Supplementation of l‐arginine boosts the therapeutic efficacy of anticancer chemoimmunotherapy

Myeloid‐derived suppressor cells (MDSCs) play a crucial role in immunosuppression in tumor‐bearing hosts. MDSCs express arginase‐I and indoleamine 2,3‐dioxygenase; they suppress T‐cell function by reducing the levels of l ‐arginine and l ‐tryptophan, respectively. We examined the anticancer effects of supplementation of these amino acids in CT26 colon carcinoma‐bearing mice. Oral supplementation of l ‐arginine or l ‐tryptophan (30 mg/mouse) did not affect tumor growth, whereas oral supplementation of d ‐arginine was lethal. Supplementation of l ‐arginine showed a tendency to augment the efficacy of cyclophosphamide (CP). CP reduced the proportions of granulocytic MDSCs and increased the proportions of monocytic MDSCs in the spleen and tumor tissues of CT26‐bearing mice. l ‐Arginine supplementation alone did not affect the MDSC subsets. CP treatment tended to reduce the plasma levels of l ‐arginine in CT26‐bearing mice and significantly increased the number of tumor‐infiltrating CD8⁺ T cells. In addition, l ‐arginine supplementation significantly increased the proportions of tumor peptide‐specific CD8⁺ T cells in draining lymph nodes. Importantly, additional supplementation of l ‐arginine significantly increased the number of cured mice that were treated with CP and anti‐PD‐1 antibody. Totally, l ‐arginine supplementation shows promise for boosting the therapeutic efficacy of chemoimmunotherapy.     

Risk Factors and Management of Bile Leakage after Hepatic Resection

The aim of this study was to identify the perioperative risk factors for postoperative bile leakage after hepatic resection and to propose a treatment strategy for such leakage when it does occur. Between 1992 and 2000 a total of 313 hepatic resections without choledocojejunal anastomosis were performed at our institute. Risk factors related to bile leakage were identified with univariate analysis, and strategies were evaluated in relation to the findings of postoperative fistulography. Postoperative bile leakage developed in 17 patients (5.4%). Univariate analysis identified high risk factors as advanced age, a wide surface area of the incision (bile leakage group versus no bile leakage group: 102.1 vs. 66.4 cm², p < 0.05), and exposure of Glissons sheath at the cut surface (e.g., central bisegmentectomy, S4, S8 subsegmentectomy). Groupings of patients by their postoperative fistulography results showed that patients with involvement of the proximal bile duct were slower to heal than those with no demonstrable bile duct involvement. The one patient whose fistulogram demonstrated peripheral bile duct involvement had uncontrollable leakage and required reoperation. Hepatectomies with a wide surface area and those that expose the major Glissons sheath present serious risk factors for bile leakage. When the fistulogram shows proximal bile duct involvement, endoscopic nasobiliary tube drainage is necessary; when the fistulogram shows peripheral bile duct involvement, reoperation is needed.     

New Reconstructive Procedure After Intestinal Resection for Crohn’s Disease: Modified Side-to-Side Isoperistaltic Anastomosis With Double Heineke-Mikulicz Procedure

Although side-to-side isoperistaltic anastomosis is a useful strictureplasty technique when long segments of intestinal stenosis complicate Crohns disease, concerns have been raised regarding disease recurrence adjacent to the anastomosis. We performed side-to-side isoperistaltic anastomosis without spatulated intestinal ends as a method of reconstruction after intestinal resection for Crohns disease; both intestinal ends were transversely closed like a Heineke-Mikulicz-type strictureplasty. With this procedure, the luminal diameter proximal and distal to the anastomosis became wider than the original diameter of the intestine. This new procedure, which we refer to as the modified side-to-side isoperistaltic anastomosis with double Heineke-Mikulicz procedure could become an alternative operation after intestinal resection in persons with Crohns disease, although long-term outcome analysis is necessary.     

Incidence of asymptomatic cerebral microthromboembolism after atrial fibrillation ablation guided by complex fractionated atrial electrogram

Cerebral Microthromboembolism After CFAE Ablation . Background: The incidence of cerebral thromboembolism after pulmonary vein isolation (PVI) ranges from 2% to 14%. This study investigated the incidence of cerebral thromboembolism after complex fractionated atrial electrogram (CFAE) ablation with or without PVI. Methods: One hundred consecutive atrial fibrillation (AF) patients (50 paroxysmal and 50 persistent, including 10 longstanding) who underwent CFAE ablation combined with (n = 41, PVI+CFAE group) or without (n = 59, CFAE group) PVI were studied. Coronary angiography (CAG) was conducted with AF ablation in 5 cases in which coronary artery stenosis was suspected on 3D‐computed tomography. PVI was performed before CFAE ablation without circular catheter during AF. After termination of AF, additional ablation was performed to complete PVI with a circular catheter. All patients underwent cerebral magnetic resonance imaging (MRI) including diffusion‐weighted MRI and T2‐weighted MRI the day after ablation. Results: New thromboembolism was detected in 7.0%, and there was no significant difference between the 2 strategies (7.3% in PVI+CFAE group, 6.8% in CFAE group). CHADS2 score (1.6 ± 1.0 vs 0.8 ± 0.9, P < 0.05), left atrial volume (LAV; 83.8 ± 27.1 vs 67.8 ± 21.8, P < 0.05), and left ventricular ejection fraction (LVEF, 53.1 ± 9.2 vs 65.1 ± 9.7, P < 0.01) were significantly different when comparing patients with or without thromboembolism. In multivariate analysis, LVEF (odds ratio [OR], 0.92; 95% confidence interval [CI], 0.84–0.99; P < 0.05) and concomitant CAG (OR 18.82; 95% CI, 1.77–200.00; P < 0.05) were important predictors of new cerebral thromboembolism. Conclusions: The incidence of cerebral microthromboembolism after CFAE ablation was not greater than previous reports in PVI. Cautious management is required during AF ablation, especially in the patients with low LVEF. (J Cardiovasc Electrophysiol, Vol. 23, pp. 567–573, June 2012)     

Three dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer under field adjustment with implanted gold markers: early clinical outcome

Three dimensional conformal radiotherapy (3D-CRT) for localized prostate cancer under field adjustment with gold marker implantation was performed according to the treatment strategy based on the clinical risk factors to the patients who chose external beam radiotherapy. The treatment strategy contains indications for laparoscopic staging lymphadenectomy and neoadjuvant combined androgen blockade (CAB). This protocol was applied to 19 patients at Kagawa University Hospital from July 2001 to December 2003. The patients were divided into high-risk group (n=14): T3-4N0M0 or PSA > or = 20 ng/ml or Gleason sum > or = 8 or suspicious node, and low-risk group (n=5): T1c-2bN0M0 and PSA < 20 ng/ml and Gleason sum < or = 7 and no suspicious nodes. Basically, high-risk patients underwent laparoscopic staging lymphadenectomy prior to radiotherapy. One of the 14 patients had a positive node and underwent endocrine therapy. The high-risk group received neoadjuvant CAB for 3 to 4 months, followed by gold marker implantation. One patient chose endocrine therapy at this point. Low-risk patients underwent marker implantation without endocrine therapy. Every patient successfully completed planned irradiation. The changes of prostate volume and serum PSA after neoadjuvant CAB were significant [28.7 ml to 15.7 ml (p=0.004) and 53.9 ng/ml to 1.4 ng/ml (p=0.023), respectively]. Only one patient in the high-risk group had biochemical failure. No grade 3 or 4 adverse events occurred in NCI-CTC grading. The analysis of gravity center migration of the implanted gold markers in the first 8 patients showed that the planned safety margin might not be wide enough to avoid neighboring organ irradiation. These results suggested that 3D-CRT under field adjustment with implanted gold markers contributes to both higher efficacy and lower morbidity.     

Primary liver cancers with nonalcoholic steatohepatitis

Nine patients with hepatocellular carcinoma (HCC) in nonalcoholic steatohepatitis (NASH) (six men and three women, median age 71.5 years) and one patient with intrahepatic cholangiocarcinoma (ICC), a 50-year-old man, in NASH are described. Most patients were associated with obesity, diabetes, hypertension, hypercholesterolemia, or hypertriglyceridemia. Seven patients showed insulin resistance and hyperinsulinemia. All patients except one met the criteria for metabolic syndrome. An HCC or ICC diagnosis was confirmed by tumor biopsy, surgery or autopsy except in two patients, who were diagnosed by computed tomography or hepatic angiography. The underlying liver disease was liver cirrhosis in six patients and chronic liver disease including mild hepatic fibrosis in four patients. The treatment of liver cancers consisted of surgery, radio-frequency ablation (RFA), transcatheter arterial embolization and transcatheter arterial infusion. Although the follow-up period was relatively short (median 27.5 months, average 32.1 months), all postoperative and post-RFA patients have not had a recurrence of HCC to date, except for one patient who had a palliative operation with intra-arterial infusion of anticancer drugs through an implanted reservoir port. Older age and liver cirrhosis are considered risk factors for HCC in NASH, and regular screening of these patients is necessary. Diabetes may contribute to the development of ICC in NASH. Curative therapy (surgery or RFA) and weight loss by the active therapeutic intervention (nutritional care and exercise therapy) after curative therapy may help us improve the prognosis of HCC in NASH.     

Prognosis and risk factors for idiopathic membranous nephropathy with nephrotic syndrome in Japan

BACKGROUND: Idiopathic membranous nephropathy (IMN) is a representative form of refractory nephrotic syndrome in Japan. Although IMN is thought to run a more benign course in Japanese than in the Caucasian population, risk factors and appropriate treatment are controversial issues. METHODS: The research group supported by a grant for "Progressive Renal Disease" from the Ministry of Health, Labor and Welfare, Japan, carried out a national survey of patients with IMN and nephrotic syndrome. Of 1066 nephrotic patients with histopathologically proven IMN registered from 1975 to 1993 in 85 institutions, 949 patients were studied. RESULTS: The overall renal survival rates were 95.8%, 90.3%, 81.1%, and 60.5% at 5, 10, 15, and 20 years after diagnosis, respectively. When clinical and histopathologic features at onset of nephrotic syndrome were evaluated by multivariate analysis, male gender, old age (> or =60 years), high serum creatinine concentration (> or =1.5 mg/dL), and the development of tubulointerstitial lesions (> or =20% of the biopsy sample area) were significant predictors of progression to end-stage renal disease (ESRD). The renal survival rate in patients on steroid therapy was significantly higher than in patients on supportive therapy alone. Patients achieving a remission showed a significant reduction of risk for progression. CONCLUSION: IMN is a disease with a comparatively good prognosis in Japan even when it is associated with nephrotic syndrome. Steroid therapy, which has not been recommended for IMN in most review articles, seems to be useful at least for Japanese patients. In particular, a remission from heavy proteinuria likely results in a favorable outcome.     

Survival after surgical treatment of early gastric cancer: surgical techniques and long-term survival

Background and aims Recent results from long-term follow-up of a large number of patients who have undergone gastric resection for early gastric cancer (EGC) have not yet been fully evaluated.Patients and methods A total of 848 patients who had undergone gastric resection for EGC (262 female, 586 male; mean age 58.0 years; range 20–86 years) were studied with respect to surgical technique, long-term survival and prognostic factors on the basis of current TNM classification.Results Death related to recurrence occurred in only eight patients (0.9%). Hematogenous metastasis to the liver or bone represented the most common pattern of recurrence, developing in six of the eight recurrences (75%). The 5-year and 10-year cancer-related survival rates were 98.6% and 94.8%, respectively. The 5-year and 10-year overall survival rates were 95.2% and 85.0%, respectively. Lymph node metastasis represented an independent prognostic factor when analyzed on the basis of cancer-related survival.Conclusion The present findings indicate that long-term survival of patients who undergo gastric resection for EGC is extremely good and that lymph node metastasis represents an independent prognostic factor when analyzed according to cancer-related survival. Future developments for the treatment of EGC are expected to improve quality of life for patients after gastric resection.     

Successful therapy with argatroban for superior mesenteric vein thrombosis in a patient with congenital antithrombin deficiency

A 38-year-old woman was admitted with superior mesenteric vein (SMV) thrombosis, which was refractory to anticoagulation therapy. The plasma antithrombin activity was decreased and hardly compensated by concentrated antithrombin preparation due to high consumption rate. However, successful anticoagulation was achieved by administration of direct thrombin inhibitor, argatroban. Family studies of antithrombin activity revealed that she had type I congenital antithrombin deficiency. A novel heterozygous mutation in the gene for antithrombin (single nucleotide T insertion at 7916 and 7917, Glu 272 to stop in exon 4) was identified. Argatroban administration would be effective in the treatment of congenital antithrombin deficiency with SMV thrombosis.