Real-world safety and effectiveness of inhaled nitric oxide therapy for pulmonary hypertension during the perioperative period of cardiac surgery: a post-marketing study of 2817 patients in Japan.

OBJECTIVE: To evaluate the real-world safety and effectiveness of inhaled nitric oxide (INOflo® for Inhalation 800 ppm) for perioperative pulmonary hypertension associated with cardiac surgery in Japan. METHODS: This was a prospective, non-interventional, all-case, post-marketing study of pediatric and adult patients who received perioperative INOflo with cardiac surgery from November 2015-December 2020. Safety and effectiveness were monitored from INOflo initiation to 48 h after treatment completion or withdrawal. Safety outcomes included adverse drug reactions, blood methemoglobin concentrations, and inspired nitrogen dioxide concentrations over time. Effectiveness outcomes included changes in central venous pressure among pediatrics, mean pulmonary arterial pressure among adults, and the partial pressure of arterial oxygen/fraction of inspired oxygen ratio (PaO2/FiO2) in both populations. RESULTS: The safety analysis population included 2,817 Japanese patients registered from 253 clinical sites (pediatrics, n = 1375; adults, n = 1442). INOflo was generally well tolerated; 15 and 20 adverse drug reactions were reported in 14 pediatrics (1.0%) and 18 adults (1.2%), respectively. No clinically significant elevations in blood methemoglobin and inspired nitrogen dioxide concentrations were observed. INOflo treatment was associated with significant reductions in both central venous pressure among pediatrics and mean pulmonary arterial pressure among adults, and significant improvements in PaO2/FiO2 among pediatrics and adults with PaO2/FiO2 ≤ 200 at baseline. CONCLUSIONS: Perioperative INOflo treatment was a safe and effective strategy to improve hemodynamics and oxygenation in patients with pulmonary hypertension during cardiac surgery. These data support the use of INOflo for this indication in Japanese clinical practice.

Orthogeriatric co-management at a regional core hospital as a new multidisciplinary approach in Japanese hip fracture operation.

BACKGROUND: This study aimed to evaluate the effects of orthogeriatric co-management of hip fractures at a regional core hospital. METHODS: This study included patients with proximal hip fracture. Patients were divided into two groups, conventional multidisciplinary group I including patients attending the hospital between April 2015 and March 2016 and orthogeriatric group II including patients attending the hospital between April 2016 and March 2017, which were compared etrospectively. In the control group, the conventional multidisciplinary team treated patients as whole-body controls. In the intervention group, the newly recruited geriatricians performed physical examinations, laboratory tests, radioactive imaging, and physiological tests. Furthermore, they consulted ward pharmacists, rigorously conducted positive polypharmacy interventions , and evaluated the type and number of mediated drugs on admission. RESULTS: The number of medicated drugs significantly decreased from 6.03 ± 4.3 on admission to 5.50 ± 3.59 on discharge in group II, whereas group I did not show a significant decrease. Despite the more number of hospitalized patients in group II (166 patients) than in group I (126 patients), the recovery rate from postoperative urinary retention increased significantly from 57.8% (19/30) in group I to 84.3% (32/59) in group II (p = 0.049), while the incidence of aspiration pneumonia decreased from 7.1% (9/126) in group I to 2.49% (4/166) in group II (p = 0.08). The patients received six or more prescribed drugs on admission, and the number remained constant. However, the number of medicated drugs on discharge showed a marginally significant decrease from 6.03 ± 4.3 in group I to 5.50 ± 3.59 in group II (p < 0.05). CONCLUSIONS: Compared to the conventional multidisciplinary group, the orthogeriatric team contributed to reducing the number of multi-effect drugs and perioperative complications without negatively affecting mortality despite the increased number of patients. The in-hospital mortality rate did not change between the groups. The orthogeriatric program succeeded in preventing and treating perioperative complications.

Postoperative Urinary Retention in Japanese Elderly Males with a Femoral Neck or Trochanteric Fracture.

We assessed risk factors for postoperative urinary retention (UR) in elderly males with femoral bone fractures: 169 Japanese males (mean age 81.95 ± 1.19 years) who had undergone hip surgery at a municipal hospital (Toyama, Japan). A multiple logistic regression analysis was used to test possible risk factors for UR: age, body mass index, serum albumin, cognitive impairment, activities of daily living (ADL), and history of diabetes mellitus (DM). UR occurred in 24 (14.2%) of the 169 patients. A multivariate logistic regression analysis with age adjustment showed that ADL (odds ratio [OR] 3.88; 95% confidence interval [CI]: 1.2-12.5, p=0.023) was significantly associated with the development of UR, and a history of DM showed marginal significance for UR occurrence (OR 0.36, 95%CI: 0.11-10, p=0.064). These results suggests that ADL is a risk factor for UR development in elderly males who have undergone surgery for femoral neck or trochanter fractures.

Mortality and the Risk Factors in Elderly Female Patients With Femoral Neck and Trochanteric Fractures.

BACKGROUND: The main purpose of this study is to exhaustively explore risk factors, including age, gender, and several clinical indices, for mortality in elderly patients with femoral neck fracture and to evaluate some of them using survival analyses. METHODS: This was a retrospective study tracking 1 year for vital prognosis. Data were collected at post-operation from medical records of the cases. Survival analysis was conducted to investigate the risk factors for death, including albumin, urinary retention, activity of daily living (ADL), and cognitive disorder. RESULTS: We recruited 318 patients with a history of hip surgery carried out at Toyama Municipal Hospital, in which 39 patients died for 1 year after discharge. The results showed a significant decrease in survival rate in low albumin, positive urinary retention, and low ADL (P < 0.01, by log-rank test). The hazard ratios (95% confidence interval) of albumin, urinary retention, ADL, and cognitive disorder were 0.36 (0.19 - 0.69), 0.4 (0.2 - 0.8), 0.29 (0.15 - 0.58) and 0.65 (0.32 - 1.29), respectively. CONCLUSIONS: This study demonstrated that albumin, urinary retention and ADL were the important risk factors for mortality, and suggested that the postoperative management of albumin, urinary retention and ADL is important, especially in elderly female patients receiving surgery of femoral neck and trochanteric fractures.

Risk factors for the development of aspiration pneumonia in elderly patients with femoral neck and trochanteric fractures: A retrospective study of a patient cohort.

Aspiration pneumonia (AP) has been recognized as one of the most common postoperative complications after hip surgery in elderly. The objective of the present study was to evaluate risk for postoperative complications of AP in elderly patients with femoral neck fractures.We recruited 426 patients (age 84.9 ±â€Š7.4 years) with a history of hip surgery carried out at Toyama Municipal Hospital. AP occurred in 18 out of 426 cases (4.23%). Statistical test has found significant differences in age, gender, serum albumin level, and cognitive impairment, between AP and non-AP groups. Subsequently multiple logistic regression analysis was conducted to investigate the risk factors for AP, including age, gender, serum albumin, cognitive impairment, and activities of daily living (ADL). Adjusted odds ratio showed significant differences in age, gender, and serum albumin, whereas no significant differences were found in cognitive impairment and ADL.This study suggested that serum albumin seemed to be a risk factor for AP but were necessary to assess under adjustment of confounding factors, including age and gender. Monitoring serum albumin level seemed to be important for the postoperative management of AP, especially in elderly patients receiving surgery of femoral neck and trochanteric fractures.

Urinary retention as a postoperative complication associated with functional decline in elderly female patients with femoral neck and trochanteric fractures: A retrospective study of a patient cohort.

Urinary retention (UR) has been recognized as one of the most common postoperative complications after hip surgery in elderly. The objective of the present study was to evaluate risk for postoperative complications of UR in elderly female patients with femoral neck fractures.We recruited 221 female patients (age 85.3 ±â€Š7.0 years) with a history of hip surgery carried out at Toyama Municipal Hospital. UR occurred in 34 out of 221 cases (15.4%). Multiple logistic regression analysis was conducted to investigate the risk factors for UR, including age, body mass index (BMI), serum albumin, cognitive impairment, and activities of daily living (ADL).The results showed significant association of UR with cognitive impairment (P = .005, odds ratio [OR] 4.11, 95% confidence interval [CI] 1.53-11.03), and ADL (P = .029, OR 2.61, 95% CI 1.11-6.18), under adjustment with age and BMI.This study demonstrated that cognitive function and ADL were the important risk factors for UR, suggested that the postoperative management of UR is important with taking account of neurofunctional assistance and nursing care in daily living, especially in elderly female patients receiving surgery of femoral neck and trochanteric fractures.

Efficacy of postoperative UFT (Tegafur/Uracil) plus PSK therapies in elderly patients with resected colorectal cancer.

To establish the sufficient therapy for elderly colorectal cancer patients, we retrospectively compared postoperative Tegafur/Uracil (UFT; Taiho Pharmaceutical Co., Ltd., Tokyo, Japan) and UFT plus protein-bound polysaccharide kureha (PSK) therapies in elderly patients with resected colorectal cancer. A total of 63 patients were collected; 39 patients were administered only with UFT (control group) and 24 patients were treated with UFT+PSK (PSK group). There were no differences in patient background, surgical outcomes, and drug compliance between the two groups. The 3-year relapse-free survival rate was 47.8% in the control group and 76.2% in the PSK group (p = 0.041). The 3-year overall survival (OS) rate was 52.8% in the control group and 80.8% in the PSK group (p = 0.0498). By subset analysis, in the patients whose tumor location was the colon (p = 0.016) and whose preoperative lymphocyte percentage was below 18.7% (p = 0.017), RFS was significantly better in the PSK group. Adverse drug reactions were rarely observed. All the adverse reactions were grade 2 or below, with no severe reactions. The present retrospective study suggests a possible efficacy of postoperative adjuvant therapy with UFT plus PSK in elderly patients over 70 years of age with resected colorectal cancer.

Clinicopathological characteristics of advanced colorectal cancer 30 mm or smaller in diameter.

OBJECTIVE: To investigate the clinicopathological characteristics of advanced colorectal cancer which was 30 mm or smaller in diameter. METHODS: Retrospective analysis documented 80 patients with small advanced colorectal cancer from May 1985 to May 2002. According to the diameter of tumors, all patients were divided into three groups: Group A (10 mm or less), Group B (11-20 mm), Group C (21-30 mm). Considering the number of patients in Group A was smaller, we combined Group A with Group B as Group D. Then various clinicopathological characteristics were compared between Group C and Group D. RESULTS: The most common site of small advanced colorectal cancer was sigmoid colon and rectum that accounted for 36.2% and 35.0% of all cases. The average diameter of total tumors was 23.3 mm. Type 2 was the most common macroscopic type (63.7%) and the moderate differentiation was seen in 77.5% of cases. Thirty-eight (47.5%) cases had lymph node metastasis. Three (3.8%) cases had liver metastasis and three (3.8%) cases had peritoneal metastasis. The frequency of lymph node metastasis was found significantly different between Group C and Group D (54.2% vs. 28.6%, P < 0.05) , as well as between the groups with different depth of invasion (P < 0.05). Curability A resection was performed in 69 (86.2%) cases. CONCLUSIONS: Tumor size and depth of invasion are related to lymph node metastasis in small advanced colorectal cancer. However, the small size of tumor may not always be a reliable parameter for estimating the risk of lymph node metastasis. Small colorectal cancers also do not always mean the early stage. Surgeons should be aware of the features of small advanced colorectal cancers to select ideal management and perform perfect resection.

Citrus auraptene suppresses azoxymethane-induced colonic preneoplastic lesions in C57BL/KsJ-db/db mice.

The current study was designed to investigate whether dietary citrus auraptene (AUR) suppresses the development of azoxymethane (AOM)-induced colorectal preneoplastic lesions in C57BL/KsJ-db/db (db/db) mice with obese and diabetic phenotypes. Female db/db and wild (+/+) mice were divided into the AOM + AUR, AOM alone, AUR alone, and the untreated groups in each phenotype. AOM was given 3 weekly intraperitoneal injections (10 mg/kg bw). AUR (250 ppm) was given in diet during the study (for 10 wk). Dietary AUR significantly reduced the number of aberrant crypt foci (ACF) and Beta -catenin-accumulated crypt (BCAC) in both phenotypes. The treatment also lowered cell proliferation activity and increased apoptotic cells in both lesions. Our findings indicate that dietary AUR is able to suppress the early phase of colon carcinogenesis in both phenotypes, suggesting possible application of AUR as a chemopreventive agent in both the high-risk and general populations for colorectal cancer.

Insulin responses to selective arterial calcium infusion under hyperinsulinemic euglycemic glucose clamps: case studies in adult nesidioblastosis and childhood insulinoma.

Selective arterial calcium stimulation and hepatic venous sampling (ASVS) for insulin secretion is used as a diagnostic procedure in patients with insulinomas or adult nesidioblastosis. In some of those patients, severe hypoglycemia requiring urgent glucose administration occurs during the procedure. Such glucose administration, however, may affect the results and damage the validity of the test. We report two cases of hyperinsulinemic hypoglycemia, in which ASVS tests were successfully performed under hyperinsulinemic euglycemic glucose clamps. A 40-year-old male with nesidioblastosis developed continual severe hypoglycemia several years after a Billroth II-Braun gastrectomy, and continuous glucose infusion could not be stopped even during ASVS tests. A 9-year-old girl with an insulinoma that showed atypical hypovascularity on imaging examinations had ASVS tests under a glucose clamp for safety. Hyperinsulinemic (approximately 100 microU/ml) euglycemic (approximately 90 mg/dl) clamps were achieved by an artificial endocrine pancreas. The insulin analogue lispro was utilized for clamps and endogenous insulin was measured with an assay that does not cross-react with the analogue. Diagnostically significant responses (more than twofold) of insulin secretion were observed under hyperinsulinemic clamps in both cases. The use of the hyperinsulinemic glucose clamp technique during the ASVS test should be considered for maintaining the safety of some hypoglycemic patients.

Paraaortic lymph node dissection for gastric cancer in 244 consecutive cases.

BACKGROUND/AIMS: More than 20% of patients with advanced gastric cancer show paraaortic lymph node metastasis. However, whether extensive paraaortic lymphadenectomy is beneficial remains controversial. We performed a prospective study of paraaortic lymphadenectomy for patients with advanced gastric cancer. METHODOLOGY: From January 1991 to March 2004, 244 consecutive patients with advanced gastric cancer underwent gastrectomy with paraaortic lymphadenectomy with curative intent. The patients were divided into 3 groups according to the period: Group 1 (1991-1995), Group 2 (1996-1999), and Group 3 (2000-2004). RESULTS: Overall mortality rate was 2.4%, and it fell rapidly from 7.1% in Group 1 to 0% in Group 3. Postoperative complications occurred in 35.6%. High age and postoperative complications were significant predictive factors for operative death. Preoperative comorbidity, positive distal margin, and pancreatectomy were significant predictive factors of postoperative complications. Depth of cancer invasion was correlated with paraaortic node metastasis. Ten patients with paraaortic node metastases survived for more than 5 years. Operative curability and postoperative complications were significant prognostic factors for patients who underwent this procedure. CONCLUSIONS: Paraaortic lymph node dissection for gastric cancer should be performed in patients with tumors deeper than the serosa. Pancreatectomy should be avoided, with careful management required in cases of unavoidable pancreatectomy.

[Results of local ablation therapy for liver metastases from colorectal cancer using radiofrequency ablation and microwave coagulation therapy (RFA/MCT)].

UNLABELLED: In addition to hepatectomy and chemotherapy with intra-arterial infusion, local ablation therapy using RFA and MCT has been used for treatment of liver metastases derived from colorectal cancer. We investigated the results of local ablation therapy in such cases conducted at our department. SUBJECTS AND METHODS: This study was conducted in 9 out of 21 patients with liver metastases derived from colorectal cancer, who underwent local ablation therapy with RFA from September 2001. As adjuvant therapy, the divided administration of low-doses CDDP/FU was conducted in all cases. RESULTS: RFA and MCT were used in 9 cases (25 lesions) and in 15 cases (82 lesions), respectively. The three cases of RFA were combined with MCT. The severity of liver metastasis was H1 and H2 in one case each and H3 in seven cases. The tumor diameter was 1.0-4.7 cm (mean, 2.7 cm) and patients underwent cauterization from 1-6 times (mean, 2.4 times). Although there were no critical complications, pyrexia and increased AST/ALT were found. The three-year survival rate was 50%, and thus favorable prognoses were obtained. CONCLUSION: There were no notable complications associated with local ablation therapy for liver metastases derived from colorectal cancer, and this method was thus indicated to be effective for local control in cases in which hepatectomy is impossible.

Results and controversial issues regarding a para-aortic lymph node dissection for advanced gastric cancer.

More than 20% of the patients with advanced gastric cancer display para-aortic lymph node (PAL) metastasis. Numerous retrospective comparative studies have reported an improved prognosis using an extensive lymph node dissection (D2) with PAL dissection, compared with D2 alone. However, many issues associated with a PAL dissection remain, such as the importance of stage migration, learning curves, and micrometastasis. This review focuses on the results and controversial issues associated with a PAL dissection. The depth of tumor invasion correlates with PAL metastasis, and whether PAL should be dissected in patients with T2 tumors remains controversial. The rate of PAL positivity is higher for cancers involving tumors of the upper third of the stomach. The most important lymphatic terminals for the stomach seem to comprise the a2 lateroaortic and b1 interaorticocaval PAL areas in tumors of the upper third and lower third, respectively. While the 5-year survival rate is about 10% after D2 plus a PAL dissection, patients with a potentially curative operation live longer. Early major complications after a PAL dissection occur in 25% of all cases, predominantly due to a pancreatectomy. A randomized clinical study evaluating a PAL dissection was launched in 1995 in Japan. Furthermore, numerous reports of patients with gastric cancer and PAL metastases responding to chemotherapy should also be considered.

[A case of gastric cancer patient with liver metastasis treated by radiofrequency ablation therapy combined with intra-arterial chemotherapy].

We performed radio-frequency ablation (RFA) therapy combined with intra-arterial chemotherapy for a 71-year old female gastric cancer patient with liver metastasis. She underwent total gastrectomy due to advanced gastric cancer in July of 1996. Because CT scans revealed multiple liver tumors with her, she also underwent intra-arterial chemotherapy comprising of 5-fluorouracil, cis-platinum and Leucovorin. Although her liver tumors decreased in size and number, after 9 months, we had to remove the catheter because of hepatic artery obstruction. Immediately after the removal, 5 hepatic metastases appeared, which were 3.5 cm in maximum diameter. After RFA therapy, CT scans revealed homogenously attenuated lesions. Liver biopsy demonstrated a complete coagulation necrosis. She is currently alive going into 19 months after liver metastasis and 7 months after RFA.

[A case of long-term survival after chemo-radiation for postoperative local recurrence of rectal cancer].

The patient was a 64-year-old male who underwent an abdomino-perineal resection (D3) for advanced lower rectal carcinoma with a formulated vesicorectal abscess. The tumor was a well-differentiated adenocarcinoma, type 2 in the Japanese Classification of Colorectal Carcinoma, and was measured 5.5x4.3 cm in size. Histologically, the tumor was considered to be stage II (H0, P0, a2, n0 (0/86), ly0, v0). He received a postoperative chemotherapy with oral UFT-E (400 mg/day) for 1 year. After 2 years from the surgery, the patient developed a perineal pain, and pelvic CT scans revealed a 4 cm mass anterior to the sacrum. The CEA level was increased to 11 ng/ml. Consequently, a diagnosis of local recurrence was made, and radiochemotherapy was commenced. Radiotherapy was given to the pelvic region at a total dose of 70 Gy (Given 2 Gy each x 35 fragments). Chemotherapy with CDDP and 5-FU was administered via the right internal iliac artery followed by administration of 5'-DFUR (600 mg/day). After that regimen, a recurrence of the pelvic tumor caused an increase in pain, and the patient developed renal failure. He died after 4 years and 10 months from the initial detection of recurrence. This report presents a case of local recurrence of advanced rectal carcinoma, in which we were able to achieve a long-term survival and improvement in QOL by an intensive multidisciplinary therapy.

Effects of thymidine phosphorylase levels in cancer, background mucosa, and regional lymph nodes on survival of advanced gastric cancer patients receiving postoperative fluoropyrimidine therapy.

Due to the contradictory roles that thymidine phosphorylase (TP) plays in both tumor aggressiveness and fluoropyrimidine activation, its impact on drug responses has yet to be clearly established. Therefore, the present study was performed to clarify the effects of TP levels on the prognosis of gastric cancer patients treated postoperatively with different fluoropyrimidines. A total of 52 gastric cancer patients who underwent gastrectomy from January 1997 to March 1998 were enrolled in the present study. The TP levels in the specimens were assayed by enzyme-linked immunosorbent assay (ELISA). Survival was significantly poorer for the 27 patients with high normal tissue TP activity than for the 25 with low normal tissue TP activity. Normal tissue TP level showed different effects on survival according to the chemotherapy regimen used. While the survival rate was significantly poorer in patients with high normal TP level than in those with low normal TP in the 5-FU group, the rate was almost the same in the 5'-DFUR group. Cox's proportional hazard model revealed that tumor TP was an independent prognostic factor in gastric cancer patients. Since activating and catabolizing enzymes for fluoropyrimidines differ from each other, alterations in gene expression of these enzymes should be useful predictive factors.

Rupture of infectious aneurysm of the thoracic aorta into the lung after radical esophageal cancer surgery.

A 60-year-old male underwent radical operation for esophageal cancer 45 days prior to complaining of several incidents of hemoptysis. The hemoptysis was found to be caused by infectious aneurysm of the descending thoracic aorta penetrating the lung. The aneurysm was resected and the aortic wall was sutured directly under percutaneous circulatory pulmonary support system. The sutured thoracic aorta was wrapped with the pedicle of an intercostal muscle flap to prevent reinfection. Forty-eight days after the aortic wall suture operation, however, the patient experienced massive hemoptysis and went into shock. Angiography was reveal no arterial lesions, so emergency left lower lobectomy was performed on suspicion of lung vessel rupture. Immediately after the lower lobectomy, recurrence of the aortic wall rupture caused uncontrollable bleeding. The patient died intraoperatively.

Primary hepatic non-Hodgkin's lymphoma in a patient with chronic hepatitis C: report of a case.

We report a case of primary hepatic non-Hodgkin's lymphoma in a 77-year-old man with chronic hepatitis C. Laboratory data revealed slightly elevated liver function parameters and positive antibody for hepatitis C virus (HCV). Abdominal ultrasonography showed a low-echogenic tumor, about 5 cm in diameter, in the left lateral segment. Abdominal computed tomography showed that the tumor was marginally enhanced in the early phase, but no enhancement was seen in the late phase. Magnetic resonance imaging showed that the tumor was hypointense in relation to the liver on T1-weighted images, but hyperintense on T2-weighted images. Hepatic angiography showed a homogeneously stained hypervascular tumor. Under the diagnosis of a liver tumor, thought to be a hepatocellular carcinoma, left lateral segmentectomy was performed. Histological examination confirmed a diagnosis of non-Hodgkin's diffuse large B-cell lymphoma that was positive for L-26 and CD79Alpha, but negative for CD3 and UCHL-1. The surrounding liver tissue showed signs of chronic active hepatitis. Multiple recurrent lesions were found in the liver, spleen, and iliac bones 4 months postoperatively. However, complete remission was achieved after five courses of systemic chemotherapy using pirarubicin, cyclophosphamide, vincristine sulfate, and prednisolone. The patient has been carefully followed up for about 1 year since his operation, and has been doing well. We review the literature on primary non-Hodgkin's lymphoma arising in the liver infected by HCV.

Fibrolamellar hepatocellular carcinoma: report of a case.

We report a case of fibrolamellar hepatocellular carcinoma, which occurred in a 58-year-old man with normal liver function. Preoperative ultrasonography, computed tomography and magnetic resonance imaging depicted a large tumor in the left lateral segment, which was compatible with the typical radiological features of fibrolamellar hepatocellular carcinoma. He underwent left lobectomy and no lymphadenopathy or distant metastasis was demonstrated. Macroscopic findings of the resected liver demonstrated a well-defined whitish-yellow tumor with a central scar. Microscopic findings of the tumor showed cords of tumor cells, which were surrounded by abundant collagenous fibrous tissue arranged in a lamellar distribution. He has been doing well for approximately one year since the surgery without any signs of recurrence. In addition, we discuss the clinicopathological features of fibrolamellar hepatocellular carcinoma based on a review of 22 Japanese patients who have been previously reported.