[A Case of Advanced Gastric Cancer Who Experienced Multiple Immune-Related Adverse Events with Nivolumab and SOX Therapy].

A 59-year-old woman who has HER2-negative advanced gastric cancer with peritoneal dissemination was treated with nivolumab plus SOX therapy as primary treatment, and hemorrhagic cystitis occurred on the 28th day after the 6 courses. On the 21st day after the 7 courses, right knee arthralgia appeared, and on the 26th day, she was admitted to the hospital due to a fever of 39℃ and anorexia. After admission, frequent diarrhea occurred and new symptoms of neck pain and left knee arthralgia appeared. Abdominal CT showed increased fatty tissue density around the sigmoid colon, and wall thickening and contrast enhancement of the mucosal surface of the bladder. Lower gastrointestinal endoscopy revealed the diffuse redness and erosions in some areas, and lymphocytic infiltration in the epithelium of the crypts was seen in biopsy from the erosions. The hemorrhagic cystitis was aseptic pyuria. Therefore, we suspected that the series of symptoms were immune-related adverse events(irAE)and started prednisolone 50 mg(1 mg/kg/day), which quickly relieved the diarrhea, cystitis and arthralgia. As a result, the patient was diagnosed as having irAE. We report a case of advanced gastric cancer who experienced multiple irAE with nivolumab plus SOX therapy, with some discussion of the literature.

[A Case of Simultaneous Laparoscopic Surgery for Intrahepatic Cholangiocarcinoma and Sigmoid Colon Cancer].

The patient was an 83-year-old woman. CT scan showed a 20 mm mass in the surgical anatomy of the medial segment (S4)of the liver, but the patient refused to undergo surgery and continued periodic clinical follow-up. After 1 year and 3 months of initial examination, a CT scan showed an enlargement of 36 mm. Therefore, surgical treatment was adopted. Preoperative lower gastrointestinal endoscopy revealed a type 1 tumor of the sigmoid colon quarter circumference 30 mm from the anal verge, and the biopsy led to a diagnosis of adenocarcinoma equivalent to tub 1. The hepatic mass showed heterogeneous contrast effect centered on the arterial phase margins and prolonged contrast effect in the equilibrium phase. Since the liver tumor was a single S4 mass with a 36 mm diameter, laparoscopic sigmoidectomy and laparoscopic partial hepatic resection were performed subsequently. Pathology results showed that the sigmoid colon tumor and hepatic S4 mass were predominantly well-differentiated and moderately-differentiated adenocarcinomas, respectively. Immunohistochemical results were cytokeratin 7 antibody-positive and cytokeratin 20 antibody-negative, leading to a definitive diagnosis of intrahepatic cholangiocarcinoma. The patient's postoperative course was well and was discharged from the hospital on postoperative day 12. After 1 year postoperatively, the patient remains recurrence-free.

[A Case of Tumor Embolization to the Internal Iliac Vein Four Years after the Surgery for Rectal Cancer].

60-year-old man was admitted to our hospital with a chief complaint of melena. Lower gastrointestinal endoscopy revealed a type 2 tumor on the anterior wall of the rectum(Rb). He was referred to our department, and he underwent abdominoperineal rectal resection with D3 dissection and right lateral node dissection for Rb, cT2, N0, M0 intestinal cancer. Pathological diagnosis was a tub2, pT2, N0, Ly0, V0, pDM0(30 mm), pPM0(160 mm), pR0, pStage Ⅰ cancer. Therefore, postoperative adjuvant chemotherapy was not performed. Subsequent follow-up examinations were conducted on a regular basis to confirm no recurrence. However, 4 years after the surgery, high levels of tumor markers, such as CEA(59.2 ng/mL) and CA19-9(75.5 U/mL), were detected. CT showed tumor embolism to the internal iliac vein and multiple lung metastases. After IVC filter placement, chemoradiotherapy was performed. Although the tumor embolism disappeared, multiple lung metastases increased. Additionally, brain metastasis appeared 6 years after the operation. After that, according to the policy of BSC, he died 7 years after the surgery.

[A Case of Laparoscopic Gastric Local Resection for Simultaneous Multiple Gastric GIST Discovered Owing to Gastrointestinal Bleeding].

An 80-year-old woman with anemia presented to our hospital. Upper gastrointestinal endoscopy revealed a 4 cm submucosal tumor(SMT)with a delle and 2 cm SMT in the upper part of the stomach. CT revealed sustained enhancement of both tumors. The posterior tumor was an intraductal growth, and the anterior tumor was an extravascular growth. We performed a laparoscopic gastric local excision for the multiple SMTs. The anterior tumor was resected with an automatic suture instrument. However, the posterior tumor could not be identified from within the abdominal cavity because it was resected while confirming using an endoscope, and all layers were sutured. On histopathological examination, the posterior tumor was 40mm in size, with spindle-shaped atypical cells growing in the submucosal layer. Immunostaining was c-kit(+), CD34(+), S-100(-), and desmin(-). The Ki-67 level was<1%. The anterior wall tumors showed similar findings, but some showed smooth muscle differentiation. From the results, a diagnosis of simultaneous multiple gastric GIST(low risk)was made.

Low invasiveness of thoracoscopic esophagectomy in the prone position for esophageal cancer: a propensity score-matched comparison of operative approaches between thoracoscopic and open esophagectomy.

BACKGROUND: In this study, cytokine levels, outcome, and survival rates after esophagectomy for esophageal cancer were retrospectively investigated in a propensity score-matched comparison of operative approaches between the thoracoscopic esophagectomy (TE) in the prone position and open esophagectomy (OE). PATIENTS AND METHODS: Between 2005 and 2014, TE was performed on a group of 85 patients, which was compared with a group of 104 OE cases. Eventually, 65 paired cases were matched using propensity score matching. RESULTS: Although the TE group underwent a significantly longer operation time than the OE group (P < 0.001), the TE group exhibited less blood loss (P < 0.001) and had a shorter postoperative hospital stay (P = 0.038) than the OE group. The serum interleukin-6 levels on ICU admission (P < 0.001) and on POD 1 (P < 0.001) were significantly lower in the TE group. The interleukin-10 levels on ICU admission (P < 0.001), POD 1 (P = 0.016), and POD 3 (P < 0.001) were also significantly lower in the TE group. Pulmonary complication was significantly lower in the TE group (P = 0.043). The 5-year PFS rates in the TE and OE groups were 70.6 and 58.7% (P = 0.328), respectively, and OS rates were 64.9 and 50.2% (P = 0.101), respectively. CONCLUSION: TE compared to OE is a less invasive procedure with lower surgical stress and less pulmonary complication for the treatment of esophageal squamous cell carcinoma.

[A Case of Metastasis of Ascending Colon Cancer to the Small Intestine That Was Diagnosed Based on Ileus].

A 69-year-old man was administered an ileus tube for ileus by ascending colon cancer. The next day, he underwent right hemicolectomy with D3 lymph node dissection for perforative peritonitis due to ascending colon cancer. The pathological diagnosis was A, type 2, muc>tub1, pT3, pN0. M0, pStageⅡ. He received 5 courses of UFT/Leucovorin(LV)chemotherapy. Two years later, he was hospitalized for ileus. He underwent surgery. The peritoneal dissemination was absent in the surgical findings. We resected a small intestinal tumor from the oral side of anastomosis. Because the tumor appearance and pathological findings were similar to those of ascending colon cancer, the patient was diagnosed with metastasis of ascending colon cancer to the small intestine. We report our rare encounter with metastases of colorectal cancer to the small intestine.

[A Case of Rectal Neuroendocrine Carcinoma That Showed a Sharp Turning Point after Neoadjuvant Radiochemotherapy and Conversion Surgery].

A 45-year-old man presented with the chief complaint of anal discomfort to a previous doctor. The symptoms remained after undergoing seton surgery following the diagnosis of intermuscular anal fistula. CT showed a tumor that was 3 cm in diameter on the right wall of the rectum, and he received a diagnosis of neuroendocrine carcinoma(NEC)based on a biopsy. Subsequently, he was admitted to our hospital. Liver metastasis accompanied NEC, and chemotherapy was performed for stage Ⅳ diagnosis. We detected tumor disappearance after administering 8 courses of CDDP plus CPT-11. However, after 3 months, a 1 cm nodule appeared at the primary lesion, which was considered as recurrence. We selected reintroduction of CDDP plus CPT-11 treatment, but the tumor progressed. CDDP plus VP-16 plus radiation therapy was introduced, and tumor shrinkage was observed without distant metastasis. We judged that radical resection was possible, and performed Miles' operation, total prostate gland resection, and urethra reconstruction. He was discharged on the 28th day after surgery. The pathological findings indicated neuroendocrine small cell carcinoma, and the CRT effect was judged as Grade 2 and curability A. However, he was admitted to the emergency room following convulsions on the 46th day after surgery was performed. CT revealed multiple cerebral metastasis, meningeal dissemination, and liver metastasis. He underwent cyber knife surgery for brain metastasis. Drainage was required for cerebral hypertension due to meningeal dissemination. He died on the 115th postoperative day.

Prediction of the efficacy of immunotherapy by measuring the integrity of cell-free DNA in plasma in colorectal cancer.

We previously reported a phase II study of a cancer vaccine using five novel peptides recognized by HLA-A*2402-restricted CTL in combination with oxaliplatin-containing chemotherapy (FXV study) as first-line therapy for patients with metastatic colorectal cancer and demonstrated the safety and promising potential of our five-peptide cocktail. The objective of this analysis was to identify predictive biomarkers for identifying patients who are likely to receive a clinical benefit from immunochemotherapy. Circulating cell-free DNA (cfDNA) in plasma has been reported to be a candidate molecular biomarker for the efficacy of anticancer therapy. Unlike uniformly truncated small-sized DNA released from apoptotic normal cells, DNA released from necrotic cancer cells varies in size. The integrity of plasma cfDNA (i.e. the ratio of longer fragments [400 bp] to shorter fragments [100 bp] of cfDNA), may be clinically useful for detecting colorectal cancer progression. We assessed plasma samples collected from 93 patients prior to receiving immunochemotherapy. The cfDNA levels and integrity were analyzed by semi-quantitative real-time PCR. Progression-free survival was significantly better in patients with a low plasma cfDNA integrity value than in those with a high value (P = 0.0027). Surprisingly, in the HLA-A*2402-matched group, patients with a low plasma cfDNA integrity value had significantly better progression-free survival than those with a high value (P = 0.0015). This difference was not observed in the HLA-A*2402-unmatched group. In conclusion, the integrity of plasma cfDNA may provide important clinical information and may be a useful predictive biomarker of the outcome of immunotherapy in metastatic colorectal cancer.

[A Case of Esophageal Submucosal Tumor Undiagnosed Preoperatively and Treated with Thoracoscopic Enucleation].

An asymptomatic 35-year-old man visited our hospital because of an esophageal abnormality identified on a medical check-up. Gastrointestinal endoscopic examination revealed a 4 cm diameter submucosal tumor(SMT)in the upper esophagus. endoscopic ultrasound fine-needle aspiration biopsy(EUS-FNAB)was performed. Histopathological examination showed that it was strongly positive for a-SMA and partially positive for c-kit. An esophageal leiomyoma was suspected but esophageal gastrointestinal stromal tumor(GIST)could not be completely ruled out. After considering the patient's age and the location of the tumor, we performed thoracic enucleation of the esophageal SMT. Immunostaining findings showed that it was a-SMA positive and S-100 negative. Mast cells, but not tumor cells were partially stained with c-kit. The final pathological diagnosis was leiomyoma. The postoperative course was uneventful. We report this case together with a review of the literature.

[A Case of Heterochronic Cervical Esophageal Cancer with a Subcutaneous Abscess Showing a Complete Response to Chemoradiation Therapy].

We report a case of heterochronic cervical esophageal cancer with a subcutaneous abscess successfully treated using chemoradiation. A 68-year-old man underwent esophagectomy for middle thoracic esophageal cancer 13 years ago. In April 2015, upper gastrointestinal endoscopy revealed advanced residual cervical esophageal cancer. Enhanced CT showed a massive tumor with a subcutaneous abscess, and the tumor had invaded the left internal jugular vein and the 8th cervical spine. We firstly performed abscess drainage and administered antibiotics. After the inflammation decreased, we started chemora- diation. Chemotherapy consisted of 70mg/m / 2 cisplatin(day 1)and 700 mg/m2 5-FU(days 1-5)combined with almost 60 Gy radiotherapy(1.8 Gy/day, 5 days/week, days 1-49). We administered cisplatin and 5-FU only once because renal dys- function occurred. Consequently, we changed the regimen to weekly 100mg/m2 paclitaxel administration(day 1). After 2 months, a clinical complete response(CR)was obtained and we stopped chemotherapy. Eight months after chemotherapy cessation, the patient shows no sign of recurrence. These results suggest that chemoradiation is an effective treatment for cervical esophageal cancer with a subcutaneous abscess.

[A case of cytomegalovirus colitis during chemotherapy for esophageal cancer].

We report a case of a patient who developed cytomegalovirus colitis during chemotherapy for esophageal cancer. A 62- year-old man was admitted to our hospital complaining of epigastralgia and dysphagia. He was diagnosed as having esophageal cancer( Mt, type 3, cT3, cN2, cM0, cStage III). Neoadjuvant chemotherapy with 5-fluorouracil( 5-FU) and cisplatin (CDDP) was initiated. However, after 1 course of chemotherapy, the patient experienced a stroke. Subsequently, he was treated with radical chemoradiotherapy. Chemoradiotherapy with low-dose docetaxel was administered. However, he developed interstitial pneumonia, and thus received pulse corticosteroid therapy with methylprednisolone. On the 26th day after steroid therapy, he developed melena. Colonoscopy revealed multiple punched-out ulcers in the transverse colon, and the patient was diagnosed as having cytomegalovirus colitis on the basis of positive cytomegalovirus antigenemia. Intravenous ganciclovir therapy was initiated. On the 13th day after ganciclovir therapy, the patient required an emergency surgery because of perforation-related peritonitis. We identified a perforation in the ascending colon and performed ileocecal resection. Although he was treated with paclitaxel, he died of esophagotracheal fistula and aspiration pneumonitis. We should be aware of cytomegalovirus colitis during chemotherapy and corticosteroid therapy.

Active auroral arc powered by accelerated electrons from very high altitudes.

Bright, discrete, thin auroral arcs are a typical form of auroras in nightside polar regions. Their light is produced by magnetospheric electrons, accelerated downward to obtain energies of several kilo electron volts by a quasi-static electric field. These electrons collide with and excite thermosphere atoms to higher energy states at altitude of ~ 100 km; relaxation from these states produces the auroral light. The electric potential accelerating the aurora-producing electrons has been reported to lie immediately above the ionosphere, at a few altitudes of thousand kilometres1. However, the highest altitude at which the precipitating electron is accelerated by the parallel potential drop is still unclear. Here, we show that active auroral arcs are powered by electrons accelerated at altitudes reaching greater than 30,000 km. We employ high-angular resolution electron observations achieved by the Arase satellite in the magnetosphere and optical observations of the aurora from a ground-based all-sky imager. Our observations of electron properties and dynamics resemble those of electron potential acceleration reported from low-altitude satellites except that the acceleration region is much higher than previously assumed. This shows that the dominant auroral acceleration region can extend far above a few thousand kilometres, well within the magnetospheric plasma proper, suggesting formation of the acceleration region by some unknown magnetospheric mechanisms.

[Two cases of advanced gastric cancer with peritoneal dissemination, and Virchow's metastases successfully treated by combination therapy of S-1 and docetaxel].

We report two cases of advanced gastric cancer successfully treated with combination S-1 and docetaxel (DOC) therapy. Case 1: A 43-year-old woman underwent radical total gastrectomy for advanced type 4 gastric cancer one and a half years ago. She was diagnosed as peritonitis carcinomatosa with much ascites, so the following combination chemotherapy was started. Case 2: A 53-year-old man underwent palliative gastrectomy for advanced type 3 gastric cancer with multiple lymph node metastases involving Virchow's metastases. After surgery, he received the following combination chemotherapy: DOC at the starting dose of 40 mg/m2 by iv infusion over 1 hour on day 1 and S-1 at the full dose of 80 mg/m2 daily for two weeks every three weeks. After administration of this combination therapy, the Case 1 gastric cancer with much ascites and the Case 2 gastric cancer with multiple lymph nodes metastases had entirely disappeared. Thereafter the 2 cases received therapy with S-1 alone. No recurrence in Case 1 has been seen with S-1 chemotherapy. Case 2 revealed a few lymph node swellings in the abdominal cavity, so he is undergoing combination therapy of DOC and S-1. The combination DOC and S-1 show a high degree of safety and can be a new tool for the management of advanced gastric cancer with peritoneal dissemination and Virchow's metastases.

Efficacy of perioperative immunonutrition in esophageal cancer patients undergoing esophagectomy.

OBJECTIVE: Malnutrition is common in patients with esophageal cancer, resulting in increased postoperative complications and mortality. Although preoperative immunonutrition can significantly reduce the incidence of postoperative infectious complications, its effect in patietns with esophageal cancer undergoing esophagectomy remains unclear. The aim of this study was to investigate the effects of perioperative immunonutritional support on the postoperative course and long-term survival of this group of patients. METHODS: This prospective, randomized study enrolled 40 patients with thoracic esophageal carcinoma undergoing esophagectomy. The patients were divided into two groups and received either immunomodulating enteral nutrition (IMPACT group; IG) or standard enteral nutrition (Ensure group; EG) continuously for 7 d before and 7 d after surgery. Nutritional status, such as rapid turnover protein, postoperative intensive care unit (ICU) length of stay (LOS), postoperative hospital LOS, morbidity, and mortality were investigated prospectively. RESULTS: There were no significant differences in patient demographic characteristics between the two groups. Levels of retinol-binding protein, as a rapid-turnover protein, were significantly higher on postoperative day (POD) -1, 7, and 14 in the IG compared with the EG group (P = 0.009, P = 0.004, and P = 0.024, respectively). The incidence of postoperative infectious complications and changes to therapeutic antibiotics were significantly lower in the IG group than in the EG group (P = 0.048 and P = 0.012, respectively). There was no significant difference in postoperative ICU or postoperative hospital LOS between the two groups. The 5-y progression-free survival rates in the IG and EG groups were 75% and 64%, respectively (P = 0.188), and the overall survival rates were 68% and 55%, respectively (P = 0.187). CONCLUSIONS: Perioperative immunonutrition may improve early postoperative nutritional status and reduce postoperative infectious complications in patients with esophageal cancer undergoing esophagectomy.

[Combination chemotherapy composed of mFOLFOX 6, FOLFIRI 2 and surgery and radiation therapy for locoregional recurrences and multiple lung metastases from rectal cancer--a case report].

A 61-year-old man underwent amputation of the rectum for advanced lower rectal cancer in April 2005. UFT-E granules were administered orally daily at 400 mg/body/day following surgery. He developed perineal pain and perineal discharges following an increase the CEA level in April 2006. PET revealed a tumor in the perineum and multiple lung metastases. Chemotherapy with mFOLFOX 6 for 8 courses and FOLFIRI 2 for 4 courses were administered since July in 2006. Although CT revealed a the reduction in multiple lung metastases, CEA was increased to over a maximum 109, high fever continued and the pinealtumor was enlarged in December 2006. The patient underwent resection of the perinealmass, but he developed perinealsevere pain and perinealdischarge. So radiotherapy of the pelvic region was given at a total dose of 40 Gy(given 2 Gy each fragment)followed by administration of FOLFIRI 2 for 12 courses. After chemoradiotherapy, the CEA level was remarkably decreased. PET could not detect any mass in lung fields and revealed a little accumulation in the pelvic region. Chemotherapy with FOLFIRI 2 is administered monthly now, and the CEA level has been within the normal range since July of 2007. The pineal pain and pineal discharge disappeared, so the quality of life has improved dramatically.

Association of tumor necrosis factor-α polymorphism with chemotherapy-induced oral mucositis in patients with esophageal cancer.

The purpose of this study was to evaluate the association between tumor necrosis factor (TNF)-α polymorphisms and oral mucositis (OM) from 5-fluorouracil (5-FU) plus cisplatin (CDDP) chemotherapy for esophageal cancer. The rs1799964 polymorphism of TNF-α was genotyped using the tetra-primer amplification refractory mutation system polymerase chain reaction. The experimental group comprised 64 patients who received chemotherapy for esophageal cancer between 1997 and 2004; a total of 106 patients between 2005 and 2013 were investigated as the validation group. Univariate analysis of the experimental group revealed that the TT genotype of TNF-α rs1799964 was significantly higher in patients with grade 1-4 OM compared with the TC/CC genotypes [univariate odds ratio (OR)=4.0; P=0.029]. Similarly, univariate analysis of the validation group revealed that the percentage of the TT genotype was significantly higher in patients with grade 1-4 OM compared with the TC/CC genotypes (OR=2.8; P=0.043). This difference in risk was replicated in the validation cohort. Thus, the TT genotype of TNF-α rs1799964 may be a predictor of chemotherapy-induced OM in patients with esophageal cancer.

Efficacy and Safety of Biweekly Docetaxel in Combination with Nedaplatin as Second-line Chemotherapy for Unresectable or Recurrent Esophageal Cancer.

AIM: In Japan, chemotherapeutic agents that have been approved for the treatment of esophageal cancer include cisplatin, nedaplatin, 5-fluorouracil, vindesine, and docetaxel. The aim of this study was to retrospectively investigate the efficacy and safety of docetaxel and nedaplatin combination chemotherapy for unresectable or recurrent esophageal cancer in an outpatient setting. PATIENTS AND METHODS: In total, 33 patients with recurrent esophageal cancer after initial treatment (esophagectomy, chemotherapy, or chemoradiotherapy) were enrolled. Patients received docetaxel (30 mg/m(2)intravenously) and nedaplatin (30 mg/m(2)intravenously) on day 1 biweekly. The response rate (RR), time to treatment failure (TTF), overall survival time (OS), and toxicity were analyzed. RESULTS: The median number of cycles of combination therapy was five (range=2-25 cycles). The RR was 21.2%, and the disease control rate was 60.6%. The median TTF was 71 days, and median OS was 211 days. The most frequent toxicities were leukopenia and anemia; non-hematological toxicities were generally mild. There were no treatment-related deaths. CONCLUSION: This outpatient combination chemotherapy was useful as second-line chemotherapy for unresectable or recurrent esophageal cancer.

Attenuation of axonal injury and oxidative stress by edaravone protects against cognitive impairments after traumatic brain injury.

Traumatic axonal injury (TAI), a feature of traumatic brain injury (TBI), progressively evolves over hours through impaired axonal transport and is thought to be a major contributor to cognitive dysfunction. In spite of various studies suggesting that pharmacologic or physiologic interventions might reduce TAI, clinical neuroprotective treatments are still unavailable. Edaravone, a free radical scavenger, has been shown to exert neuroprotective effects in animal models of several brain disorders. In this study, to evaluate whether edaravone suppresses TAI following TBI, mice were subjected to weight drop injury and had either edaravone (3.0mg/kg) or saline administered intravenously immediately after impact. Axonal injury and oxidative stress were assessed using immunohistochemistry with antibodies against amyloid precursor protein, a marker of impaired axonal transport, and with 8-hydroxy-2'-deoxyguanosine, a marker of oxidative DNA damage. Edaravone significantly suppressed axonal injury and oxidative stress in the cortex, corpus callosum, and hippocampus 24h after injury. The neuroprotective effects of edaravone were observed in mice receiving 1.0, 3.0, or 10mg/kg of edaravone immediately after impact, but not after 0.3mg/kg of edaravone. With treatment 1h after impact, axonal injury was also significantly suppressed and this therapeutic effect persisted up to 6h after impact. Furthermore, behavioral tests performed 9 days after injury showed memory deficits in saline-treated traumatized mice, which were not evident in the edaravone-treated group. These results suggest that edaravone protects against memory deficits following TBI and that this protection is mediated by suppression of TAI and oxidative stress.