Gas leakages from gastrointestinal endoscopy system-its visualization and semi-quantification utilizing schlieren optical system in the swine models.

BACKGROUND AND AIMS: With the global epidemic of SARS-CoV-2, there has been a growing concern regarding the risk of aerosol exposure to healthcare workers and patients during medical/surgical interventions. The Schlieren device is capable of visualizing fine gas-flows by using refractive index differences in the medium. We aimed to reveal the existence of gas leakage from gastro-intestinal endoscopy system by utilizing Schlieren device and to clarify the factors which relates to the amount of gas leakage. METHODS: The experiments were performed on the excised swine stomach while maintaining a constant pressure environment in the stomach. The System Schlieren (SS100,KatoKoken) was used to visualize possible gas leakages from forceps plugs of endoscopy. We attempted to semi-quantify the leakage by referring to the image of the gas from the forceps plug and by measuring the initial velocity and diffusion area of the leakage. RESULTS: Regardless of the type of forceps plugs, a certain amount of leakage was detected during both insertion and removal of forceps. The initial velocity and the diffusion area of the leakage increased with the increase in intragastric pressure. Semi-quantitative comparison showed that there was a difference in the amount of gas leakage among various forceps plugs. Furthermore, the amount of gas leakage was significantly greater in the forceps plugs that were used repeatedly. CONCLUSION: It was possible to visualize gas leakages from the gastrointestinal endoscope system using the Schlieren optical device. Avoiding too high intragastric pressure and not using deteriorated plugs may reduce the risk of aerosol exposure.

Management of abdominal gas leakage from surgical trocars in laparoscopic surgery: a preclinical study.

Introduction: There is an ongoing concern about the potential infectious risk due to pneumoperitoneal gas leakage from surgical trocars in laparoscopic surgery. We aimed to visually confirm the presence of leakage from trocars and investigate the changes in the leakage scale according to intra-abdominal pressures and trocar types. Material and methods: We established a porcine pneumoperitoneum model and performed experimental forceps manipulation using 5-mm grasping forceps with 12-mm trocars. The gas leakage, if any, was imaged using a Schlieren optical system, which can visualize minute gas flow invisible to the naked eye. For measuring the scale, we calculated the gas leakage velocity and area using image analysis software. Four types of unused and exhausted disposable trocars were compared. Results: Gas leakage was observed from trocars during forceps insertion and removal. Both the gas leakage velocity and area increased as the intra-abdominal pressure increased. Every type of trocar we handled was associated with gas leakage, and exhausted disposable trocars had the largest scale gas leakage. Conclusions: We confirmed gas leakage from trocars during device traffic. The scale of leakage increased with high intra-abdominal pressure and with the use of exhausted trocars. Current protection against gas leakage may not be sufficient and new surgical safety measures and device development may be needed in the future.

Multicenter randomised trial of two versus three courses of preoperative cisplatin and fluorouracil plus docetaxel for locally advanced oesophageal squamous cell carcinoma.

BACKGROUND: The optimal number of neoadjuvant chemotherapy (NAC) cycles remains to be established for treating oesophageal squamous cell carcinoma (ESCC). We compared two versus three courses of NAC for treating locally advanced ESCC in a multi-institutional, randomised, Phase II trial. METHODS: We randomly assigned 180 patients with locally advanced ESCC at 6 institutions to either two (N = 91) or three (N = 89) courses of DCF (docetaxel 70 mg/m2, cisplatin 70 mg/m2 i.v. on day 1, fluorouracil 700 mg/m2 continuous infusion for 5 days) every 3 weeks, prior to surgery. The primary endpoint was 2-year progression-free survival (PFS) with an intention-to-treat analysis. RESULTS: Patient background parameters were well-balanced. The R0 resection rates were 98.9 and 96.5% in the two- and three-course groups, respectively (P = 0.830). In resected cases, the two- and three-course groups had comparable pN0 rates (P = 0.225) and histological responses (P = 0.898). The 2-year PFS rate was also comparable between the two groups (71.4 vs. 71.1%, P = 0.669). Among subgroups based on baseline characteristics, only patients aged under 65 years old showed a tendency for better survival with the three-course treatment (hazard ratio = 2.612, 95% confidence interval: 1.012-7.517). CONCLUSIONS: Two courses of a DCF regimen showed potential as an optional NAC treatment for locally advanced ESCC. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry of Japan (identification number UMIN 000015788).

New response evaluation criteria using early morphological change in imatinib treatment for patients with gastrointestinal stromal tumor.

BACKGROUND: The introduction of molecularly targeted drugs, including imatinib, has greatly improved the prognosis of gastrointestinal stromal tumor (GIST), and based on the different response image, the methods of response evaluation have been established for GISTs. Furthrmore, the best response evaluation using them has been reported to be associated with progression-free survival (PFS) in imatinib treatment. However, since it is more important to predict the clinical outcomes of imatinib treatment in "early treatment phase", new predicting factor in earlier stage is desired to work out the whole strategy of each patient. Early morphological change (EMC) was previously reported as a predictive marker for molecularly targeted drugs in metastatic colorectal cancer. The purpose of the present study was to verify the efficacy of EMC in predicting the outcome in patients with GIST receiving imatinib at early evaluation. METHODS: We retrospectively reviewed 66 patients. EMC in computed tomography (CT) image was evaluated, and the patients were categorized into two groups: active MR (morphological response) (+) group and active MR (-) group. We investigated the association between the presence of active MR and clinical outcomes. RESULTS: Forty-five patients had active MR ( +). The median progression-free survival (PFS) in patients with/without active MR was 49/23 months (P = 0.0039). CONCLUSION: The evaluation criteria based on EMC could be a sensitive method to predict the clinical outcome of imatinib treatment for patients with unresectable GIST.

Targeted therapy for drug-tolerant persister cells after imatinib treatment for gastrointestinal stromal tumours.

BACKGROUND: Despite the effectiveness of tyrosine kinase inhibitors (TKI), gastrointestinal stromal tumours (GIST) develop after the withdrawal of TKI. Based on previous studies, a subpopulation of drug-tolerant cells called "persister cells" may be responsible for the recurrence and have thus, gained attention as a novel target in cancer therapy. METHODS: The metabolic changes were investigated in imatinib-derived persister GIST cells. We investigated the efficacy and the mechanism of GPX4 inhibitor, which is known as a major inducer of "ferroptosis". We also evaluated the effects of RSL3 to the gefitinib-derived persister lung cancer cells. RESULTS: We demonstrated a downregulation of glucose metabolism, subsequent decrease in the glutathione level and sensitivity to glutathione peroxidase 4 (GPX4) inhibitor, RSL3 in persister cells. As the cell death induced by RSL3 was found to be "iron-dependent" and "caspase-independent", loss of GPX4 function could have possibly induced selective persister cell ferroptotic death. In the xenograft model, we confirmed the inhibition of tumour regrowth after discontinuation of imatinib treatment. Moreover, RSL3 prevented the growth of gefitinib-derived persister lung cancer cells. CONCLUSIONS: RSL3 combined with TKI may be a promising therapy for both GIST and epidermal growth factor receptor-mutated lung cancer.

Quantity and Quality of Skeletal Muscle as an Important Predictor of Clinical Outcomes in Patients with Esophageal Cancer Undergoing Esophagectomy after Neoadjuvant Chemotherapy.

BACKGROUND: Sarcopenia was previously linked to clinical outcomes for several cancer types, including esophageal cancer (EC), but most studies only measured the quantity of skeletal muscle mass. We aim to assess the clinical significance of evaluating the quantity and quality of skeletal muscle in patients with EC who underwent neoadjuvant chemotherapy (NAC) followed by esophagectomy. METHODS: We included 333 consecutive patients with EC who underwent NAC followed by esophagectomy. The psoas muscle index (PMI) and intracellular muscle adipose tissue content (IMAC) were measured by computed tomography. We defined low PMI combined with high IMAC as severe sarcopenia, and assessed its impact on clinical outcomes. RESULTS: Thirty-seven patients (11.1%) had severe sarcopenia. Compared with patients without severe sarcopenia, those with severe sarcopenia showed a significantly worse NAC response rate (54.1% vs 74.7%; P = 0.008), worse pathological response rate (24.3% vs 40.2%, P = 0.061), higher morbidity rate (67.6% vs 38.5%; P = 0.001), particularly for pneumonia (32.4% vs 14.9% P = 0.007) and expectoration disorder (37.8% vs 13.5% P < 0.001), and unfavorable survival (3-year overall survival rate: 54.1% vs 66.6% P = 0.027). Multivariable analysis of overall survival showed that severe sarcopenia (HR 1.68, P = 0.025) and cT (HR 1.52, P = 0.032) were independent prognostic factors of poor outcome. CONCLUSIONS: PMI combined with IMAC represents a new criterion for sarcopenia that might be useful for predicting NAC response, postoperative complications, and long-term survival in patients with EC undergoing multidisciplinary treatments.

Propranolol suppresses gastric cancer cell growth by regulating proliferation and apoptosis.

BACKGROUND: Despite improvements in gastric cancer treatment, the mortality associated with advanced gastric cancer is still high. The activation of ß-adrenergic receptors by stress has been shown to accelerate the progression of several cancers. Accordingly, increasing evidence suggests that the blockade of ß-adrenergic signaling can inhibit tumor growth. However, the effect of ß-blockers, which target several signaling pathways, on gastric cancer remains to be elucidated. This study aimed to investigate the anti-tumor effects of propranolol, a non-selective ß-blocker, on gastric cancer. METHODS: We explored the effect of propranolol on the MKN45 and NUGC3 gastric cancer cell lines. Its efficacy and the mechanism by which it exerts anti-tumor effects were examined using several assays (e.g., cell proliferation, cell cycle, apoptosis, and wound healing) and a xenograft mouse model. RESULTS: We found that propranolol inhibited tumor growth and induced G1-phase cell cycle arrest and apoptosis in both cell lines. Propranolol also decreased the expression of phosphorylated CREB-ATF and MEK-ERK pathways; suppressed the expression of matrix metalloproteinase-2, 9 and vascular endothelial growth factor; and inhibited gastric cancer cell migration. In the xenograft mouse model, propranolol treatment significantly inhibited tumor growth, and immunohistochemistry revealed that propranolol led to the suppression of proliferation and induction of apoptosis. CONCLUSIONS: Propranolol inhibits the proliferation of gastric cancer cells by inducing G1-phase cell cycle arrest and apoptosis. These findings indicate that propranolol might have an opportunity as a new drug for gastric cancer.

Two versus three courses of preoperative cisplatin and fluorouracil plus docetaxel for treating locally advanced esophageal cancer: short-term outcomes of a multicenter randomized phase II trial.

OBJECTIVE: To compare short-term outcomes between two- vs. three courses of neoadjuvant chemotherapy (NAC) to clarify the optimal treatment for esophageal squamous cell cancer (ESCC) in a multicenter, randomized, phase II trial. BACKGROUND: An optimal number of NAC cycles remains to be established for locally advanced ESCC. METHODS: Patients with locally advanced ESCC were randomly assigned to either two (N = 91) or three (N = 89) courses of DCF (70 mg/m2 intravenous docetaxel and 70 mg/m2 intravenous cisplatin on day 1, and a continuous 700 mg/m2 fluorouracil infusion for 5 days) every 3 weeks followed by surgery. We compared the two groups for perioperative parameters, adverse events, and the response to NAC. RESULTS: The two- and three-course groups showed similar completion rates and overall NAC dose reductions. Although the two-course group showed significantly lower overall grades 3-4 leukopenia and anemia compared to the three-course group, the two groups had similar overall toxicity rates. Postoperative complications were not significantly different between the two groups, except arrhythmia (13 vs. 0%, P = 0.0007). Only two postoperative in-hospital deaths occurred in the three-course group, due to sepsis following severe pneumonia. Compared to the two-course group, the three-course group was associated with a significantly better clinical response (42.9 vs. 65.2%, P = 0.0027) and a relatively higher rate of pathological complete response (9.1 vs. 15.3%, P = 0.212). CONCLUSION: Both two- and three-course DCF regimens in the NAC setting seemed to be equally feasible in locally advanced ESCC patients. Additional DCF courses led to a better NAC response without increasing the incidence of adverse events or postoperative morbidity. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Clinical Trials Registry of Japan (Identification Number UMIN 000015788).

TAS-116 inhibits oncogenic KIT signalling on the Golgi in both imatinib-naïve and imatinib-resistant gastrointestinal stromal tumours.

BACKGROUND: Despite the effectiveness of imatinib mesylate (IM), most gastrointestinal stromal tumours (GISTs) develop IM resistance, mainly due to the additional kinase-domain mutations accompanied by concomitant reactivation of KIT tyrosine kinase. Heat-shock protein 90 (HSP90) is one of the chaperone molecules required for appropriate folding of proteins such as KIT. METHODS: We used a novel HSP90 inhibitor, TAS-116, which showed specific binding to HSP90α/ß with low toxicity in animal models. The efficacy and mechanism of TAS-116 against IM-resistant GIST were evaluated by using IM-naïve and IM-resistant GIST cell lines. We also evaluated the effects of TAS-116 on the other HSP90 client protein, EGFR, by using lung cell lines. RESULTS: TAS-116 inhibited growth and induced apoptosis in both IM-naïve and IM-resistant GIST cell lines with KIT activation. We found KIT was activated mainly in intracellular compartments, such as trans-Golgi cisternae, and TAS-116 reduced autophosphorylated KIT in the Golgi apparatus. In IM-resistant GISTs in xenograft mouse models, TAS-116 caused tumour growth inhibition. We found that TAS-116 decreased phosphorylated EGFR levels and inhibited the growth of EGFR-mutated lung cancer cell lines. CONCLUSION: TAS-116 may be a novel promising drug to overcome tyrosine kinase inhibitor-resistance in both GIST and EGFR-mutated lung cancer.

[Nab-Paclitaxel plus Gemcitabine Hydrochloride in Patients with Metastatic or Recurrent Pancreatic Cancer - A Single Institution Experience].

BACKGROUND: Pancreatic adenocarcinoma is one of the leading causes of cancer deaths in Japan.Albumin -bound paclitaxel (nab-paclitaxel)plus gemcitabine hydrochloride(GEM)combination chemotherapy provided significant improvements in the overall and progression-free survival in a phase III trial in Europe and America and a phase II trial in Japan.As a result, this combination therapy was approved for use in Japan. METHODS: We evaluated the efficacy of nab-paclitaxel plus GEM with metastatic or recurrent pancreatic cancer.Between December 2014 and March 2016, 11 patients received nab-paclitaxel plus GEM as follows: nab-paclitaxel(125mg/m2 of body-surface area)followed by GEM(1,000mg/m2)on days 1, 8, and 15 every 4 weeks.The treatment was continued until disease progression, unacceptable adverse events, discontinuation as decided by the investigators, or patient refusal. RESULTS: The mean age was 65.6 years(range, 48-75 years), and 8 out of 11 patients were men.Ten patients had an Eastern Cooperative Oncology Group(ECOG)performance status(PS)of 0.Ten patients had metastatic disease.Only 4 patients had no prior therapy.The mean duration of treatment was 10.2 weeks(range, 2-41 weeks).The relative dose intensities of nab-paclitaxel and GEM were 90.6%(66.7-100%)and 87.5%(62.9-100%), respectively.The major Grade 3 or 4 hematological toxicities were leucopenia(54.5%), neutropenia(36.4%), anemia (27.3%), and thrombocytopenia(18.2%).The major grade 2 or 3 non-hematological toxicities were fatigue(45.6%), skin rash(27.3%), peripheral sensory neuropathy(9.1%), anorexia(9.1%), and stomatitis(9.1%).There were no treatmentrelated deaths.Interstitial lung disease was not observed.The 6 month progression-free and overall survival rate were 25.7% and 66.7%, respectively. The disease control rate was 90.9%(complete response, n=0; partial response, n=1; stable disease, n=9; progressive disease, n=1). CONCLUSIONS: Nab-paclitaxel plus GEM is well tolerated and associated with efficacy and improved survival outcomes.Nab -paclitaxel plus GEM can be the standard treatment for patients with metastatic pancreatic adenocarcinoma.

[A Case of a Patient with Metastatic Rectal-Uterine Cancer from the Ascending Colon Who Underwent NOSE].

An 80-year-old woman had undergone a right hemicolectomy for ascending colon cancer 9 months prior to the current presentation. CT and PET-CT showed a solitary tumor measuring 55mm in diameter at the uterus and rectum. Three 5mm ports and two 12mm two ports were placed. The sigmoid colon was mobilized using a medial approach as usual in laparoscopic surgery. The rectum and uterus were mobilized and were resected. We inserted the End-catchTM in from the vagina and removed the specimen. The patient had no abdominal pain and was discharged from the hospital 9 days after the operation.

[Multidisciplinary Treatment for High-Risk GIST of the Stomach].

A 59-year-old man underwent total gastrectomy(with D2 dissection)and cholecystectomy for gastric cancer and a submucosal tumor of the stomach. The specimen was immunohistochemically positive for c-kit, the Ki-67 label index was 10%, and the mitotic count was 20/HPF. Finally, the patient was diagnosed with high-risk gastrointestinal stromal cancer with normal type gastric cancer. After discharge from hospital, we started administration of TS-1 as adjuvant therapy for the gastric cancer. As multiple recurrences of the GIST in the abdomen developed, the patient underwent 3 radical local resections. Mutational analysis revealed a PDGFRA mutation in exon 18, which causes resistance to both imatinib and sunitinib. As he was refractory to imatinib, the patient received regorafenib. After a while, it caused liver failure, which required 7 rounds of plasmapheresis. The patient died from multiple organ failure resulting from multiple recurrences 4 years after the first surgery.

[A Case of Schwannoma Originating from the Sciatic Nerve].

A 75-year-old man was admitted with abdominal pain and taken to our hospital. CT and MRI showed a tumor measuring 60mm in diameter in the pelvic cavity. Based on the imaging findings, we suspected a schwannoma and decided to perform surgery. As the tumor was found to be benign in intraoperative frozen section diagnosis, the tumor was enucleated. Histopathological findings showed no nuclear atypia, and the patient was diagnosed with a schwannoma. He complained of paresthesia in his right leg after surgery, and underwent walking training. Six months after surgery, no recurrence was found.

[A Case of Malignant Anorectal Melanoma with Laparoscopic Abdominoperineal Resection].

A 69-year-old man with anemia underwent colonoscopy. Colonoscopy showed a black tumor, 2 cm from the anal verge. The biopsy specimen revealed malignant melanoma, which was preoperatively diagnosed as T1(SM), N0, M0, Stage I . We performed laparoscopic abdominoperineal resection. The tissue type and diagnosis were malignant melanoma, pT1b(10 mm), pN0, pM0, ly0, v0, pDM0, pPM0, pRM0, pStage I b, according to the Colon Cancer Handling Terms, 8th edition). The patient did not receive adjuvant chemotherapy. However, he survived postoperatively for 9 months, with no sign of recurrence.

[Multiple Metachronal Liver Metastases from a Rectal Neuroendocrine Tumor Controlled by Repeated Transcatheter Arterial Chemoembolization].

A 60-year-old woman was diagnosed with a rectal neuroendocrine tumor(NET)with SM invasion.We performed laparoscopic low anterior resection with D3 lymph node dissection.Pathological findings were rectal NET, G1, pSM(9,000 mm), ly0, v0, pN0, PM0, DM0, pR0, pStage I .Four years and 6 months later, contrast enhanced abdominal computed tomography (CECT)and contrast enhanced magnetic resonance imaging revealed multiple liver metastases.The tumors were unresectable because they were bilobar; therefore, we performed transcatheter arterial chemoembolizaion(TACE).One month later, CECT showed the lesions had shrunk.The metastases were well controlled via repeated TACE.For unresectable liver metastases from rectal NET, TACE can be an effective treatment.

[A Case of Neuroendocrine Tumor of the Ileum Manifesting as Fecal Occult Blood].

A 42-year-old woman was admitted to our hospital because of a positive fecal occult blood test. Colonoscopy examination revealed an elevated lesion measuring 25mm in diameter at the terminal ileum. A histological diagnosis of neuroendocrine tumor(NET)was made based on biopsy specimens taken from the lesion. Since no apparent distant metastasis other than the ileocolic lymph nodes was noted, laparoscopy-assisted ileocecal resection with regional lymph node dissection was performed. In the resected material, NET(G2)limited to the subserosa layer was present. The NET tested positive for synaptophysin, chromogranin A, and CD56. Metastases in the paraileal lymph nodes was detected. NET metastasis to the ileum is frequent, even if the tumor is small in diameter; therefore, it is necessary to resect the tumor entirely and to dissect the regional lymph nodes.

[A Case of Successful Multidisciplinary Therapy for Advanced Esophagogastric Junction Cancer with Multiple Lymph Node Metastase].

A 64-year-old man reporting dysphagia was examined. Upper gastrointestinal endoscopy showed a type 3 cancer at the esophagogastric junction. Enhanced CT scan showed several swollen mediastinal and abdominal lymph nodes. We diagnosed the patient with advanced adenocarcinoma of the esophagogastric junction with multiple lymph node metastases(Siewert type II , cT3N2M1[LYM], Stage IV ). After 5 courses of chemotherapy(S-1 plus cisplatin), a significant reduction was observed in the size of the tumor and lymph nodes. Therefore, we performed conversion surgery. The patient underwent esophagectomy and mediastinal lymph node dissection using a right thoracotomy approach. He has survived without recurrence in the 10 months since this radical surgery.

[A Case of Pure Squamous Cell Carcinoma of the Breast in an Elderly Woman Diagnosed by Cytology].

A n 85-year-old woman presented with a mass in the left breast. A3 7mm lobulated mass including enhancement of a cyst of 37mm was detected by sonography. An axillary lymph node had increased to 16 mm. Atypical cells dyed by light green and orange G were identified by fine needle aspiration and cytology. She was diagnosed with left breast cancer(cT2N1M0, Stage II B), histologically suspected to be squamous cell carcinoma. She underwent a left-breast-conserving surgery and axillary lymph node dissection. On pathology, a cyst of 34×30mm was noted. The tumor grew from inside the cyst to the surround- ing tissue and it had a trend for keratinocytes. Lymph node metastases affected 1/11. By immunostaining, the tumor was found to be ER(+), PgR(-), HER2(-), CK5/6(+), p40(+), mammaglobin(-), and GCDFP15(-). There was no component of ductal carcinoma. She received radiotherapy to the left breast and tamoxifen as an adjuvant therapy. Squamous cell carcinoma of the breast is rare. We encountered a case of pure squamous cell carcinoma of the breast in an elderly woman. We report this case with a discussion of the relevant literature.

[A Case of Neuroendocrine Carcinoma of the Gallbladder].

A 58-year-old woman presented to our hospital with a huge hepatic mass. A CT scan showed an enhanced mass lesion on the fundus of the gallbladder and an enhanced mass ring on the gallbladder bed. Since FDG-PET showed no evidence of metastasis, we performed cholecystectomy, hepatectomy of S4a/5, and regional lymph node dissection. The immunohistochemical study of the specimen was positive for CK7, CK20, chromogranin A, and synaptophysin. The Ki-67 labeling index was 50%, and the SSTR2 score was 2+. The patient was diagnosed with neuroendocrine carcinoma. Since she was in poor condition and on hemodialysis, we started administration of somatostatin analog at the time of recurrence, and soon her diarrhea improved but the tumor increased in size.

[A Case of Concurrent Primary Gastric Malignant T-Cell Lymphoma and Pulmonary Mucosa-Associated Lymphoid Tissue Lymphoma].

A 71-year-old man was admitted to our hospital for epigastric pain. Upper gastrointestinal endoscopy revealed a type 2- like ulcerative lesion in the posterior wall of the upper and middle part of the stomach. Endoscopic biopsies showed malignant T-cell lymphoma histologically. A chest CT scan revealed a nodule in the apex of right lung, suggestive of primary lung cancer. A total gastrectomy with D2 lymphadenectomy and distal pancreatectomy with splenectomy was performed. Seventy-three days after surgery, the patient developed a lung abscess in the middle lobe of the right lung. A wedge-shaped resection of the upper lobe and total resection of the middle lobe of the right lung was performed. Histological examination revealed a primary pulmonary mucosa-associated lymphoid tissue lymphoma in the upper lobe of right lung and an abscess caused by Pseudomonas aeruginosa in the middle lobe of the right lung. Twelve months after surgery the man died of suffocation because of aspiration due to esophageal stenosis caused by progression of metastasis of the paraesophageal lymph node.