammation appears to be associated with a longitudinal increase of arterial stiffness. In turn, this longitudinal increase of arterial stiffness appears to be associated with longitudinal elevation of blood pressure to the hypertensive range. Thus, systemic inflammation may play a role in the pathogenesis of hypertension by the progression of arterial stiffness.

Comparison of the clinical significance of single cuff-based arterial stiffness parameters with that of the commonly used parameters.

BACKGROUND: We examined the following: (1) whether the new simple markers related to the arterial stiffness/central hemodynamics [i.e. arterial pressure-volume index (API) and arterial velocity pulse index (AVI)] are clinically interchangeable with the commonly used markers [brachial-ankle pulse wave velocity (baPWV) and radial augmentation index (rAI)]; (2) whether the new simple markers reflect vascular damage as reliably as the commonly used markers; (3) which cardiovascular risk factors are reflected by these new simple markers. METHODS: API, AVI, baPWV, and rAI were measured simultaneously in consecutive patients admitted for the management of cardiovascular disease and/or cardiovascular risk factors (n=322). RESULTS: The API was correlated with the baPWV (R=0.492, p<0.001) and the AVI correlated with the rAI (R=0.462, p<0.001). The API, AVI, baPWV, and rAI were higher in the patients admitted for coronary angiography (CAG group: n=152) than in those admitted for reasons other than coronary angiography (nonCAG group: n=170). After adjustments for confounding factors, only the AVI was found to be higher in the CAG group than in the nonCAG group. Multivariate linear regression analysis revealed that age and the systolic blood pressure were independently associated with the API and AVI after adjustments. CONCLUSION: In patients with cardiovascular diseases or cardiovascular risk factors, the new simple markers and the commonly used markers are not interchangeable for assessing vascular damage and/or cardiovascular risk. Further study is proposed to examine whether AVI is higher in subjects with cardiovascular disease than in those without a history of cardiovascular disease. Similar to the case for the commonly used markers, age and the blood pressure significantly influenced both the new markers; therefore, age and the blood pressure need to be taken into account while interpreting the changes in these new simple markers.

Longitudinal changes of the serum calcium levels and accelerated progression of arterial stiffness with age.

BACKGROUND AND AIMS: The progression of arterial stiffness is accelerated by aging, although the underlying mechanisms have not yet been clarified. This prospective observational study was conducted to clarify whether longitudinal changes in the serum calcium/phosphate levels are associated with the accelerated progression of arterial stiffness with age. METHODS: In a cohort of employees at a construction company (1507 middle-aged Japanese men), the serum calcium/phosphate levels and brachial-ankle pulse wave velocity (baPWV) were measured at the start and at the end of a 3-year study period. RESULTS: A general linear model multivariate analysis revealed a significant interaction of the 2 factors {age and longitudinal changes of the serum calcium levels (delCa) during the follow-up period} on the longitudinal changes of the baPWV during the study period (delPWV). The delCa was significantly correlated with the delPWV even after adjustments for covariates in subjects aged ≥48 years. The delPWV in subjects aged ≥48 years with the delCa in the upper tertile (69 ± 137 cm/s) was significantly larger than that in the other groups even after adjustments for covariates (e.g., del PWV in subjects aged <48 years with the delCa in the lower tertile = 1 ± 94 cm/s) (p < 0.01). CONCLUSIONS: The association between the arterial stiffness and serum calcium levels differed with age. Pathophysiological abnormalities related to increased serum calcium levels appeared to be associated with accelerated progression of arterial stiffness with age.

Longitudinal changes in late systolic cardiac load and serum NT-proBNP levels in healthy middle-aged Japanese men.

BACKGROUND: We determined whether any significant association exists between change in late systolic cardiac load with time, estimated by radial pressure waveform analysis, and development of cardiac hemodynamic stress in individuals with preserved cardiac function. METHODS: Brachial-ankle pulse wave velocity, radial augmentation index (rAI), first peak of the radial pressure waveform (SP1), systolic and pulse pressure at the second peak of the radial pressure waveform (SP2 and PP2), and serum levels of N-terminal fragment B-type natriuretic peptide (NT-proBNP) were measured at the start (first examination) and at the end (second examination) of this 3-year study in healthy Japanese men (n = 1,851). RESULTS: A stepwise multivariate linear regression analysis demonstrated that among the parameters of radial pressure waveform analysis and markers of arterial stiffness analyzed, only PP2 was significantly associated with serum NT-proBNP levels in study participants at both the first and second examinations. Furthermore, among the parameters analyzed, only change in PP2 was significantly correlated with the change in serum NT-proBNP levels during the study period (beta = 0.131, P < 0.001). CONCLUSIONS: Sustained late systolic cardiac load might be a more significant determinant of the development of cardiac hemodynamic stress than sustained early systolic cardiac load or arterial stiffening in individuals with preserved cardiac function.

Correlations of arterial stiffness/central hemodynamics with serum cardiac troponin T and natriuretic peptide levels in a middle-aged male worksite cohort.

BACKGROUND: Elevated serum levels of cardiac troponin T (cTnT) and N-terminal fragment of B-type natriuretic peptide (NT-proBNP), and also increased arterial stiffness/abnormal central hemodynamics, are well-known risk factors for future cardiovascular events. The present study was conducted to clarify which of the two - the serum level of cTnT or that of NT-proBNP - might be more closely associated with the arterial stiffness/central hemodynamics. METHODS: In 2374 male employees of a company (46±9 years), the following parameters were measured: second peak of the radial systolic pressure waveform (SP2), radial augmentation index (rAI), PP2 (SP2 minus the diastolic blood pressure), brachial-ankle pulse wave velocity (baPWV), and serum levels of cTnT and NT-pro BNP. RESULTS: After adjustments for confounding variables, binary logistic regression analyses demonstrated that baPWV was associated with a significant odds ratio for serum NT-proBNP ≥125pg/mL (1.690; 95% confidence interval=1.136-2.514, p=0.002) and rAI was associated with a significant odds ratio for serum NT-proBNP ≥55pg/mL (1.205; 95% confidence interval=1.012-1.435, p=0.036). The baPWV, rAI, SP2, and PP2 were not associated with significant odds ratios for elevated serum cTnT levels (≥0.014ng/mL and ≥0.010ng/mL). CONCLUSIONS: In the middle-aged male worksite cohort studied, increased arterial stiffness/abnormal central hemodynamics appeared to be associated with elevated serum NT-proBNP levels, rather than with minimally elevated serum cTnT levels. This difference may be one of the plausible explanations for the independency of the predictive values of the two serum markers for future cardiovascular events.

Differences in effects of age and blood pressure on augmentation index.

BACKGROUND: The effect of age on the augmentation index (AI) differs between young adults and the elderly, and the AI reaches a plateau after the age of 60 years. We examined whether the effects of age and an elevation in blood pressure on the AI differ between young adults and the elderly, between subjects with and without high blood pressure, or between subjects with and without a high AI. METHODS: The radial AI was measured in 10,190 subjects who were either healthy or had hypertension (n = 5,477 men and 4,743 women). RESULTS: In both sexes, a phased increase in the radial AI with age could only be confirmed up to an age of 60 years. A phased increase in the radial AI with the systolic blood pressure (SBP) could be confirmed up to an SBP of >170 mm Hg. Among subjects categorized within the highest age tertile, the highest SBP tertile, or the highest radial AI tertile, stepwise multivariable analyses demonstrated that SBP, but not age, was a significant independent factor influencing the radial AI. CONCLUSIONS: The effect of age and blood pressure on AI differ not only between young adults and the elderly but also between those with and those without high blood pressure or between those with and those without a high AI. The effect of an elevation in blood pressure, but not aging, on the AI is significant in the elderly, in subjects with high blood pressure, or in those with a high AI.

Pathophysiological contribution of vascular function to baroreflex regulation in hypertension.

BACKGROUND: We examined which pathophysiological abnormalities of vascular function might be closely associated with abnormal baroreflex regulation in subjects with hypertension. METHODS AND RESULTS: In the cross-sectional assessment, 280 subjects with hypertension were enrolled for measurement of brachial-ankle pulse wave velocity (baPWV), radial augmentation index (rAI), flow-mediated vasodilatation (FMD) of the brachial artery and baroreceptor sensitivity (BRS). These parameters were measured again as prospective assessment in some of these subjects. In the cross-sectional assessment, after adjustment for confounding variables including anti-hypertensive medication, the baPWV, but not the rAI or FMD, was found to have a significant independent relationship with BRS (standardization coefficient, -0.149, P<0.043). In the subjects who were newly started on anti-hypertensive medication (n=40), regression of baPWV before and 1 year after the start of medication was significantly associated with change in BRS during the same period. In subjects already on anti-hypertensive medication (n=92) also, the evolutional change of baPWV over a follow-up period >1.5 years was significantly associated with change in BRS during the same period. CONCLUSIONS: Increased stiffness of the large- to middle-sized arteries, rather than abnormal central hemodynamics or endothelial dysfunction, appears to contribute to abnormal baroreflex regulation in patients with hypertension.

Arterial stiffness/central hemodynamics, renal function, and development of hypertension over the short term.

OBJECTIVES: We examined the following: whether the estimated glomerular filtration rate calculated from the serum cystatin C levels (eGFRcys) and the brachial-ankle pulse wave velocity (baPWV) might be independent predictors of the development of hypertension over the short term, without any interaction; whether the baPWV may be directly associated with the development of hypertension without the mediation of the arterial stiffness-related acceleration of renal functional decline; whether the second peak of the radial pressure waveform (SP2) might also be a significant independent predictor of the development of hypertension. METHODS: In 1229 middle-aged normotensive Japanese men with preserved renal function, the baPWV, SP2 and eGFRcys were measured at the baseline and at the end of the 3-year study period. RESULTS: Hypertension was detected at the end of the 3-year study period in 127 men. The logistic regression analysis with adjustments demonstrated significant independent odds ratios of the baPWV and eGFRcys for the presence of hypertension at the end of the 3-year study period, without any interaction. When entered simultaneously in this model, the SP2 also showed a significant odds ratio. General linear model analysis revealed that none of the baPWV or SP2 measured at the baseline was related to the renal function assessed at the end of the 3-year study period. CONCLUSIONS: The mechanisms underlying the association between arterial stiffness/central hemodynamics and the short-term development of hypertension appear to differ from those underlying the association between kidney function and the short-term development of hypertension.