Skeletal Muscle Mass Index Reduction Rate as a Prognostic Indicator for Patients Undergoing Pancreatectomy for Pancreatic Cancer.

Background/Aim: There have been many studies on skeletal muscle depletion before surgery, and skeletal muscle depletion is a known risk factor for poor prognosis. However, reports on the association between changes in skeletal muscle mass and prognosis after surgery for pancreatic cancer are very few. Patients and Methods: The data of 137 patients who underwent pancreatectomy for pancreatic cancer between 2005 and 2022 were reviewed. Muscle areas were measured at the third lumbar vertebral level, and skeletal muscle mass index (SMI) reduction rates were calculated. Patients were divided into two groups using receiver operating characteristic (ROC) curve analysis based on the SMI reduction rate with a cutoff of 14% reduction rate. The clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Survival rates were analyzed both univariately and multivariately to clarify the factors associated with poor prognosis after pancreatectomy. Results: A total of 102 patients met the inclusion criteria. SMI reduction rate ≥14% significantly correlated with advanced age and higher incidence of postoperative complications. In the multivariate Cox regression analysis, preoperative prognostic nutritional index (PNI) <40 and SMI reduction rate ≥14% were significantly associated with poor OS. Tumor size ≥3.0 cm, preoperative neutrophile-lymphocyte ratio ≥3.0, and SMI reduction rate ≥14% were significantly associated with poor RFS. Conclusion: The rate of skeletal muscle mass reduction after pancreatic surgery is an independent prognostic factor for survival in patients with pancreatic cancer.

A case of difficult-to-diagnose hepatic reactive lymphoid hyperplasia finally diagnosed by using PCR analysis of IgH-gene rearrangements: a case report.

Reactive lymphoid hyperplasia (RLH) of the liver is extremely rare. Despite advancements in diagnostic imaging technology, it is still difficult to distinguish from hepatocellular carcinoma (HCC). Herein, we present a case of hepatic RLH mimicking HCC that was postoperatively diagnosed using several imaging modalities. A 78-year-old female was referred to our hospital with a positive hepatitis C virus antibody (HCV Ab) test. Ultrasonography revealed a 13 mm isoechoic lesion in segment 8 of the liver. Contrast-enhanced computed tomography (CE-CT) demonstrated arterial hyperintensity and washout during the later phase. On ethoxybenzyl magnetic resonance imaging (EOB-MRI), the lesion was hyperenhanced in the arterial phase and of low intensity in the hepatocyte phase. Although the tumor markers were all within normal limits, the pattern of contrast enhancement of the tumor on CT and MRI was consistent with that of HCC. We performed S8 segmentectomy of the liver. Histological examination of the resected specimen revealed dense lymphoid tissue of variable sizes and shapes with expanded germinal centers. Immunohistochemical examination was positive for CD3, CD10 (germinal center), and CD20, and negative for B-cell lymphoma 2 (bcl-2) (germinal center) and Epstein-Barr virus (EBV). A polymerase chain reaction (PCR) analysis of IgH-gene rearrangements revealed polyclonality. Based on these findings, hepatic RLH was diagnosed. The postoperative course was uneventful, and the patient was discharged on the 10th postoperative day. She had a good quality of life after surgery and no liver nodule recurrence was detected at the 4-month medical follow-up. Hepatic RLH is an extremely rare disease and preoperative diagnosis is difficult. This should be considered in the differential diagnosis of single small hepatic tumors. An echo-guided biopsy and careful observation of imaging may help diagnose hepatic RLH, and a PCR analysis of IgH-gene rearrangements would be necessary for the definitive diagnosis of hepatic RLH.

[A case of retrograde intussusception due to transverse colon cancer detected by abdominal ultrasonography].

A 78-year-old female patient presented to our hospital with abdominal pain and melena. Abdominal ultrasonography detected a multiple concentric ring sign and retrograde invagination mass near the hepatic flexure. Colonoscopy revealed a 40-mm diameter type 1 tumor in the transverse colon near the splenic flexure, and the biopsy specimen demonstrated a well-differentiated adenocarcinoma. Retrograde intussusception due to transverse colon cancer was diagnosed, and laparoscopic transverse colon resection with lymph node dissection was performed. The resected specimen revealed a 48×40mm diameter type 1 tumor in the transverse colon and was diagnosed as pT2N0M0 pStage I. Contrast-enhanced computed tomography was unavailable, but real-time assessment of the invaginated mass and bowel blood flow was possible by abdominal ultrasonography, which was useful in determining the diagnosis and treatment strategy.

Antihypertensive and Vasorelaxant Effects of Citric Acid and Lemon Juice in Spontaneously Hypertensive Rats: In Vivo and Ex Vivo Studies.

Hypertension is a key risk factor for heart, brain, and kidney disease development. Fruit consumption has been associated with a decrease in blood pressure. Lemon juice, which contains antihypertensive compounds, may exert antihypertensive effects. However, no research has verified the antihypertensive effects of citric acid, the most abundant ingredient in lemon juice. In the present study, we demonstrated the antihypertensive effects of citric acid and lemon juice by performing single oral administration tests and the aortic ring assay using spontaneously hypertensive rats (SHRs). Single oral doses of both agents markedly reduced the systolic and diastolic blood pressures in the SHRs. In addition, both these agents relaxed the thoracic aorta from the SHRs; however, these effects were notably attenuated by the removal of the aortic endothelium. Orally administered citric acid was rapidly absorbed and metabolized in vivo. Among the functional compounds in lemon juice, citric acid was identified as the primary antihypertensive component. Although more detailed studies are required to validate our findings, the novel functional attributes of citric acid can achieve the normalization of blood pressure when it is consumed via diet.

Phase II clinical trial to study the safety and efficacy of combined S-1 + oxaliplatin therapy as neoadjuvant chemotherapy for locally advanced gastric cancer in older patients.

BACKGROUND: Gastrectomy with D2 dissection and adjuvant chemotherapy is the standard treatment for locally advanced gastric cancer (LAGC) in Asia. However, administering chemotherapy with sufficient intensity after gastrectomy is challenging. Several trials demonstrated the efficacy of neoadjuvant chemotherapy (NAC). However, limited studies explored the feasibility of NAC-SOX for older patients with LAGC. This phase II study (KSCC1801) evaluated the safety and efficacy of NAC-SOX in patients with LAGC aged ≥ 70 years. METHODS: Patients received three cycles of SOX130 (oxaliplatin 130 mg/m2 on day 1, oral S-1 40-60 mg twice daily for two weeks every three weeks) as NAC, followed by gastrectomy with lymph node dissection. The primary endpoint was the dose intensity (DI). The secondary endpoints were safety, R0 resection rate, pathological response rate (pRR), overall survival, and relapse-free survival. RESULTS: The median age of 26 enrolled patients was 74.5 years. The median DI in NAC-SOX130 was 97.2% for S-1 and 98.3% for oxaliplatin. Three cycles of NAC were administered in 25 patients (96.2%), of whom 24 (92.3%) underwent gastrectomy with lymphadenectomy. The R0 resection rate was 92.3% and the pRR (≥ grade 1b) was 62.5%. The major adverse events (≥ grade 3) were neutropenia (20.0%), thrombocytopenia (11.5%), anorexia (11.5%), nausea (7.7%), and hyponatremia (7.7%). Postoperative complications of abdominal infection, elevated blood amylase, and bacteremia occurred in one patient each. Severe diarrhea and dehydration caused one treatment-related death. CONCLUSIONS: NAC-SOX130 is a feasible therapy for older patients, although systemic management and careful monitoring of adverse events are necessary.

Esophageal Neuroendocrine Carcinoma With Pathological Complete Response After Neoadjuvant Chemotherapy Followed by Robot-assisted Surgery: A Case Report.

BACKGROUND/AIM: Malignant esophageal neuroendocrine carcinoma (ENEC) is rare, and its prognosis is poor. Therefore, a standard strategy for treating ENEC remains controversial, and few reports have described a pathological complete response of ENEC to neoadjuvant chemotherapy (NAC) followed by surgery. CASE REPORT: A 74-year-old woman presented with an esophageal tumor, discovered as a result of dysphagia, that was clinically diagnosed as ENEC (small-cell type). The clinical stage was cT2N1M0 stage II (Union for International Cancer Control, eighth edition). Two cycles of carboplatin and etoposide were administered as NAC, and the overall treatment response to NAC was judged as a partial response according to Response Evaluation Criteria for Solid Tumors v.1.1. The patient then underwent robot-assisted, minimally-invasive esophagectomy with thoracoabdominal lymph node dissection. Postoperative histopathology revealed no residual tumor or lymph node metastasis, and pathological complete response to NAC was achieved. The postoperative course was free of major complications, and the patient has remained recurrence-free for 1 year. CONCLUSION: We treated ENEC with NAC and robotic surgery. To our knowledge, this is the first report of a pathological complete response for ENEC after NAC with carboplatin and etoposide.

Total pancreatectomy preserving the right gastroepiploic artery following proximal gastrectomy.

Total pancreatectomy (TP) after proximal gastrectomy (PG) requires more attention than ordinary TP during surgery in terms of the preservation of blood flow to the remnant stomach that was supplied via only the right gastric and gastroepiploic arteries. The current report presents the details of a case in which the remnant stomach was safely preserved when performing TP. A 74-year-old man who underwent PG for gastric cancer 17 years previously was diagnosed with pancreatic head cancer during follow-up for intraductal papillary mucinous neoplasm of the pancreatic body and tail. To preserve digestive function and reduce postoperative complications, TP preserving the right gastroepiploic artery and splenic vessels was performed. The remnant stomach and function were safely preserved without any complications after surgery.

A novel combined carbohydrate antigen 19-9 and lymphocyte-to-monocyte ratio score can predict early recurrence of resectable pancreatic ductal adenocarcinoma.

PURPOSE: Pancreatic ductal adenocarcinoma (PDAC) often recurs early after radical resection, which causes a poor prognosis. This study aimed to establish a scoring model to assess the optimal treatment in patients who underwent surgery for PDAC. METHODS: This single-center retrospective study included 127 patients who underwent radical resection for PDAC between 2005 and 2021. Early recurrence (ER) was defined as recurrence within 12 months after resection. The predictive effect for ER was evaluated using receiver operating characteristic (ROC) curves of preoperative parameters. RESULTS: ER occurred in 43 (33.9%) patients. The ER group had a significantly worse prognosis than the non-ER group (p < 0.0001). The carbohydrate antigen 19-9 (CA19-9) level and lymphocyte-to-monocyte ratio (LMR) were the strongest diagnostic factors (areas under the ROC curves: 0.74 and 0.68, respectively). The ER prediction score was calculated using optimal cutoff values. A higher CA19-9-LMR score was associated with a worse prognosis in terms of the overall and recurrence-free survival (p = 0.0017 and p < 0.0001, respectively). A multivariate analysis identified a high CA19-9-LMR score as an independent predictor of ER. CONCLUSIONS: The CA19-9-LMR scoring model can predict ER after surgery and is applicable for risk stratification in the assessment of patients with resectable PDAC.

Evaluation of the Antihypertensive Activity of Eggplant Acetylcholine and γ-Aminobutyric Acid in Spontaneously Hypertensive Rats.

Daily consumption of eggplant powder containing 2.3 mg acetylcholine (ACh) is known to alleviate hypertension and improve mental status. However, eggplant powder used in clinical trials also contains the antihypertensive compound γ-aminobutyric acid (GABA). Although our previous study indicated that the main antihypertensive compound in eggplant is ACh, given that GABA amounts in eggplant do not reach the effective dosage, the effects of GABA on the antihypertensive effect of eggplant remain unclear. It is necessary to establish whether there is a synergistic effect between GABA and ACh and whether GABA in eggplant exerts antihypertensive effects. Consequently, here we sought to evaluate the effects of GABA on the antihypertensive effects of eggplant. We used a probability sum (q) test to investigate the combined effects of ACh and GABA and prepared eggplant powder with very low ACh content for oral administration in animals. ACh and GABA exhibited additive effects but the GABA content in eggplants was not sufficient to promote a hypotensive effect. In conclusion, ACh is the main component associated with the antihypertensive effects of eggplant but GABA within eggplants has a minimal effect in this regard. Thus, compared with GABA, ACh could be a more effective functional food constituent for lowering blood pressure.

Prognostic Impact of a Novel Albumin-Platelet Index as Selection Criterion for Hepatic Resection in Intermediate Stage Hepatocellular Carcinoma.

BACKGROUND/AIM: Hepatic resection for Barcelona Clinic Liver Cancer (BCLC) stage B (intermediate-stage) hepatocellular carcinoma (HCC) is not recommended by BCLC treatment algorithms. We sought to develop a new prognostic model for determining appropriate treatment strategies in patients with intermediate-stage HCC. PATIENTS AND METHODS: This single-center retrospective study included patients who underwent hepatic resection for HCC between 2000 and 2018. A total of 498 patients were classified according to the BCLC staging system (0, n=116; A, n=319; B, n=63). The predictive impact for surgical outcomes was evaluated using receiver operating characteristic (ROC) curves. Based on a survival outcome probability formula, a new predictive model was established. RESULTS: The preoperative albumin level and platelet count were the strongest diagnostic values in patients with intermediate-stage HCC (areas under the ROC curves, AUCs: 0.710 and 0.676, respectively). Logistic regression analysis provided the albumin-platelet index [API; 156.2×albumin (g/dl)+platelet count (×109/l)] was defined as a new prognostic model for the probability of poor survival. The optimal cutoff value (781.2; AUC 0.755) divided patients with BCLC-B into B1 (>781.2, n=27) and B2 (≤781.2, n=36) categories. Patients in substage B2 had a significantly worse prognosis than patients in other stages (p<0.0001), whereas there was no difference in prognosis between patients in substage B1 and those in other stages. CONCLUSION: The API stratifies prognosis in patients with intermediate-stage HCC. For subgroup B1, hepatic resection can be considered a radical treatment, even for intermediate-stage HCC.

Correction: Wang et al. LC-MS/MS Analysis of Choline Compounds in Japanese-Cultivated Vegetables and Fruits. Foods 2020, 9, 1029.

The authors wish to make a correction to the published version of their paper [...].

Correction: Wang et al. Investigation of the Distribution and Content of Acetylcholine, a Novel Functional Compound in Eggplant. Foods 2021, 10, 81.

The authors wish to make a correction to the published version of their paper [...].

Impact of aspartate aminotransferase-to-platelet ratio index based score to assess posthepatectomy liver failure in patients with hepatocellular carcninoma.

BACKGROUND: Posthepatectomy liver failure (PHLF) is a life-threatening complication following hepatic resection. The aspartate aminotransferase-to-platelet ratio index (APRI) is a non-invasive model for assessing the liver functional reserve in patients with hepatocellular carcinoma (HCC). This study aimed to establish a scoring model to stratify patients with HCC at risk for PHLF. METHODS: This single-center retrospective study included 451 patients who underwent hepatic resection for HCC between 2004 and 2017. Preoperative factors, including non-invasive liver fibrosis markers and intraoperative factors, were evaluated. The predictive impact for PHLF was evaluated using receiver operating characteristic (ROC) curves of these factors. RESULTS: Of 451 patients, 30 (6.7%) developed severe PHLF (grade B/C). Multivariate logistic analysis indicated that APRI, model for end-stage liver disease (MELD) score, operating time, and intraoperative blood loss were significantly associated with severe PHLF. A scoring model (over 0-4 points) was calculated using these optimal cutoff values. The area under the ROC curve of the established score for severe PHLF was 0.88, which greatly improved the predictive accuracy compared with these factors alone (p < 0.05 for all). CONCLUSIONS: The scoring model-based APRI, MELD score, operating time, and intraoperative blood loss can predict severe PHLF in patients with HCC.

Prediction of protein mononucleotide binding sites using AlphaFold2 and machine learning.

In this study, we developed a system that predicts the binding sites of proteins for five mononucleotides (AMP, ADP, ATP, GDP, and GTP). The system comprises two machine learning (ML)-based predictors using a convolutional neural network and a gradient boosting machine, two template-based predictors based on sequence and structure alignment, and a predictor that performs ensemble learning of these four predictors. In this study, data augmentation of ligand binding sites with similar ligand structures was performed. For example, in the prediction of ADP-binding sites using ML methods, the binding sites of AMP and ATP, which have similar structures, are considered. In addition, we constructed the structure models using AlphaFold2, a highly accurate protein prediction method. The secondary structure and dihedral angle information obtained using the model structures were used as ML predictor features. Additionally, in the template-based predictor, the structures of the binding sites were used as templates to be explored based on structure alignment to identify the binding site of the target. Consequently, the template-based predictor based on structure alignment showed the best performance among the four individual predictors, and the ensemble predictor achieved the best performance, with an area under the curve of 0.958 for all mononucleotides.

Antihypertensive Mechanism of Orally Administered Acetylcholine in Spontaneously Hypertensive Rats.

Acetylcholine (ACh) acts as a neurotransmitter and neuromodulator. A small dose of eggplant powder rich in ACh (equivalent to 22 g fresh eggplant/d) has been shown to reduce blood pressure (BP) in individuals with higher BP. Here, we investigated the mechanisms underlying the antihypertensive effects of low-dose orally administered ACh in spontaneously hypertensive rats (SHRs). The effects of ACh on BP and sympathetic nervous activity (SNA), including lumbar SNA (LSNA) and renal SNA (RSNA), were evaluated by subjecting conscious SHRs to a telemetry method. Single oral administration of ACh decreased LSNA and lowered BP. Repeated oral administration of ACh for 30 d decreased RSNA and suppressed the elevated BP. Noradrenaline levels in the urine also decreased. However, vagotomy and co-administration of M3 muscarinic ACh receptor antagonist reversed the BP-lowering effect; the dynamics of non-absorbable orally administered ACh was revealed using stable isotope-labeled ACh. In conclusion, ACh acts on the gastrointestinal M3 muscarinic ACh receptor to increase afferent vagal nerve activity, which decreases SNA by autonomic reflex, suppressing noradrenaline release and lowering BP. This study suggests the use of exogenous ACh as an antihypertensive food supplement for controlling the autonomic nervous system, without absorption into the blood.

A novel combined prognostic nutritional index and aspartate aminotransferase-to-platelet ratio index-based score can predict the survival of patients with hepatocellular carcinoma who undergo hepatic resection.

PURPOSE: Inflammation-, nutrition-, and liver fibrosis-related markers are recognized as prognostic for hepatocellular carcinoma (HCC) patients. This study, therefore, assessed the preoperative prognostic utility of the combination of these markers in patients with HCC. METHODS: This single-center retrospective study included patients who underwent hepatic resection for HCC between 2004 and 2017. A total of 454 patients were divided into training (n = 334) and validation (n = 120) cohorts by random sampling. The predictive impact on surgical outcomes was evaluated using receiver operating characteristic (ROC) curves of these prognostic values in the training cohort. RESULTS: The prognostic nutritional index (PNI) and aspartate aminotransferase-to-platelet ratio index (APRI) were the strongest diagnostic values (areas under the ROC curves: 0.627 and 0.646, respectively). A scoring system (over 0-2 points) was developed using optimal cutoff values (for PNI < 46.5 scored as 1 point; for APRI > 0.98 scored as 1 point). An increased PNI-APRI score was an independent prognostic factor for both the overall and disease-free survival in HCC patients. Finally, the clinical feasibility of the PNI-APRI score was confirmed in the validation cohort. CONCLUSIONS: The PNI-APRI score is a useful marker for predicting surgical outcomes of HCC patients.

Mac-2-Binding Protein Glycosylation Isomer as a Novel Predictor of Hepatocellular Carcinoma Recurrence in Patients with Hepatitis C Virus Eradication.

BACKGROUND: Hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC) can recur even after achievement of a sustained virologic response (SVR). Mac-2-binding protein glycosylation isomer (M2BPGi) is a newly identified biomarker correlated with liver fibrosis. This study aimed to clarify outcomes for patients with an SVR and to assess the prognostic value of M2BPGi. METHODS: This single-center retrospective study analyzed patients who underwent surgical resection for primary HCV-related HCC between 2008 and 2018. The study enrolled 81 patients whose M2BPGi could be evaluated after an SVR. The relationship between liver fibrosis-related factors and scores (including M2BPGi) and HCC recurrence, was evaluated. RESULTS: Of the 81 patients, 57 (70.4%) with HCV-related HCC obtained an SVR, whereas 24 patients (29.6%) did not. The patients with an SVR had a significantly more favorable recurrence-free survival (RFS) than the patients with no SVR (P < 0.0001, log-rank). Among the SVR groups, M2BPGi predicted a shorter RFS after hepatic resection with a higher degree of accuracy than other markers and scores in the SVR group. The high-M2BPGi group had worse liver function, RFS, and overall survival (OS) (P = 0.0014 and 0.0006, log-rank, respectively). In the multivariate analysis, high M2BPGi was significantly associated with worse RFS and OS. CONCLUSIONS: Even after achievement of an SVR, the risk of HCC recurrence cannot be eliminated. Measurement of M2BPGi after an SVR can be applied for risk stratification in the assessment of patients with HCV-related HCC.

Prognostic Impact of Lymphocyte-C-Reactive Protein Ratio in Patients Who Underwent Surgical Resection for Hepatocellular Carcinoma.

BACKGROUND: Systemic inflammation-related factors, either independently or in combination, are recognized as prognostic factors for various cancers. The ratio of lymphocyte count to C-reactive protein concentration (lymphocyte-CRP ratio; LCR) is a recently identified prognostic marker for several cancers. Here, we examined the prognostic value of the LCR in patients with hepatocellular carcinoma (HCC). METHODS: This was a single-center retrospective study of patients who underwent surgical resection for HCC between 2004 and 2017. Patients were divided into high- and low-LCR status groups, and the relationships between LCR status, prognosis, and other clinicopathological characteristics were analyzed. RESULTS: A total of 454 patients with HCC were enrolled and assigned to the high- (n=245) or low- (n=209) LCR groups. Compared with the high-LCR group, patients in the low-LCR group had a significantly lower serum albumin level (median 4.1 vs. 3.9 g/dL, P <0.0001), lower platelet count (median 14.0 vs. 12.0 ×104/µL, P=0.0468), lower prothrombin time (median 93.2 vs. 89.6 %, P=0.0006), and larger tumor size (median 2.3 vs. 2.5 cm, P=0.0056). Patients with low-LCR status had significantly worse outcomes of overall survival and disease-free survival than patients with high-LCR status (P=0.0003 and P=0.0069, respectively). Low-LCR status was significantly associated with worse overall survival in multivariate analysis (hazard ratio 1.57, 95% confidence interval 1.14-2.17, P=0.0058). CONCLUSIONS: Low-LCR status may predict worse outcomes in patients with HCC. Measurement of LCR is routine and can easily be applied for risk stratification in the assessment of patients with HCC.