Efficacy and safety of once‐weekly semaglutide in Japanese individuals with type 2 diabetes by baseline age and body mass index

Aims/IntroductionMany East Asians with type 2 diabetes are elderly and have a low body mass index (BMI), especially in ''super‐aged'' populations, such as Japan. This post‐hoc analysis assessed once‐weekly semaglutide efficacy and safety in Japanese individuals with type 2 diabetes across baseline age and BMI subgroups.Materials and MethodsData were derived from the Semaglutide Unabated Sustainability in Treatment of Type 2 Diabetes (SUSTAIN) Japan monotherapy and SUSTAIN Japan oral antidiabetes drug (OAD) combination trials comparing once‐weekly semaglutide with sitagliptin or OADs, respectively. Participants were grouped by baseline age (<65 and ≥65 years) and/or BMI (<25 and ≥25 kg/m²). Reductions from baseline in glycosylated hemoglobin and bodyweight (efficacy), and adverse events (safety) were assessed.ResultsIn this analysis, participants from the SUSTAIN Japan monotherapy trial (n = 308; n per subgroup; range, 8–73) and SUSTAIN Japan OAD combination trial (n = 601; n per subgroup; range, 20–168) were included. Reductions in glycosylated hemoglobin and bodyweight were numerically greater with semaglutide versus comparators across all age and BMI subgroups. Reductions from baseline in glycosylated hemoglobin ranged from –1.7 to –2.1 with semaglutide 0.5 mg, –1.8 to –2.4 with semaglutide 1.0 mg and –0.6 to –1.0 with comparators. Corresponding ranges for bodyweight (kg) were –1.0 to –2.5, –2.4 to –4.3 and 1.0 to –1.0 kg, respectively. The safety profile of semaglutide was broadly similar across BMI and age subgroups.ConclusionsIn this post‐hoc analysis with modest subgroup numbers, once‐weekly semaglutide appeared consistently more efficacious versus comparators across age and BMI subgroups in Japanese patients, with a similar safety profile.     

Hepatitis B Virus Infection Predicts Extrahepatic Metastasis After Hepatic Resection in Patients With Large Hepatocellular Carcinoma

Background Although extrahepatic metastasis occurs rarely after hepatic resection for hepatocellular carcinoma (HCC), the prognosis of these patients is extremely poor. Predictors of extrahepatic metastasis have not been fully investigated. Methods To identify predictors of extrahepatic metastasis after resection, we retrospectively investigated 77 patients with HCC tumors >50 mm in diameter who underwent hepatic resection. We investigated correlations between postoperative extrahepatic metastasis and clinicopathologic factors as well as extrahepatic metastasis-free survival rate by log rank test and predictors of extrahepatic metastasis by univariate and multivariate logistic regression models. Results Hepatitis B surface antigen (HBs-Ag) was found in 25 (32.5%) of 77 patients, and extrahepatic metastasis occurred in 26 (33.8%). Patients with extrahepatic metastasis showed better liver function and a high occurrence of HBs-Ag positivity than those without. The 5-year extrahepatic metastasis-free survival rate was worse in patients with HBs-Ag positivity, larger tumors (≥70 mm), higher alfa-fetoprotein level (≥300 ng/mL), and lower indocyanine green retention rate at 15 minutes (ICGR₁₅) (<15%) than in those without. By univariate logistic regression analysis, HBs-Ag positivity, larger HCC tumor (≥70 mm), lower ICGR₁₅ (<15%), and lower preoperative lymphocyte count (<1000/mm³) were predictors of extrahepatic metastasis (P < .1). By multivariate analysis, HBs-Ag positivity was an independent predictor of postoperative extrahepatic metastasis (P = .04). Conclusions In patients positive for HBs-Ag, radiologic examination of extrahepatic organs should be performed as a part of the postoperative surveillance. Hepatitis B virus infection may promote establishment of extrahepatic metastasis.     

Protective effect of sivelestat,a neutrophil elastase inhibitor,on ipsilateral and contralateral testes after unilateral testicular ischaemia–reperfusion injury in rats

What’s known on the subject? and What does the study add? Following ischemic damage, reperfusion may cause further injury paradoxically in the ischemic tissue, known as reperfusion injury. Decreased blood flow causes hypoxia, leading to increased levels of lactic acid, hypoxanthine, and lipid peroxides in ischemic tissues and subsequent increase in blood flow after lipid peroxidation produces reactive oxygen species. In addition, several experimental studies and clinical trials demonstrated that unilateral testicular torsion has a detrimental effect also to the contralateral testis. Although the basic pathological mechanism underlying testicular ischemia/reperfusion injury has not been completely understood, it has been shown that reactive oxygen species formed during ischemia/reperfusion play the key role in this process. In the international literature there is no information available regarding the effects of neutrophil elastase inhibitors such as sivelestat sodium aminoacetate tetrahydrate on the ischemia/reperfusion injury of the testis. In this study we investigated the effects of sivelestat in the testes bilaterally, after unilateral testicular ischemia/reperfusion injury using an experimental unilateral testicular ischemia/reperfusion rat model. We found that sivelestat reduces the oxidative stress and partially prevents the testicular damage both in the ischemic and in the contralateral testis.

OBJECTIVE

To investigate the effect of a neutrophil elastase inhibitor, sivelestat sodium hydrate, on testicular ischaemia–reperfusion (IR)‐injury.

MATERIAL AND METHODS

Eight‐week‐old male Sprague–Dawley rats were divided into four groups: sham‐operated control rats; IR rats (group IR); and IR rats that received intra‐abdominal administration of 15 mg/kg or 60 mg/kg sivelestat (group IR15 and group IR60, respectively). Right testicular vessels were clamped for 90 min in groups IR, IR15 and IR60. Sivelestat had been administered 45 min after the induction of the ischaemia in groups IR15 and IR60. In subpopulations of IR, IR15 and IR60 rats, reperfusion was performed after ischaemia for 2 h (groups IR‐A, IR15‐A and IR60‐A, respectively) or 48 h (groups IR‐B, IR15‐B and IR60‐B, respectively). At the end of the reperfusion period, blood samples were aspirated from both spermatic veins of each rat and testosterone was evaluated. Then both testes from all rats were collected and tissue levels of malondialdehyde (MDA), myeloperoxidase (MPO), and heat‐shock protein‐70(HSP‐70) were evaluated. Testicular tissue samples were also processed for histological evaluation and TUNEL staining.

RESULTS

MDA, MPO and HSP‐70 levels in the ischemic testis were significantly higher in the IR group compared with the control group. MDA and HSP‐70 in the contralateral testis were significantly higher in the IR group compared with the control group. Bilateral testosterone levels were lower in all rat groups in comparison with the control group. Bilateral testicular samples in group IR showed extensive histopathologic degenerative alterations and increased percentage of apoptotic cells. Sivelestat treatment lowered the MDA concentration and the percentage of apoptotic cells bilaterally and ameliorated the testicular histological pattern bilaterally.

CONCLUSIONS

Unilateral testicular ischaemia causes significant contralateral testicular damage. Sivelestat may be a novel adjunct tool for reducing oxidative stress and partially preventing bilateral testicular damage.     

Reconstruction of the middle hepatic vein tributaries draining segments V and VIII of a right liver graft by using the recipient’s own middle hepatic vein and vascular closure staples

A right liver graft lacking the middle hepatic vein can result in congestion of the anterior segment. We describe a method of reconstructing the middle hepatic vein tributaries by using the recipient’s own middle hepatic vein with vascular closure staples. During a living donor right liver transplantation, the middle hepatic vein tributaries draining segments V (V5) and VIII (V8) of the right lobe graft were reconstructed using the recipient’s own middle hepatic vein and secured with vascular closure staples. Computed tomography showed good venous outflow from the middle hepatic vein and no congestion or atrophy of the anterior segment of the right liver grafts. Thus, using the recipient’s own middle hepatic vein is a suitable option for reconstructing the middle hepatic vein tributaries (V8 and V5) in right-liver living donor transplantation and the application of vascular closure staples helps to accomplish this.     

Diagnostic significance of digital rectal examination and transrectal ultrasonography in men with prostate-specific antigen levels of 4 ng/mL or less

Objectives. To investigate the usefulness of digital rectal examination (DRE) and transrectal ultrasonography (TRUS) for prostate cancer diagnosis and to propose a diagnostic algorithm for individual-based cancer screening in subjects with prostate-specific antigen (PSA) levels of 4.0 ng/mL or less.Methods. Between January 1992 and March 2000, 129 subjects with PSA levels of 4.0 or less and abnormal findings on DRE or TRUS underwent prostate biopsy. The subjects were divided into four groups according to the PSA range: 0 to 0.9 ng/mL, 1.0 to 1.9 ng/mL, 2.0 to 2.9 ng/mL, and 3.0 to 4.0 ng/mL. The reliability of the DRE and TRUS and the clinicopathologic features of prostate cancer were investigated among these four groups.Results. Of the 129 subjects, 17 (13.2%) patients with prostate cancer were diagnosed. The detection rate was 2.2% (1 of 45), 0% (0 of 27), 20.6% (7 of 34), and 39.1% (9 of 23) in subjects with PSA levels of less than 1.0 ng/mL, 1.0 to 1.9 ng/mL, 2.0 to 2.9 ng/mL, and 3.0 to 4.0 ng/mL, respectively. The proportion of patients with Stage II, III, and IV was 58.8%, 41.2%, and 0%, respectively. The percentage with Gleason scores of 8 to 10 was 17.6%. The detection rate of abnormal findings on DRE and TRUS was 14.4% (13 of 90) and 9.5% (7 of 74), respectively. Adding TRUS to DRE in the screening program of subjects with PSA levels of 2.0 to 4.0 ng/mL, increased the detection rate of prostate cancer to 30.8% (4 of 13).Conclusions. Routine prostate biopsy should not be undertaken except for highly suspicious DRE findings in subjects with PSA levels less than 2.0 ng/mL. The additional use of TRUS in subjects with PSA levels of 2.0 to 4.0 ng/mL would improve the sensitivity of prostate cancer detection. The diagnostic algorithm proposed in the present study is useful as a screening method for prostate cancer in subjects with PSA levels of 4.0 ng/mL or less.     

Vascular Relaxant Effects of Toborinone on the Isolated Canine Internal Mammary Artery

This study was conducted to evaluate the vascular relaxant effects of toborinone on canine internal mammary ring preparations. We determined the concentration–contraction curves for various vasoconstrictors, namely norepinephrine, serotonin, U46619, endothelin-1, phenylephrine, and KCl in internal mammary artery (IMA) preparations, then assessed the vascular relaxant effects of the test drugs. As models, preparations with and without functional endothelium were used. As vasorelaxants, we used milrinone, papaverine, and nitroglycerin. Toborinone produced concentration-dependent relaxation in preparations precontracted with norepinephrine and serotonin. However, the vascular relaxant effect of toborinone on KCl-induced contraction was weaker than those on norepinephrine- and serotonin-induced contraction. Toborinone produced concentration-dependent relaxation in preparations with, and those without functional endothelium. There was no difference in the potency between the preparations with, and those without functional endothelium. The relaxing effect of toborinone on norepinephrine-induced contraction (EC₅₀ = 1.3 × 10⁻⁶ M) was significantly weaker than that of nitroglycerin (EC₅₀ = 7.8 × 10⁻⁸ M), equal to that of papaverine (EC₅₀ = 2.2 × 10⁻⁶ M), and significantly stronger than that of milrinone (EC₅₀ = 3.3 × 10⁻⁶ M). These results demonstrate that toborinone produces relaxant effects on canine IMA preparations, and that it may be effective in the treatment of IMA malperfusion syndrome. Received: December 7, 2000 / Accepted: May 15, 2001     

Survival and sinus rhythm maintenance after modified Cox/maze procedure and mitral valve operation in patients with chronic atrial fibrillation

OBJECTIVE: Sinus rhythm gained after the Cox/maze procedure concomitant with mitral valve operation has demonstrated long-term attrition during the follow-up, no information exists on whether the type of mitral valve operation--(repair vs. replacement)--affects this sinus rhythm maintenance rate. We retrospectively studied patients undergoing concomitant mitral valve operation and Cox/maze procedure to answer this question. METHODS: Between April 1993 and August 1995, 87 consecutive patients--35 men and 52 women (mean age: 59.3 years)--with chronic atrial fibrillation and mitral valve disease underwent the modified Cox/maze procedure and concomitant mitral valve operation, with 56 having mitral valve repair (repair group) and 31 mitral valve replacement (replacement group). Patients were followed up and changes in rhythm studied retrospectively. RESULTS: Follow-up for a mean 51.3 +/- 11.6 months was completed in 82 of 83 long-term survivors (99%). Repair group surgery survival was 98.1 +/- 1.9% at 1 year and 94.2 +/- 3.2% at 5 based on the Kaplan-Meier method. Replacement group surgery survival was 85.7 +/- 5.9% at 1 year and 82.9 +/- 6.4% at 5. Probability in sinus rhythm maintenance for the repair group at 1 year was 88.6 +/- 5.4% and at 5 years was 67.6 +/- 9.1%. Probability in sinus rhythm maintenance for the replacement group at 1 year was 95.7 +/- 4.3% and at 5 years was 65.0 +/- 11.1%. CONCLUSIONS: Medium-term results after the Cox/maze III procedure concomitant with mitral valve operation are good. The attrition of sinus rhythm maintenance appears similar by the completion of 5-year follow-up.     

Annuloaortic Repair in the Treatment of Aortic Regurgitation and Aortic Root Pathology

We developed a new technique of aortic root repair which may be able to eliminate the potential problem of leaflet damage, resulting from the direct contact of the aortic leaflets with synthetic vascular grafts during systole. This report describes our technique of annuloaortic repair and the operative results. Between February 1995 and October 1998, 13 patients underwent annuloaortic repair. The patients included 8 males and 5 females (mean age 50 years). Four patients had grade IV/IV aortic regurgitation (AR), 5 had III/IV AR, 2 had II/IV AR, and 1 had no AR preoperatively. Regarding the preoperative functional status, 1 patient was classified as New York Heart Association class IV, 5 were class III, 6 class II, and 1 class I. Concomitant cardiovascular procedures were performed in 12 cases. Aortic valvuloplasty or annuloplasty was performed in 7 patients. Both operative and short-term postoperative results with pre- and postoperative echocardiographic findings were studied retrospectively. The mean total cardiopulmonary bypass time was 212 min. The mean aortic cross-clamp time was 130 min. Circulatory arrest was induced in 5 patients. Postoperatively, 7 patients had no AR. Three patients had grade I/IV AR and 3 had grade II/IV AR. Perioperative changes in aortic annulus, mid-sinus portion, and sinotubular junction diameters were determined echocardiographically in 5 patients. The preoperative diameters were 2.7 +/- 0.4, 5.4 +/- 0.5, and 4.7 +/- 1.0 cm, respectively. The postoperative diameters were 2.3 +/- 0.5, 4.2 +/- 0.5, and 3.5 +/- 0.5cm, respectively. Ten patients were class I and 2 were class II. This technique of annuloaortic repair with or without aortic valvuloplasty is applicable to a certain subset of patients with aortic root disease and AR. Both the indications for this procedure and the long-term results should be confirmed.     

An intraoperative evaluation of the cerebral circulation using the ophthalmic artery Doppler method in a case of brachiocephalic trunk occlusion

A 57-year-old man underwent left-right subclavian artery bypass for brachiocephalic trunk occlusion. The cerebral circulation was evaluated by ophthalmic artery Doppler method during the operation. Before the bypass, maximal flow velocity (Vmax) of the right ophthalmic artery was 6.09 cm x sec(-1), compared to 43.8 cm x sec(-1) of the left. The preoperative flow acceleration (FA) was 8.3 cm x sec(-2) and 500 cm x sec(-2) in the right and left, respectively. Both Vmax and FA of the right ophthalmic artery improved to 17.6 cm x sec(-1) and 96.7 cm x sec(-2) at the end of the bypass. Additional sutures were performed because of difficulty in stopping bleeding at the site of anastomosis. However, this additional procedure blunted the Doppler waveform, with decreases in Vmax to 8.69 cm x sec(-1) and FA to 33.1 cm x sec(-2) Re-anastomosis at the leftsubclavian artery was performed. Anaphylactic shock induced by transfusion was encountered at the end of re-bypass. Vmax of the right ophthalmic artery at that time was only 10.2 cm x sec(-1) However, the fact, that the Doppler waveform was no more blunt and FA had improved up to 116.4 cm x sec(-2), let us conclude that the cerebral circulation had recovered. In conclusion, the ophthalmic artery Doppler method is a useful tool for evaluation of the cerebral circulation.