Heavy Ion Irradiation Reduces Vulnerability to Atrial Tachyarrhythmias　- Gap Junction and Sympathetic Neural Remodeling.

BACKGROUND: Low-invasive stereotactic body radiation therapy is a novel anti-arrhythmic strategy. The mechanisms underlying its effects against ventricular tachycardia/fibrillation (VT/VF) are gradually becoming clear, whereas those underlying atrial tachycardia/fibrillation (AT/AF) remain unknown. This study investigated the effects of carbon ion beam on gap junction expression and sympathetic innervation.Methods and Results: Atrial and ventricular tachyarrhythmia models was established in 26 hypercholesterolemic (HC) 3-year-old New Zealand white rabbits; 12 rabbits were irradiated with a single 15-Gy carbon ion beam (targeted heavy ion irradiation [THIR]) and 14 were not (HC group). Eight 3-month-old rabbits (Young) were used as a reference group. In vivo induction frequencies in the Young, HC, and HC+THIR groups were 0%, 9.9%, and 1.2%, respectively, for AT/AF and 0%, 7.8%, and 1.2%, respectively, for VT/VF (P<0.01). The conduction velocity of the atria and ventricles on optical mapping was significantly reduced in the HC group; this was reversed in the HC+THIR group. Connexin-40 immunolabelling in the atria was 66.1-78.7% lower in the HC than Young group; this downregulation was less pronounced in the HC+THIR group (by 23.1-44.4%; P<0.01). Similar results were obtained for ventricular connexin-43. Sympathetic nerve densities in the atria and ventricles increased by 41.9-65.3% in the HC vs. Young group; this increase was reversed in the HC+THIR group. CONCLUSIONS: Heavy ion radiation reduced vulnerability to AT/AF and VT/VF in HC elderly rabbits and improved cardiac conductivity. The results suggest involvement of connexin-40/43 upregulation and suppression of sympathetic nerve sprouting.

[A Case of Peritoneal Metastasis from an Unresectable Advanced Gastric Cancer with a Good Response to Nivolumab].

A 74-year-old woman presented with abdominal discomfort and was diagnosed with an unresectable advanced gastric cancer(T4aN3aM1, stage Ⅳ)based on a thorough examination. S-1/cisplatin therapy was administered as first-line treatment and paclitaxel/ramucirumab therapy as the second-line treatment. However, because the patient developed a peritoneal dissemination and her lymph node metastasis increased despite these regimens, nivolumab was introduced as a third- line treatment. The CT scan revealed that after the 5 courses of nivolumab, both the peritoneal dissemination and metastatic lymph nodes shrunk; after 12 courses of nivolumab, the peritoneal dissemination almost disappeared. Although nivolumab, an anti-programmed cell death-1(PD-1)antibody, has the possibility to cause immune-related adverse events not seen with conventional chemotherapy, in the present case, these events did not occur and the antitumor effects were maintained for a relatively long period without a decrease in the performance status(PS). We experienced a case of peritoneal metastasis from gastric cancer with a good response to nivolumab. Herein, this case is reported with some literature review.

[Clinical Evaluation of the Efficacy and Adverse Effects of Nivolumab Treatment for Patients with Advanced Gastric Cancer].

BACKGROUND: Nivolumab, a fully human IgG4 monoclonal antibody inhibitor of programmed death-1(PD-1), was approved for use in the treatment of patients with advanced gastric or gastroesophageal junction cancer who had been previously treated with B2 chemotherapy regimens in Japan. METHODS: We investigated the efficacy of nivolumab therapy in 15 consecutive patients with advanced gastric cancer between October 2017 and December 2018 in our facility. RESULTS: In our study, the 6-month overall survival rate was 67.7%, and the median survival time(MST)was 6.3 months. Immune-related adverse events(irAEs)occurred in the following patients: 2 patients, interstitial pneumonia(13%); 1 patient, myocarditis (6.7%); 1 patient, hypothyroidism(6.7%); and 1 patient, liver dysfunction(6.7%). Of the patients with an absolute lym- phocyte count(ALC)of C2,000/mL at baseline, 33%(4/12)experienced irAEs, while of those with an ALC of >2,000/mL, 67% had irAEs. The 6-month overall survival rate was better in patients with an ALC >1,600/mL(100%, 4/4)than in those with an ALC of C1,600/mL(35%, 4/11). The 6-month overall survival rate of the patients with a neutrophil-to-lymphocyte ratio(NLR)of <4 was 63%, which was better than the 33% rate in those with an NLR of B4. CONCLUSIONS: Nivolumab therapy was a safe and feasible treatment option. The cutoff values of ALC of 2,000/mL for irAEs and of ALC of 1,600/mL and NLR of 4 for prognosis might be effective surrogate markers in nivolumab treatment.

Is curative gastrectomy justified for gastric cancer with cytology positive as the only stage IV factor?

AIMS: The prognosis of patients with gastric cancer and stage IV factors is poor. However, several recent studies have identified that curative surgery followed by S-1 chemotherapy for cytology positive (CY1) only patients contributed to a better prognosis. This study was designed to compare the prognosis between curative and palliative gastrectomy followed by chemotherapy in CY1 only stage IV gastric cancer. METHODS: Between 2001 and 2016, 1507 patients underwent gastrectomy for gastric cancer. Of these, 51 consecutive patients with only CY1 factor who underwent gastrectomy followed by chemotherapy were enrolled in this study. RESULTS: (1) Twenty three (45%) patients underwent curative D2 or D2+ gastrectomy, and the remaining 28 (55%) patients underwent palliative gastrectomy, followed by S-1 based or another historical recommended chemotherapy postoperatively. (2) Compared with patients undergoing palliative gastrectomy, patients undergoing curative gastrectomy had a significantly better prognosis (P = 0.042; median survival time: curative vs. palliative, 22.6 months vs. 11.8 months) and a lower incidence of recurrences (P = 0.091). Two- and five-year overall survival rates of patients following curative gastrectomy were 48.2% and 18.2%, respectively. A multivariate analysis showed that venous invasion [P = 0.006; hazard ratio (HR), 3.70 (95% CI: 1.27-9.43)] and curative gastrectomy [P < 0.005; HR, 0.28 (95% CI: 0.12-0.87)] were independent prognostic factors. CONCLUSION: Curative gastrectomy followed by chemotherapy might be justified to improve the prognosis of patients with only CY1 Stage IV gastric cancer.

Effect of adding individualized occupational therapy to standard care on rehospitalization of patients with schizophrenia: A 2-year prospective cohort study.

AIM: We examined the effect of individualized occupational therapy (IOT) compared to the usual group occupational therapy (GOT) on the rehospitalization of patients with schizophrenia. METHODS: A prospective cohort study included patients with schizophrenia who were discharged within 1 year from a psychiatric hospital. Time to rehospitalization by treatment group (GOT + IOT or GOT-alone) was evaluated with Kaplan-Meier survival analysis. The impact of demographics and clinical factors associated with rehospitalization was investigated using Cox proportional hazards models. RESULTS: Of the 111 patients who met the criteria, 54 were in the GOT + IOT group and 57 in the GOT-alone group. Over the 2 years from discharge, the overall rehospitalization rate was 51.376% (56 patients); the GOT + IOT group demonstrated a significantly lower rehospitalization rate with 16 patients rehospitalized compared to 40 patients from the GOT-alone group. Time to rehospitalization was significantly longer for the GOT + IOT group compared to those in the GOT-alone group (P < 0.001). The multivariate Cox proportional hazards models showed that type of occupational therapy (hazard ratio [HR] = 0.543), medication adherence (HR = 0.343), access to resident support persons (HR = 0.450), and executive function at discharge (HR = 0.740) were all significantly associated with rehospitalization. CONCLUSION: Our results provide support for the prolonging effects of IOT in relation to rehospitalization and the reduction of rehospitalization risk compared to patients with schizophrenia who receive GOT alone, in addition to supporting good cognition at discharge and favorable medication adherence.

[Validation of the 8th Edition of the UICC TNM Classification for Stage â ¢ Gastric Cancer].

BACKGROUND: The 8th edition of the UICC TNM Classification was released in 2017 and introduced N3a/N3b groupings for gastric cancer. The purpose of this study was to evaluate the validity of the new classification for Stage Ⅲ gastric cancer. PATIENTS AND METHODS: Clinical and pathological data on 388 patients who underwent R0 resection from January 1992 to December 2016 in our institution were retrospectively analyzed. The survival in the 7th and 8th edition stage groupings were compared. Differences in survival according to N classification were also examined in the groups with T4a tumor depth. RESULTS: 1. The 5-year overall survival(OS)probabilities for Stage ⅢA, ⅢB, and ⅢC of 7th edition were 47.6%, 55.0%, and 28.5%(p=0.0003)and the recurrence-free survival(RFS)rates were 81.1%, 79.4%, and 58.7%(p=0.0013), respectively. In contrast, the OS probabilities of the 8th edition were 50.2%, 41.3% and 30.1%(p=0.0009)and the RFS were 81.6%, 70.9% and 50.0%(p=0.0003), respectively. 2. For T4a tumor depth, the OS probabilities of N1, N2, N3a, and N3b were 48.8%, 54.0%, 27.5%, and 25.1%(p=0.0012)and the RFS were 82.7%, 81.2%, 57.0% and 48.7%(p=0.0013), respectively. CONCLUSION: The 8th edition of the UICC TNM classification may provide better accuracy than that of the 7th edition in predicting the prognosis of Stage Ⅲ gastric cancer.

[A Case of Gastric Remnant Necrosis Following Laparoscopic Distal Gastrectomy for Gastric Cancer Successfully Treated Using a Conservative Approach].

INTRODUCTION: The stomach is an organ considered resistant to ischemia because of the microvascular networks in the stomach wall, and gastric remnant necrosis following gastrectomy is rare. Herein, we report a case of gastric remnant necrosis following gastrectomy successfully treated using a conservative approach. CASE PRESENTATION: An 83-year-old woman underwent laparoscopic distal gastrectomy, D1 plus lymphadenectomy, Billroth Ⅰreconstruction, and suture closure of the esophageal hiatus for early gastric cancer and giant esophageal hiatal hernia. The amylase level of the drainage fluid was abnormally high on postoperative day(POD)3, and contrast-enhanced CT confirmed gastric remnant necrosis. The patient was treated using a conservative approach, as her general condition was stable. Postoperative fluoroscopy on POD 21 revealed contrast media leakage from the gastric remnant; however, adequate drainage was observed. Upper gastrointestinal(GI)endoscopy on POD 23 demonstrated circumferential gastric remnant necrosis, whereas GI endoscopy on POD 52 revealed a decrease in the size of the gastric remnant, proliferation of the granulation tissue, and regeneration of mucosa in the gastric remnant. DISCUSSION: Gastric remnant necrosis following gastrectomy is a rare complication and is associated with poor prognosis. In most cases, total resection of the remnant stomach is warranted. However, for high surgical risk cases, conservative treatment options should be considered based on an assessment of patients' general condition.

[LECS-Assisted Open Partial Gastrectomy for an Ulcerative GIST in an Elderly Patient].

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that prevents excessive resection of the gastrointestinal wall and maintains gastrointestinal functions. However, LECS is not recommended for large gastrointestinal stromal tumor(GIST)sized more than 5 cm and/or ulcerative GIST because of the oncological risk of peritoneal dissemination. Here, we report the case of an elderly patient who was successfully treated with LECS-assisted open partial gastrectomy for an ulcerative GIST near the esophagogastric junction.

[Laparoscopy and Endoscopy Cooperative Surgery(LECS)-Assisted Open Partial Gastrectomy for a High-Risk Gastrointestinal Stromal Tumor].

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure to avoid excessive resection of the gastrointestinal wall and maintain its functions. However, LECS for large gastrointestinal stromal tumor(GIST)of> 50mm and/or ulcerative GIST are not recommended because of the oncological risk of peritoneal dissemination. Here, we report a case successfully treated with LECS-assisted open partial gastrectomy for a high-risk GIST with ulceration near the esophago-gastric junction.

[Surgical Technique for Lesser Curvature Lymph Node Dissection in Laparoscopic Distal Gastrectomy].

INTRODUCTION: Lesser curvature lymph node dissection is often performed at the end of the procedure in laparoscopic distal gastrectomy. In obese patients, it can be difficult to secure a visual field, and bleeding or injury of the remnant stomach may occur. SURGICAL TECHNIQUE: After separating the duodenum using an automated suturing instrument, the stomach is rolled under the left diaphragm. An assistant holds the gastric angle near the lesser curvature with forceps in the right hand, and pulls the stomach cephalad toward the left side of the patient. As a result, the region from the esophagogastric junction to the gastric angle is aligned, enabling use of an ultrasonically activated scalpel from the right side of the operator. Dissection is performed from around the posterior wall of the esophagogastric junction to the gastric angle. After dissecting the posterior wall as much as possible, dissection of the anterior wall is performed to complete the lesser curvature procedure. CONCLUSION: This technique enables safe and reliable dissection of the lesser curvature while avoiding bleeding and damage to the stomach wall.

[A Case of Thyroid Metastasis from Rectal Cancer].

The patient was a 68-year-old man who underwent Hartmann's procedure for a fistula due to rectal cancer in August 2012. The cancer was tub2>tub1, pSE, pN2, pH2, pM1(intrapulmonary metastasis), stage IV. The patient received 5 courses of FOLFOX and bevacizumab as adjuvant chemotherapy. In December 2012, the patient was seen by Otolaryngology for hoarseness. A neck examination revealed induration of the left lobe of the thyroid, and FNA biopsy strongly suggested metastasis of rectal cancer to the thyroid. FDG-PET was performed and revealed extensive accumulation of FDG at the same site. The patient was diagnosed with thyroid metastasis of rectal cancer and underwent a left thyroid lobectomy and lymph node dissection in January 2013. Histopathology confirmed the thyroid metastasis of rectal cancer. Thyroid metastasis of rectal cancer is extremely rare: there are 11 such cases in the Japanese literature, including the case encountered by the current authors. This case is reported here, along with a discussion of some of the literature.

[Modified NEWS as a Safe and Inventive Approach for Gastrointestinal Stromal Tumor near the Esophagogastric Junction].

Laparoscopy and endoscopy cooperative surgery(LECS)is an excellent surgical procedure that utilizes the advantages of both methods. Furthermore, non-exposed endoscopic wall-inversion surgery(NEWS)is a more promising procedure that enables avoidance of tumor exposure of and dissemination to the abdominal cavity. However, NEWS has the potential risk of postoperative ulceration, leading to delayed perforation because of mucosal defect. We invented a modified NEWS, which was a safe procedure, by including the all-layer suture to close the mucosal defect. We present a case of gastrointestinal stromal tumor(GIST)near the esophagogastric junction, which was treated with modified NEWS.

[Better Effects of Inventive Nutritional Approaches for Chemotherapy and Conversion Surgery in Stage â £ Gastric Cancer].

The REGATTA trial revealed that chemotherapy is the standard strategy for gastric cancer patients with Stage Ⅳ factors. However, some recent studies have identified the prognostic effect of conversion surgery after complete response to Stage Ⅳ factors during chemotherapy. Here, we report a case with Stage Ⅳ factors successfully treated via intensive chemotherapy and conversion surgery without any adverse events and complications, using preoperative parenteral hyper-nutrition and postoperative enteral nutrition. Nutrition might be the key strategy during the treatment of gastric cancer patients with Stage Ⅳ factors.

[A Case of GIST with Extensive Peritoneal Dissemination Controlled over Long-Term by Low-Dose, Intermittent Administration of Imatinib after Weight Loss Surgery].

A 67-year-old man presented with abdominal pain and fever. Many abdominal tumors were detected by enhanced computed tomography(CT). The largest tumor, measuring 20 cm, had perforated the ileum and formed an abscess. Emergency surgery was performed to remove multiple tumors in the peritoneal cavity as much as possible. Immunostaining showed c-kit and CD34 positivity, and the tumors were diagnosed as gastrointestinal stromal tumor(GIST). During postoperative imatinib therapy for the residual tumor, low-dose intermittent administration was required due to side effects, but the disease was controlled for over 91months. For advanced GIST with peritoneal dissemination, 200mg/day imatinib or intermittent administration after volume reduction surgery might be effective depending on the patient's general condition.

Cytosolic Cl- Affects the Anticancer Activity of Paclitaxel in the Gastric Cancer Cell Line, MKN28 Cell.

BACKGROUND/AIMS: Our previous study revealed that cytosolic Cl- affected neurite elongation promoted via assembly of microtubule in rat pheochromocytoma PC12D cells and Cl--induced blockade of intrinsic GTPase enhanced tubulin polymerization in vitro. Paclitaxel (PTX) is a microtubule-targeted chemotherapeutic drug and stabilizes microtubules resulting in mainly blockade of mitosis at the metaphase-anaphase transition and induction of apoptosis. In the present study, we tried to clarify whether the cytosolic Cl- affected PTX ability to inhibit cell growth in the gastric cancer cell line, MKN28. METHODS: To clarify the cytosolic Cl- action on PTX-induced cell death and metaphase-anaphase transition in the gastric cancer cell line, MKN28 cell, and PTX-induced tubulin polymerization, we performed cell proliferation assay, cytosolic Cl- concentration measurement, immunofluorescence microscopy, and in vitro tubulin polymerization assay. RESULTS: The decline of cytosolic Cl- weakened the cytotoxic effect of PTX on cell proliferation of MKN28 cells, which could pass through the metaphase-anaphase transition. Moreover, in vitro PTX-induced tubulin polymerization was diminished under the low Cl- condition. CONCLUSIONS: Our results strongly suggest that the upregulation of cytosolic Cl- concentration would enhance the antitumor effect of PTX, and that the cytosolic Cl- would be one of the key targets for anti-cancer therapy.

Normal 123 I-MIBG uptake areas may be associated with hyperinnervation and arrhythmia risk in phenol model rabbit hearts.

BACKGROUND: Iodine-123 metaiodobenzylguanidine (123 I-MIBG) is useful for detecting sympathetic innervation in the heart, and has been closely associated with fatal arrhythmias. However, such imaging is typically calibrated to the area of highest uptake and thus is unable to identify areas of hyperinnervation. We hypothesized that normal 123 I-MIBG uptake regions in the denervated heart would demonstrate nerve sprouting and correlate with the potential for arrhythmogenesis. METHODS: Twenty New Zealand white rabbits treated with phenol or sham were prepared under anesthesia. Sympathetic innervation was quantified using autoradiography and immunostaining 4 weeks after phenol application, and electrophysiological study was performed. RESULTS: 123 I-MIBG revealed maximal local differences in isotope uptake in the border zone between areas with attenuated and abundant MIBG compared with that seen between adjacent regions within the lowest uptake areas. On immunostaining, heterogeneous and decreased expressions of growth-associated protein 43 signal were observed in the MIBG-attenuated areas; however, abundant signals were recognized in the MIBG-abundant areas. Upregulation of the tyrosine hydroxylase signal was observed at the part of the MIBG-abundant area. In electrophysiological study, the dispersion of activation recovery interval (ARI) was increased in the phenol-applied areas by norepinephrine infusion. Stellate stimulation exacerbated the ARI dispersion in both the phenol-applied and nonapplied areas, and was associated with increased inducibility of ventricular tachycardia and ventricular fibrillation. CONCLUSIONS: The presence of hyperinnervation in the nondenervated regions of denervated rabbit hearts suggests that heterogeneous neural remodeling occurs in regions with seemingly normal 123 I-MIBG uptake and contributes to electrical instability.

Inducibility of Ventricular Arrhythmia 1 Year Following Treatment with Heavy Ion Irradiation in Dogs with Myocardial Infarction.

BACKGROUND: Targeted external heavy ion irradiation (THIR) of rabbit hearts 2 weeks after myocardial infarction (MI) reduced the vulnerability of fatal ventricular tachyarrhythmias (VT/VF) in association with the increased connexin43 (Cx43). Increased Cx43 was maintained for at least 1 year in normal rabbits, but the long-term antiarrhythmic effects in the MI model are unknown. We investigated the propensity for late potentials and VT/VF inducibility. METHODS: Intracoronary injection of microspheres was performed to induce nontransmural MI in anesthetized eight beagles. Four beagles were treated with THIR (12 C6+ , 15 Gy) 2 weeks later (MI + THIR group), and four without THIR served as controls (MI group). Signal-averaged electrocardiography, programmed electrical stimulation, immunohistochemical analysis, and echocardiograms were performed at 1 year. RESULTS: Filtered QRS duration was exacerbated after MI and remained unchanged for 1 year in the MI group (118 ± 1.4 ms), but significantly returned toward baseline in the MI + THIR group (109 ± 6.9 ms). Similarly, root mean square voltage of the last 40 ms was exacerbated after MI, but recovered after THIR. VT/VF inducibility decreased to 25% in the MI + THIR group compared with 100% in the MI group. Immunostaining Cx43 expression in cardiac tissues significantly increased by 24-45% in the MI + THIR group. Left ventricular ejection fractions remained within the normal range in both groups. CONCLUSION: A single exposure of the dog heart to 12 C irradiation attenuated vulnerability to ventricular arrhythmia after the induction of MI for at least 1 year through the modulation of Cx43 expression.

[A Case of a Retroperitoneal Liposarcoma with Long-Term Survival after Four Surgical Resections].

Retroperitoneal liposarcoma is a relatively rare tumor. The only established therapy is surgical resection and the tumor often recurs. This paper deals with a case of a retroperitoneal liposarcoma in which frequent surgical resections for recurrent tumors have provided relatively long-term survival for the patient. The patient was a 70-year-old woman who had undergone surgical resection for a right retroperitoneal tumor. The pathological diagnosis was dedifferentiated liposarcoma. Thereafter she experienced frequent recurrences which required 3 surgical resections. By means of positive margin for the last surgery, chemotherapy with eribulin was administered. There has been no recurrence 13 months after the last surgery.

[Total pharyngolaryngoesophagectomy with free jejunal transfer for a patient who previously underwent distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route].

The patient in this case study was a 71-year-old male who underwent distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route for esophageal cancer 12 years previously. An endoscopy revealed a hypopharyngeal tumor in the right piriform fossa, and the histopathological diagnosis, based on a biopsy sample, was squamous cell carcinoma. Preoperative angiography of the right gastroepiploic artery revealed poor blood flow in the remnant esophagus. First, the adhesion of the gastric tube to the surrounding tissue was dissected via a right thoracotomy. Then, the gastric tube was raised using a cervical approach, and total pharyngolaryngoesophagectomy with free jejunal transfer was performed. The patient was discharged 28 days after the operation without complications. We report a patient with hypopharyngeal cancer who had previously undergone distal esophagectomy with gastric tube reconstruction via a posterior mediastinal route upon whom we successfully performed a total pharyngolaryngoesophagectomy with free jejunal transfer. In such a case, it is important to carefully decide the surgical approach in order to prevent anastomotic leakage.

Outcomes of an interdisciplinary return to work intervention including occupational therapy for mood and adjustment disorders: A single-arm clinical trial.

BACKGROUND: Mood and adjustment disorders are two major causes of long-term sick leave among employees, leading to large social losses. Therefore, a return to work (RTW) intervention was attempted, targeting patients with mood and adjustment disorders. OBJECTIVE: This study aimed to investigate the outcome of an interdisciplinary RTW intervention including occupational therapy implemented within the Japanese healthcare framework. METHODS: An interdisciplinary RTW intervention including occupational therapy was conducted five times a week for approximately three months, targeting individuals with mood and adjustment disorders who took a leave of absence. Their mental symptoms, cognitive functioning, job performance, temperament, social adaptation, psychosocial state, and readiness to RTW before and after the intervention were evaluated. Full-time RTW ratios at 3, 6, 12, 18, and 24 months from baseline were followed up and compared with those of prior studies. RESULTS: A total of 30 individuals completed the intervention. After the intervention, participants' psychological symptoms, cognitive function, vocational aptitude, temperament, social adaptation, psychosocial state, and readiness to RTW improved (p≤0.001-0.0279). The ratios of RTW at 3, 6, 12, 18, and 24 months from the baseline were 6.7%, 46.7%, 73.3%, 77.8%, and 82.6%, respectively, reflecting a higher pattern than prior reports. CONCLUSIONS: The interdisciplinary RTW intervention including occupational therapy has the potential to improve not only depressive symptoms but also cognitive functioning, job performance, social adaptation, and readiness to RTW. They can also raise RTW ratios.