Real-time analysis of heart rate variability during aerobic exercise in patients with cardiovascular disease.

Background: Exercise therapy for cardiovascular disease (CVD) is mainly evaluated based on the heart rate (HR) or Borg scale. However, these indices can be unreliable depending on the patient's medication or their subjective decisions; thus, alternative methods are required for easier and safer implementation of aerobic exercise. Here, we examined whether real-time analysis of HR variability (HRV) can help maintain exercise intensity at the ventilatory threshold (VT) during exercise. Methods: Twenty-eight patients with CVD treated at Keio University Hospital between August 2018 and March 2020 were enrolled. Initially, oxygen uptake (VO2) and HR at the VT were determined using the cardiopulmonary exercise test. Patients then performed aerobic exercise on a stationary bicycle for 30 min while a parameter of HRV, the high-frequency (HF) component, was monitored in real time using an electrocardiograph. The work rate during exercise was adjusted every 2 min to maintain the HF range between 5 and 10. The VO2 and HR values, recorded every 2 min during exercise, were compared with those at VT. The Bland-Altman method was used to confirm similarity. Results: VO2 and HR during exercise were closely correlated with those at VT (e.g., 19 min after exercise initiation; VO2: r = 0.647, HR: r = 0.534). The Bland-Altman plot revealed no bias between the mean values (e.g., 19 min; VO2: -0.22 mL/kg/min; HR: -0.07/min). Conclusion: Real-time HRV analysis with electrocardiograph alone during exercise can provide continuous and non-invasive exercise intensity measurements at VT, promoting safer and effective exercise strategies.

Interstitial lung disease associated with adjuvant and neoadjuvant chemotherapy in early breast cancer.

BACKGROUND: Interstitial lung disease (ILD) is a rare adverse event in patients receiving adjuvant or neoadjuvant chemotherapy (NAC) for breast cancer. Few studies have reported the frequency of ILD in detail, and only small numbers of cases have been described in the literature. Given these previous findings concerning ILD, we retrospectively examined the clinicopathological characteristics of five cases of ILD who had received epirubicin and cyclophosphamide (EC) and compared their findings with non-ILD cases. METHODS: The present single-center retrospective study included breast cancer patients who underwent adjuvant chemotherapy or NAC at our hospital between January 2014 and January 2021. RESULTS: Thirty-nine patients who had received EC for operable breast cancer were enrolled in this study. ILD developed 5 out of 39 patients (12.8%). The incidence of ILD in patients with non-dose-dense (dd) or dd chemotherapy was statistically significantly different (p = 0.0149). ILD occurred in three patients during dd EC treatment and two during weekly paclitaxel (wPTX) after dd EC. ILD was detected in one patient with high Krebs von den Lungen-6 (KL-6) levels, in two patients with continuous pyrexia, and in two patients from computed tomography imaging, which was taken to estimate the efficacy of chemotherapy, in two patients. Three of the 5 ILD patients underwent bronchoalveolar lavage, and 2 of these patients were diagnosed with Pneumocystis jirovecii pneumonia (PCP). There were no cases of serious ILD that required steroid pulse therapy. CONCLUSIONS: Dd chemotherapy may be associated with an increased ILD frequency, which may reflect developing PCP. Careful monitoring and a timely diagnosis are useful for detecting early-stage ILD.

Successful surgical treatment for nonocclusive mesenteric ischemia of a wide area of the intestine accompanied by gastric conduit necrosis after esophagectomy for esophageal cancer: a case report and review of the literature.

BACKGROUND: Nonocclusive mesenteric ischemia (NOMI) has been reported to be a life-threating disease. Gastric conduit necrosis is known as a critical postoperative complication after esophagectomy for esophageal cancer. We encountered a rare case of NOMI of a wide area of the intestine accompanied by gastric conduit necrosis after esophagectomy, which was successfully treated with an emergency operation. CASE PRESENTATION: A 67-year-old man presented with dysphagia. He was diagnosed with middle thoracic advanced esophageal cancer. After neoadjuvant chemotherapy, he underwent subtotal esophagectomy with lymphadenectomy and gastric conduit reconstruction. On postoperative day (POD) 2, he had diarrhea, high fever, and low blood pressure, which were treated with catecholamines. Laboratory data revealed acidosis and severe sepsis with multi-organ failure, including the kidneys. Although enhanced computed tomography did not exhibit definite findings of bowel ischemia, upper gastrointestinal endoscopy revealed necrotic mucosal changes in the whole gastric conduit. Therefore, we made a diagnosis of septic shock caused by gastric conduit necrosis and performed an emergency operation. When we explored the abdominal cavity, we found not only gastric conduit necrosis but also intermittent necrotic changes in the intestinal wall from the jejunum to the rectum. Therefore, NOMI was diagnosed. We performed an excision of the gastric conduit and 2 m of the small intestine, as well as total colectomy. After the second operation, prostaglandin E1 was administered intravenously as the treatment for NOMI, and sepsis was improved. On POD 122, he was self-discharged. He died of recurrence of lung metastasis from the esophageal cancer 9 months after the first operation. CONCLUSION: When a patient has a critical status, including severe sepsis or severe acidosis, after esophagectomy, we should consider the possibility of NOMI in addition to gastric conduit necrosis and aim to diagnose and treat it immediately with an urgent operation.

[A Case of Advanced Hepatocellular Carcinoma Successfully Treated with Liver Resection after Administration of Sorafenib].

CASE: A 76-year-old man was referred to our hospital for advanced hepatocellular carcinoma(HCC)with chronic hepatitis type B. Although he underwent right anterior sectionectomy and S3 segmentectomy, multiple recurrences were found in the hepatic remnant after 2 months. Transcatheter arterial chemoembolization(TACE)and transcatheter arterial infusion (TAI)were performed separately. One and a half month after the last TAI, AFP and PIVKA-Ⅱ levels markedly elevated, and multiple early enhancing nodules with portal vein tumor thrombosis were detected on CT. A half dose of sorafenib(400mg/ day)was administered to the patient who was refractory to TACE. Sorafenib was discontinued after 4 weeks because the patient developed general fatigue and anorexia(Grade 3). Furthermore, these adverse events became worse, and ascites appeared. He was hospitalized in the palliative care unit for best supportive care for 3 weeks and also received outpatient treatment for more than 14 months. Fifteen months after discontinuing sorafenib administration, his condition improved dramatically, and CT revealed that the multiple HCC had reduced in size. Moreover, the portal vein tumor thrombosis disappeared. As his performance status and liver function were well preserved, he underwent partial hepatectomy for residual HCC. The patient remains alive without recurrence at 18 months, despite no administration of sorafenib. CONCLUSION: This case demonstrates that sorafenib administration combined with surgical treatment could possibly cure advanced HCC refractory to TACE.

Associations Between Plasma Betatrophin Levels and Coronary and Peripheral Artery Disease.

AIM: Betatrophin, a recently identified circulating adipokine, affects lipid and glucose metabolism. However, association between plasma betatrophin levels and atherosclerotic diseases, such as coronary artery disease (CAD) and peripheral artery disease (PAD), has not been elucidated. METHODS: We investigated plasma betatrophin levels in 457 patients undergoing elective coronary angiography who also had ankle-brachial index (ABI) test for PAD screening. RESULTS: Of the 457 study patients, CAD was present in 241 patients (53%) (1-vessel [1-VD], n=99; 2-vessel [2-VD], n=71; 3-vessel disease [3-VD], n=71). Compared to 216 patients without CAD, 241 with CAD had higher betatrophin levels (median 1120 vs. 909 pg/mL, p＜0.001). A stepwise increase in betatrophin levels was found depending on the number of ＞50% stenotic coronary vessels: 909 in CAD(-), 962 in 1-VD, 1097 in 2-VD, and 1393 pg/ml in 3-VD (p＜0.001). Betatrophin levels correlated with the number of ＞25% stenotic segments (r=0.24, p＜0.001). PAD (ABI＜0.9) was found in 41 patients (9%). Plasma betatrophin levels were also significantly higher in 41 patients with PAD than in 416 without PAD (1354 vs. 981 pg/mL, p＜0.001). In the multivariate analysis, betatrophin levels were not a factor for CAD, but they were a significant factor for 3-VD and PAD independent of atherosclerotic risk factors. The odds ratios for 3-VD and PAD were 1.06 (95%CI=1.01-1.11) and 1.07 (95%CI=1.01-1.13) for a 100-pg/mL increase in betatrophin levels, respectively (p＜0.05). CONCLUSION: Plasma betatrophin levels were associated with the presence and severity of CAD and PAD, suggesting betatrophin has a role in atherosclerosis.

Identification of Heterotrimeric G Protein γ3 Subunit in Rice Plasma Membrane.

Heterotrimeric G proteins are important molecules for regulating plant architecture and transmitting external signals to intracellular target proteins in higher plants and mammals. The rice genome contains one canonical α subunit gene (RGA1), four extra-large GTP-binding protein genes (XLGs), one canonical ß subunit gene (RGB1), and five γ subunit genes (tentatively named RGG1, RGG2, RGG3/GS3/Mi/OsGGC1, RGG4/DEP1/DN1/OsGGC3, and RGG5/OsGGC2). RGG1 encodes the canonical γ subunit; RGG2 encodes the plant-specific type of γ subunit with additional amino acid residues at the N-terminus; and the remaining three γ subunit genes encode the atypical γ subunits with cysteine abundance at the C-terminus. We aimed to identify the RGG3/GS3/Mi/OsGGC1 gene product, Gγ3, in rice tissues using the anti-Gγ3 domain antibody. We also analyzed the truncated protein, Gγ3∆Cys, in the RGG3/GS3/Mi/OsGGC1 mutant, Mi, using the anti-Gγ3 domain antibody. Based on nano-liquid chromatography-tandem mass spectrometry (LC-MS/MS) analysis, the immunoprecipitated Gγ3 candidates were confirmed to be Gγ3. Similar to α (Gα) and ß subunits (Gß), Gγ3 was enriched in the plasma membrane fraction, and accumulated in the flower tissues. As RGG3/GS3/Mi/OsGGC1 mutants show the characteristic phenotype in flowers and consequently in seeds, the tissues that accumulated Gγ3 corresponded to the abnormal tissues observed in RGG3/GS3/Mi/OsGGC1 mutants.

Characterization of Heterotrimeric G Protein γ4 Subunit in Rice.

Heterotrimeric G proteins are the molecule switch that transmits information from external signals to intracellular target proteins in mammals and yeast cells. In higher plants, heterotrimeric G proteins regulate plant architecture. Rice harbors one canonical α subunit gene (RGA1), four extra-large GTP-binding protein genes (XLGs), one canonical ß-subunit gene (RGB1), and five γ-subunit genes (tentatively designated RGG1, RGG2, RGG3/GS3/Mi/OsGGC1, RGG4/DEP1/DN1/qPE9-1/OsGGC3, and RGG5/OsGGC2) as components of the heterotrimeric G protein complex. Among the five γ-subunit genes, RGG1 encodes the canonical γ-subunit, RGG2 encodes a plant-specific type of γ-subunit with additional amino acid residues at the N-terminus, and the remaining three γ-subunit genes encode atypical γ-subunits with cysteine-rich C-termini. We characterized the RGG4/DEP1/DN1/qPE9-1/OsGGC3 gene product Gγ4 in the wild type (WT) and truncated protein Gγ4∆Cys in the RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutant, Dn1-1, as littele information regarding the native Gγ4 and Gγ4∆Cys proteins is currently available. Based on liquid chromatography-tandem mass spectrometry analysis, immunoprecipitated Gγ4 candidates were confirmed as actual Gγ4. Similar to α-(Gα) and ß-subunits (Gß), Gγ4 was enriched in the plasma membrane fraction and accumulated in the developing leaf sheath. As RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutants exhibited dwarfism, tissues that accumulated Gγ4 corresponded to the abnormal tissues observed in RGG4/DEP1/DN1/qPE9-1/OsGGC3 mutants.

[A Resected Case of Adenosquamous Carcinoma of Pancreas That Relapsed in Remnant Pancreas].

A 70's man underwent subtotal stomach preserving pancreatoduodenectomy(SSPPD)for pancreatic head cancer. The pathological diagnosis was adenosquamous carcinoma(ASC)of the pancreas. Two months after surgery, a recurrent tumor in the remnant pancreas was confirmed with a CT scan and suspected to be ASC by endoscopic ultrasound-guided fine needle aspiration(EUS-FNA). As the recurrent lesion was limited in the pancreas, total remnant pancreatectomy(TP)was performed 4 months after SSPPD. The final pathological diagnosis was ASC. Two months after TP, liver and para-aortic lymph node metastases were revealed. The patient has been alive for 14 months after SSPPD with chemotherapy. Because of its rarity, it is difficult to implement treatment plans for recurrent ASC in the remnant pancreas.

Doublecortin and CaM kinase-like-1 as an independent prognostic factor in patients with resected pancreatic carcinoma.

AIM: To elucidate the effect of expression of doublecortin and CaM kinase-like-1 (DCLK1) in patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: Tumor specimens were obtained from 136 patients with pancreatic cancer who had undergone resection without preoperative therapy between January 2000 and December 2013 at the Department of Surgical Oncology, Osaka City University. The resected specimens were analyzed for associations with clinicopathological data, including DCLK1 expression, epithelial mesenchymal transition (EMT) marker expression, and cancer stem cell (CSC) marker expression. Univariate and multivariate survival analyses were performed and we assessed the association between DCLK1 expression and clinicopathological factors, including the EMT marker and CSC marker. RESULTS: In total, 48.5% (66/136) of the pancreatic cancer samples were positive for DCLK1. Patients with DCLK1-positive tumors had significantly shorter survival times than those with DCLK1-negative tumors (median, 18.7 mo vs 49.5 mo, respectively; P < 0.0001). Positive DCLK1 expression correlated with histological grade (P = 0.0290), preoperative CA19-9 level (P = 0.0060), epithelial cell adhesion molecule (EpCAM) expression (P = 0.0235), and the triple-positive expression of CD44/CD24/EpCAM (P = 0.0139). On univariate survival analysis, five factors were significantly associated with worse overall survival: histological grade of G2 to G4 (P = 0.0091), high preoperative serum SPan-1 level (P = 0.0034), R1/2 (P < 0.0001), positive expression of DCLK1 (P < 0.0001) or CD44 (P = 0.0245). On multivariate survival analysis, R1/2 [odds ratio (OR) = 2.019, 95% confidence interval (CI): 1.380-2.933; P = 0.0004] and positive DCLK1 expression (OR = 1.848, 95%CI: 1.2854-2.661; P = 0.0009) were independent prognostic factors. CONCLUSION: DCLK1 expression was found to be an independent prognostic factor and it may play a crucial prognostic role by promoting acquisition of stemness.

Analysis of the origin of anaplastic pancreatic cancer and the mechanism of its dedifferentiation.

BACKGROUND: We researched the origin and progression of anaplastic pancreatic cancer (APC) from the viewpoints of cell lineage, epithelial-mesenchymal transition (EMT) and cancer stem-like cells (CSC). METHODS: Using specimens from patients with APC and differentiated pancreatic ductal adenocarcinoma (PDAC), expression of sex-determining region Y-box 9 (SOX9), E-cadherin, vimentin, ZEB1, Snail, N-cadherin, CD24 and CD44 was estimated using immunohistochemistry. RESULTS: Almost all cases were positive for SOX9 expression. APC cases were negative, but many PDAC cases were positive for the expression of E-cadherin. A much higher number of APC cases than PDAC cases were positive for the expression of other EMT related proteins and for the expression of CSC related proteins. The ductal cancerous component of APC accounted for an average of 12% of the cancerous lesion and the expression of each marker in this component was similar to that of PDAC cases. CONCLUSIONS: Anaplastic pancreatic cancer had pancreatic duct cell like features and might gain dedifferentiate components through EMT and the acquisition of CSC properties.

[A Case of Liver Metastasis from Esophageal Cancer Successfully Treated by Surgical Resection after Chemotherapy with Weekly-Paclitaxel].

A 58-year-old man complaining of dysphagia was admitted to our hospital and diagnosed with esophageal cancer.He underwent thoracoscopic subtotal esophagectomy with 3-field lymph node dissection and reconstruction with a gastric tube created by hand-assisted laparoscopy.The pathological diagnosis was classified as AeLtG, pT3N2M0, pStage III .He was subsequently treated with systemic chemotherapy with 5-fluorouracil and cisplatin.After 2 courses, a single liver metastatic tumor appeared at segment 5.As chemotherapy against the recurrence, weekly-paclitaxel was administered.After 2 courses, the metastatic liver tumor reduced in size.Subsequently, laparoscopic partial liver resection was performed 11 months after first surgery.The pathological finding was negative for malignancy(pathological complete response).

Establishment and characterization of new cell lines of anaplastic pancreatic cancer, which is a rare malignancy: OCUP-A1 and OCUP-A2.

BACKGROUND: Anaplastic pancreatic cancer (APC) cell lines have been scarcely established. METHODS: The morphology, gene expressions, karyotyping and epithelial-mesenchymal transition markers of newly established APC cell lines OCUP-A1 and OCUP-A2 were analyzed. Their abilities of proliferation under normoxia and hypoxia, migration and invasion were compared to 4 commercially available pancreatic ductal adenocarcinoma (PDA) cell lines. Their induction of angiogenesis, stem-like cell population and subcutaneous tumor growth in nude mice were estimated, comparing 2 PDA cell lines examined here. RESULTS: OCUP-A1 and OCUP-A2 cells continuously grew with spindle and polygonal shapes, respectively. Gene analysis revealed 9 gene mutations including KRAS and TP53. Karyotyping clarified numerical structural abnormalities in both cells. Loss of E-cadherin and expression of vimentin in both cell lines were observed. The doubling time of both cell lines was approximately 20 h. Proliferation, migration and invasion abilities were not notable compared to other PDA cell lines. However stem-like cell population of both cell lines was superior to a part of PDA cell lines. Moreover OCUP-A1 showed stronger hypoxia tolerance and induction of angiogenesis than other PDA cell lines. The tumorigenicity in vivo of OCUP-A2 was stronger than conventional PDA cell lines. CONCLUSIONS: The OCUP-A1 and OCUP-A2 cell lines of rare malignancies might be useful for investigating the biology of pancreatic cancer.

Clinical and pathological features of five-year survivors after pancreatectomy for pancreatic adenocarcinoma.

BACKGROUND: Clinical factors determining short-term survival after pancreatectomy have been well studied, but factors predicting long-term survival with curative resection are poorly understood in pancreatic carcinoma. Our objective was to identify clinical and pathological features of five-year disease-free survivors after surgical resection of pancreatic adenocarcinoma. METHODS: The clinical and pathological data from 147 patients who underwent a potentially curative resection for pancreatic adenocarcinoma at our institution between 1988 and 2012 were retrospectively analyzed. RESULTS: Of 147 patients, 18 survived for more than five years after surgery without disease recurrence. A univariate analyses demonstrated that: two or fewer lymph node metastases (P=0.014), a preoperative serum carbohydrate antigen 19-9 (CA19-9) level of 40 U/mL or less (P=0.0018), an absence of intrapancreatic nerve invasion (P=0.028), and undergoing an R0 resection (P=0.011) were significantly associated with five-year survival. A logistic regression model identified the following independent cancer-related predictors of five-year survivors: having two or fewer lymph node metastases (odds ratio (OR): 6.02; 95% confidence interval (CI): 1.08 to 112.98; P=0.0385), a preoperative serum CA19-9 level of 40 U/mL or less (OR: 5.02; 95% CI: 1.68 to 16.48; P=0.0036), and undergoing an R0 resection (OR: 3.63; 95% CI: 1.12 to 14.28; P=0.0316). CONCLUSIONS: We conclude that number of lymph node metastases being two or less, a preoperative serum CA19-9 level of 40 U/mL or less, and undergoing an R0 resection may be independent predictive factors to identify actual five-year survivors after pancreatectomy for pancreatic adenocarcinoma.

[A case of a villous tumor of the rectum with electrolyte depletion syndrome].

We report a case of a villous tumor of the rectum with electrolyte depletion syndrome (EDS). A 76-year-old woman developed general fatigue, and on investigation, we found a large laterally spreading tumor of the rectum using bowel enema and colon fiber. Pathologically, the biopsy specimen was graded Group 4. We intended to perform a laparoscopy-assisted low anterior resection in the patient. However, the operation was interrupted by a short-run type of ventricular premature contraction (VPC) due to EDS-induced hypokalemia. After treating the hypokalemia, low anterior resection or laparotomy was performed. The tumor was 19 × 13 cm in size and occupied the circumference of the rectum. Histological examination revealed well differentiated tubular adenocarcinomas with tubulovillous adenoma. Pathological staging was pTis, pN0, M0, stage 0 according to the Japanese Classification of Colorectal Carcinoma (8th edition). It is now 6 months after the operation and hypokalemia has not recurred in the patient.

[Case report of long-term survival obtained for advanced sigmoid colon cancer with para-aortic lymph nodes by resection and chemotherapy].

The patient was a 66-year-old male. He underwent sigmoidectomy with D1 for an advanced sigmoid colon cancer with massive metastasis to the para-aortic lymph nodes. After the resection he underwent chemotherapy, and CT showed that the para-aortic lymph node metastasis had disappeared. However, CT showed other lymph node(No. 252, No. 273 lt)swelling. We therefore resected No. 252 and No. 273 lt lymph nodes. Two years after the resection the patient is alive and shows no sign of recurrence while being without chemotherapy.

[A case of obstruction due to right-sided colon cancer in which good quality of life was achieved after colonic stenting].

We report a case of a 60-year-old woman with abdominal distension who was treated with self-expandable metal stent (SEMS) placement in the proximal transverse colon. She was found to have severe bowel obstruction due to advanced transverse colon cancer on plain computed tomography (CT) and colonoscopy. We performed colonic stenting safely, and the symptom promptly improved. Defecation and flatus were observed on the same day of stenting, and the patient was able to start drinking and eating on the next day. Enhanced abdominal CT revealed multiple liver metastasis, peritoneal dissemination, ascites, and cystic ovarian tumor. After treatment with 1 course of 5-fluorouracil, Leucovorin, and oxaliplatin (mFOLFOX6), the patient was discharged on day 14 after admission. The rapidly enlarging ovarian tumors and primary colonic lesion with SEMS were surgically removed after treatment with mFOLFOX6 for 4 months in an outpatient basis. The patient has been alive with a good quality of life (QOL) and being treated with bevacizumab plus mFOLFOX6/Leucovorin, 5-fluorouracil, and irinotecan( FOLFIRI) for 6 months. SEMS placement could be safe and effective for the treatment of obstruction of the right colon, and could maintain a good QOL in patients.