Chemoradiotherapy for patients with recurrent lymph-node metastasis or local recurrence of gastric cancer after curative gastrectomy

Objectives

Whether chemoradiotherapy (CRT) is clinically beneficial for the management of postoperative recurrence of advanced gastric cancer remains unclear. We retrospectively studied treatment outcomes in patients who had unresectable localized recurrence after surgery for advanced gastric cancer and evaluated the safety and efficacy of CRT.

Methods

The study group comprised 21 patients who received concurrent CRT for unresectable localized recurrence after undergoing R0 resection for stage II/III advanced gastric cancer. Localized recurrence was defined as a few or limited recurrent lesions.

Results

The recurrence pattern was anastomotic recurrence in 7 patients, abdominal lymph-node recurrence in 12, and anastomotic recurrence plus abdominal lymph-node recurrence in 2. The median total dose of radiotherapy was 48.6 Gy (range 39.6–56.0), and the CRT completion rate was 100 % (21 of 21 patients). CRT-related grade 3 or higher toxicity comprised neutropenia in 33.3 % of patients and anorexia in 9.5 %. The response rate was 61.9 % (complete response 38.1 %, partial response 23.8 %). The median overall survival was 35.0 months.

Conclusions

We conclude that CRT may become one treatment strategy for the management of unresectable localized recurrence after curative resection of advanced gastric cancer.

     

Overexpression of BCLXL in Osteoblasts Inhibits Osteoblast Apoptosis and Increases Bone Volume and Strength

The Bcl2 family proteins, Bcl2 and BclXL, suppress apoptosis by preventing the release of caspase activators from mitochondria through the inhibition of Bax subfamily proteins. We reported that BCL2 overexpression in osteoblasts using the 2.3 kb Col1a1 promoter increased osteoblast proliferation, failed to reduce osteoblast apoptosis, inhibited osteoblast maturation, and reduced the number of osteocyte processes, leading to massive osteocyte death. We generated BCLXL (BCL2L1) transgenic mice using the same promoter to investigate BCLXL functions in bone development and maintenance. Bone mineral density in the trabecular bone of femurs was increased, whereas that in the cortical bone was similar to that in wild‐type mice. Osteocyte process formation was unaffected and bone structures were similar to those in wild‐type mice. A micro‐CT analysis showed that trabecular bone volume in femurs and vertebrae and the cortical thickness of femurs were increased. A dynamic bone histomorphometric analysis revealed that the mineralizing surface was larger in trabecular bone, and the bone‐formation rate was increased in cortical bone. Serum osteocalcin but not TRAP5b was increased, BrdU‐positive osteoblastic cell numbers were increased, TUNEL‐positive osteoblastic cell numbers were reduced, and osteoblast marker gene expression was enhanced in BCLXL transgenic mice. The three‐point bending test indicated that femurs were stronger in BCLXL transgenic mice than in wild‐type mice. The frequency of TUNEL‐positive primary osteoblasts was lower in BCLXL transgenic mice than in wild‐type mice during cultivation, and osteoblast differentiation was enhanced but depended on cell density, indicating that enhanced differentiation was mainly owing to reduced apoptosis. Increased trabecular and cortical bone volumes were maintained during aging in male and female mice. These results indicate that BCLXL overexpression in osteoblasts increased the trabecular and cortical bone volumes with normal structures and maintained them majorly by preventing osteoblast apoptosis, implicating BCLXL as a therapeutic target of osteoporosis. © 2016 American Society for Bone and Mineral Research.     

Uptake and intracellular activity of NM394, a new quinolone, in human polymorphonuclear leukocytes.

The uptake of NM394, a new quinolone, by and its subsequent elution from human polymorphonuclear leukocytes were studied and compared with those of ofloxacin and ciprofloxacin. The kinetics of the uptake of NM394 was similar to that of ciprofloxacin. The maximum intracellular-to-extracellular concentration ratio was 12.3, compared with 8.6 for ciprofloxacin and 4.9 for ofloxacin at the extracellular concentration of 20 micrograms/ml. The elution of NM394 from human polymorphonuclear leukocytes occurs relatively slowly; 5 min after the removal of extracellular NM394, nearly 100% still remained in polymorphonuclear leukocytes, compared with ofloxacin, which was so rapidly eluted that only 12% remained. The uptake of NM394 was significantly decreased at 4 degrees C and by the presence of NaCN but was not affected by the presence of L-glycine, L-leucine, L-serine, adenosine, or NaF. NM394 showed intracellular activity at a concentration of 0.1 microgram/ml that significantly reduced the number of phagocytosed Pseudomonas aeruginosa cells with 2 h of incubation. These results suggest that uptake of NM394 by human polymorphonuclear leukocytes occurs via an active transport system differing from that of ofloxacin, whose uptake is affected by the presence of L-glycine and L-leucine, and that once accumulated, NM394 remains intracellularly active and participates in protection against bacterial infection.     

Tryptophan and Kynurenine Enhances the Stemness and Osteogenic Differentiation of Bone Marrow-Derived Mesenchymal Stromal Cells In Vitro and In Vivo

Aging tissues present a progressive decline in homeostasis and regenerative capacities, which has been associated with degenerative changes in tissue-specific stem cells and stem cell niches. We hypothesized that amino acids could regulate the stem cell phenotype and differentiation ability of human bone marrow-derived mesenchymal stromal cells (hBMSCs). Thus, we performed a screening of 22 standard amino acids and found that D-tryptophan (10 μM) increased the number of cells positive for the early stem cell marker SSEA-4, and the gene expression levels of OCT-4, NANOG, and SOX-2 in hBMSCs. Comparison between D- and L-tryptophan isomers showed that the latter presents a stronger effect in inducing the mRNA levels of Oct-4 and Nanog, and in increasing the osteogenic differentiation of hBMSCs. On the other hand, L-tryptophan suppressed adipogenesis. The migration and colony-forming ability of hBMSCs were also enhanced by L-tryptophan treatment. In vivo experiments delivering L-tryptophan (50 mg/kg/day) by intraperitoneal injections for three weeks confirmed that L-tryptophan significantly increased the percentage of cells positive for SSEA-4, mRNA levels of Nanog and Oct-4, and the migration and colony-forming ability of mouse BMSCs. L-kynurenine, a major metabolite of L-tryptophan, also induced similar effects of L-tryptophan in enhancing stemness and osteogenic differentiation of BMSCs in vitro and in vivo, possibly indicating the involvement of the kynurenine pathway as the downstream signaling of L-tryptophan. Finally, since BMSCs migrate to the wound healing site to promote bone healing, surgical defects of 1 mm in diameter were created in mouse femur to evaluate bone formation after two weeks of L-tryptophan or L-kynurenine injection. Both L-tryptophan and L-kynurenine accelerated bone healing compared to the PBS-injected control group. In summary, L-tryptophan enhanced the stemness and osteoblastic differentiation of BMSCs and may be used as an essential factor to maintain the stem cell properties and accelerate bone healing and/or prevent bone loss.     

Effects of bidisomide (SC-40230), a new class I antiarrhythmic agent,on ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats; comparison with mexiletine and disopyramide

Summary We investigated the antiarrhythmic effects of bidisomide (SC-40230), a new class I antiarrhythmic drug, in early-phase ventricular arrhythmias induced by coronary artery occlusion and reperfusion in anesthetized rats. The effects of bidisomide were compared with those of mexiletine (MXT) and disopyramide (DSP), established class I antiarrhythmic drugs. Drugs were administered intravenously, 5 min before induction of coronary occlusion. Bidisomide (5 mg/kg) reduced the number of premature ventricular complexes and the incidence of ventricular tachycardia and ventricular fibrillation similarly to MXT and DSP in rats with ventricular arrhythmias induced by coronary artery occlusion. In rats with ventricular arrhythmias induced by coronary artery reperfusion following a 5min coronary occlusion, the antiarrhythmic effects of 5 mg/kg of bidisomide were similar to those of the same doses of MXT and DSP. All three drugs significantly slowed the heart rate. Our results suggest that bidisomide may effectively reduce the severity of lifethreatening ventricular arrhythmias that occur during acute coronary syndrome.     

Dosimetric comparison of absolute and relative dose distributions between tissue maximum ratio and convolution algorithms for acoustic neurinoma plans in Gamma Knife radiosurgery

Background

The treatment planning for Gamma Knife (GK) stereotactic radiosurgery (SRS) that performs dose calculations based on tissue maximum ratio (TMR) algorithm has disadvantages in predicting dose in tissue heterogeneity. The latest version of the planning software is equipped with a convolution dose algorithm as an optional extra and the new algorithm is able to compensate for head inhomogeneity. However, the effect of this improved calculation method requires detailed validation in clinical cases. In this study, we compared absolute and relative dose distributions of treatment plans for acoustic neurinoma between TMR and the convolution calculation.

Methods

Twenty-nine clinically used plans created by TMR algorithm were recalculated by convolution method. Differences between TMR and convolution were evaluated in terms of absolute dose (beam-on time), dosimetric parameters including target coverage, selectivity, conformity index, gradient index, radical homogeneity index and the dose-volume relationship.

Results

The discrepancy in estimated absolute dose to the target ranged from 1 to 7 % between TMR and convolution. In addition, dosimetric parameters of the two methods achieved statistical significance. However, it was difficult to see the change of relative dose distribution by visual assessment on a monitor.

Conclusions

Convolution, heterogeneity correction calculation, and the algorithm are necessary to reduce the dosimetric uncertainty of each case in GK SRS.     

Nationwide survey of middle ear cholesteatoma surgery cases in Japan: Results from the Japan Otological society registry using the JOS staging and classification system

ObjectiveThis study was aimed to determine the characteristics of middle ear cholesteatoma and to investigate short-term outcomes regarding the rates of residual and recurrent cholesteatoma and the postoperative hearing results in Japan, via a nationwide survey using staging and classification criteria for middle ear cholesteatoma, as proposed by the Japan Otological Society (JOS).MethodsThe first-round survey was conducted in 2016. The target was patients with middle ear cholesteatoma who were surgically treated in Japan between January and December 2015. Medical information on the patients was anonymized. The questionnaire entries were age, sex, cholesteatoma classification and stage, preoperative hearing level, mastoid development, status of the stapes, and surgical method. There were a total of 1,787 registered patients from 74 facilities from all over Japan. The second survey was conducted in January 2018 and received 1,456 responses from 49 facilities in Japan. Of the 1,456 cases, 1,060 were conducted in the postoperative hearing survey and 1,084 in the residual recurrence survey.ResultsThe most common cholesteatoma type was pars flaccida cholesteatoma (63.3%), followed by pars tensa cholesteatoma (13.0%), congenital cholesteatoma (12.9%), and cholesteatoma secondary to chronic tensa perforation (5.6%). Cholesteatoma of uncertain origin accounted for 5.0% (90 cases). Stage II was predominant in pars flaccida and pars tensa cholesteatoma, which frequently involves the mastoid, whereas about half of cases of cholesteatoma secondary to chronic tensa perforation and congenital cholesteatoma were classified as stage I. One hundred fifty-two of 1,084 cases (14.0%) had recurrent cholesteatoma, residual cholesteatoma, or both following first surgeries. The postoperative rates of hearing success rate was 63.3%.ConclusionWe were able to clarify not only the current epidemiological status of middle ear cholesteatoma but also the current trends of cholesteatoma surgery in Japan. The development of a staging system by the JOS Committee serving an epidemiological database for international or time-dependent comparison. It is possible to use this staging system with reasonable reliability.