Pediatric inflammatory myofibroblastic tumor of the bladder with ALK-FN1 fusion successfully treated by alectinib.

An inflammatory myofibroblastic tumor (IMT) is a mesenchymal neoplasm characterized by the proliferation of myofibroblasts and inflammatory cell infiltration. Although radical resection is the only established treatment strategy for IMT, it can cause functional disorders when vital organs are affected. We describe a case of pediatric IMT of the bladder with FN1-ALK (fibronectin 1-anaplastic lymphoma kinase) fusion. Radical resection might lead to urinary disturbance due to the large tumor size at diagnosis. However, the tumor was successfully treated with alectinib, a second-generation ALK inhibitor, followed by transurethral resection of the bladder tumor without any complications.

Presence of identical B-cell clone in both cerebrospinal fluid and tumor tissue in a patient with opsoclonus-myoclonus syndrome associated with neuroblastoma.

Opsoclonus-myoclonus syndrome associated with neuroblastoma (OMS-NB) is a refractory paraneoplastic syndrome which often remain neurological sequelae, and detailed pathogenesis has remained elusive. We encountered a pediatric patient with OMS-NB treated by immunosuppressed therapy who showed anti-glutamate receptor δ2 antibody and increased B-cells in cerebrospinal fluid (CSF), and multiple lymphoid follicles containing abundant Bcells in tumor tissue. Unbiased B-cell receptor repertoire analysis revealed identical B-cell clone was identified as the dominant clone in both CSF and tumor tissue. These identical B-cell clone may contribute to the pathogenesis of OMS-NB. Our results could facilitate the establishment of pathogenesis-based treatment strategies for OMS-NB.

[A Case of Stage â £Rectal Cancer with Dyskeratosis Congenita].

A 27-year-old man was diagnosed with dyskeratosis congenita from DKC1 gene mutation at 9 years of age and had been followed-up regularly.An upper gastrointestinal endoscopy performed for vomiting revealed gastric varices.Further examination resulted in a diagnosis of Stage Ⅳrectal cancer with portal hypertension, splenomegaly, liver, and lung metastasis and he was referred to our department.A laparoscopic splenectomy was performed, followed by a laparoscopic low anterior resection for rectal cancer.Subsequently, resection of the pulmonary and liver metastasis was performed, resulting in macroscopic radical resection.However, 3 months after the hepatectomy, unresectable multiple lung metastasis was detected and he received 5 courses of chemotherapy with cetuximab.A grade 3 skin rash was observed and chemotherapy was discontinued. After 5 courses, he had pneumothorax and received drainage.He had sudden respiratory failure 2 days after pleural adhesion therapy of OK-432 was performed.He was diagnosed with interstitial pneumonia induced by OK-432 and steroid pulse therapy, which resulted in his death without improvement 21 days after admission.

[A Case of Pathological Complete Response Induced by Preoperative Chemotherapy with Gemcitabine plus Nab-Paclitaxel in a Patient with Pancreatic Cancer on Hemodialysis].

A 59-year-old man was admitted to our hospital for further investigation of abnormal uptake in the pancreatic body on positron emission tomography-computed tomography(PET-CT). He had chronic renal failure due to diabetic nephropathy, and had been on maintenance hemodialysis since he was 45-years-old. He was diagnosed with pancreatic body cancer(cT1c, cN0, cM0, cStageⅠa)and was treated preoperatively with neoadjuvant chemotherapy(gemcitabine plus nab-paclitaxel). After 2 courses, we performed distal pancreatectomy. Histopathological examination revealed no viable tumor cells(pathological complete response). The postoperative course was uneventful, and he is alive without recurrence at 6 months after surgery, without adjuvant chemotherapy. Our findings suggest that gemcitabine plus nab-paclitaxel is a useful treatment for patients with pancreatic cancer on hemodialysis.

[A Case of Esophagogastric Junction Adenocarcinoma with Neuroendocrine Differentiation].

Gastric cancer rarely contains neuroendocrine component. This mixed tumor is defined as neuroendocrine carcinoma (NEC), mixed adenoneuroendocrine carcinoma(MANEC)and so on according to the WHO classification. We report a patient with esophagogastric junction cancer with neuroendocrine differentiation(NED). The patient was 54-year-old man who diagnosed of esophagogastric junction cancer at the medical examination. Upper gastrointestinal endoscopy revealed a type 3 tumor at esophagogastric junction, and the pathological findings were poorly differentiated adenocarcinoma with focal positivity of chromogranin A. CT and FDG/PET revealed a metastatic regional lymph node. He had undergone proximal gastrectomy and lower esophagectomy, with dissection of D1+and double-tract reconstruction. Pathological findings revealed moderate to poorly differentiated adenocarcinoma containing chromogranin A-positive tumor cells. Neuroendocrine components were lower than 30%, and we diagnosed adenocarcinoma with NED. Standard treatment for gastric cancer with NED has not been established and more reports and reviews are required.

[A Case of Pneumocystis Pneumonia Developed during Chemotherapy for Sigmoid Colon Cancer].

A 69-year-old man with multiple liver metastases from sigmoid colon cancer received mFOLFOX6 plus cetuximab(Cmab) chemotherapy. A partial response was observed; hence, we performed an extended left hepatectomy, 3 partial liver resections, and a sigmoidectomy. After 4 courses of CapeOX, a recurrent lesion occurred between S8 and S7 of the liver, and we changed the regimen to FOLFIRI plus bevacizumab(BV). Three months later, he had Grade 3 febrile neutropenia and CT scan findings showed ground glass opacity in the superior lobes of both lungs. We diagnosed pneumocystis pneumonia(PCP)and administered steroids and trimethoprim/sulfamethoxazole. The signs of PCP thus improved. PCP during chemotherapy for gastrointestinal cancer is rarely reported, but recently it has increased.

[Early Enteral Nutrition for Gastric Cancer Patients with Extended Surgery].

The effectiveness of multi-modal therapy for advanced gastric cancer were reported recently.These therapies are highly invasive, therefore the peri-operative management for regulation of general condition is important.We introduced early enteral nutrition for these cases aiming for improvement of post-operative course.We examined 18 cases with early enteral nutrition in 76 gastrectomised patient after pre-operative chemotherapy.In 15 of 18 patients, maximum dose of enteral nutrition was 960 kcal/day or more.Side effects of enteral nutrition, such as diarrhea or vomiting, abdominal pain, were observed in 11 cases.These symptoms ware controllable except 1 case with severe diarrhea.The weight loss during hospitalization was suppressed with early enteral nutrition.Early enteral nutrition was safe and essential peri-operative management for advanced gastric cancer patients received highly invasive multi-modal therapy.

Sivelestat sodium hydrate inhibits neutrophil migration to the vessel wall and suppresses hepatic ischemia-reperfusion injury.

BACKGROUND: Sivelestat sodium hydrate (sivelestat) is a specific neutrophil elastase inhibitor that is effective in treating acute lung injury associated with systemic inflammatory response syndrome. As such, it may be useful in treating hepatic ischemia-reperfusion injury (IRI), a condition in which neutrophils transmigrate into the interstitium, leading to release of neutrophil elastase from neutrophils and consequent damage to the affected tissue, particularly in cases of hepatic failure after liver transplantation or massive liver resection. AIMS: The purpose of this study was to examine whether treatment with sivelestat inhibits neutrophil adhesion and migration to the vessel wall and suppresses hepatic IRI. METHODS: Whether and, if so, the extent to which sivelestat suppresses the adhesion and migration of neutrophils and reduces liver damage in hepatic IRI was examined in a human umbilical vein endothelial cell (HUVEC) model and a rat hepatic IRI model. RESULTS: In the HUVEC model, the extent of the adhesion and migration of neutrophils stimulated by platelet-activating factor were found to be dose-dependently inhibited by sivelestat treatment (p < 0.05). In the rat model, serum liver enzyme levels were significantly lower at 12 h after reperfusion, and the number of neutrophils that had migrated to extravascular sites was significantly less in the treatment group compared to the control group (p < 0.05). CONCLUSION: Sivelestat inhibits the adhesion and migration of neutrophils to vascular endothelium in hepatic IRI, thereby suppressing liver injury.

[Gemcitabine augments major histocompatibility complex class I-related chain A expression in pancreatic cancer].

Major histocompatibility complex(MHC)class I related chain A( MICA) expressed on the cell surface of tumor cells functions as a ligand for natural killer group 2, member D (NKG2D), an important immunoreceptor expressed on natural killer ( NK ), CD8, and γδT cells. The interaction of MICA and NKG2D stimulates NK cell-mediated cytotoxicity. Gemcitabine (GEM), a key drug for pancreatic cancer treatment, stimulates the expression of cell surface MICA in tumor cells to enhance the cytotoxicity of NK cells. The combination of GEM and S-1 is used as a neoadjuvant chemotherapy (NAC) drug for pancreatic cancer in our department. We investigated the effect of GEM on pancreatic cancer. On immunohistochemistry, MICA expression was positive in 11 of 13 (85%) pancreatic ductal adenocarcinomas in the NAC group, and in 4 of 11 (36%) in the placebo control group. There was a greater proportion of NKG2D-positive cells in 5 random samples taken from both the NAC groups( 10 of 13, 77%) than in equivalent samples taken from the placebo control group( 3 of 11, 27%). In addition, CD16-positive cells were more prevalent among NK, CD8, and γδT cells in the NAC group( 9 of 13, 69%) than in the placebo control group( 3 of 11, 27%). Therefore, GEM may induce MICA expression on the surface of pancreatic cells and thus cause the accumulation of NKG2D and CD16-positive cells around tumors.

[Hepatic arterial infusion chemotherapy with gemcitabine for patients with postoperative liver metastases from pancreatic cancer].

Herein, we describe hepatic arterial infusion (HAI) chemotherapy with gemcitabine (GEM) for the treatment of patients with postoperative liver metastases from pancreatic cancer. Seven patients received HAI with GEM plus 5-fluorouracil (5- FU) or oral S-1 from 2008 to 2010 at the Kanazawa University Hospital. Of the 7 patients, partial response (PR) and stable disease( SD) were observed in 6 patients according to the Response Evaluation Criteria In Solid Tumors( RECIST) evaluation criteria (response rate, 85.7%). The median survival time was 14 months; however, all 7 patients ultimately died of another metastatic lesion. Importantly, there were no life-threatening toxicities. However, 6 patients developed catheter- related complications, and the HAI catheter and the subcutaneous implantable port system had to be removed. Peripheral blood concentrations of GEM after HAI were analyzed in 7 other patients. At a dose level of 400 to 800 mg/standard liver volume( SLV),the GEM concentrations were less than one-tenth that of the intravenously administered 1,000 mg/m2. However, at a dose level of 1,000 mg/SLV, the GEM concentration in the peripheral blood was almost the same as that administered intravenously. In conclusion, HAI chemotherapy is safe and effective for the treatment of patients with liver metastases from pancreatic cancer. Our results suggest that a dose level of 800 mg/SLV could be considered optimal for local therapy.

Mesenteric abscess caused by coinfection with Bacillus Calmette-Guérin and Phialemonium sp. in chronic granulomatous disease.

Opportunistic infections are life-threatening conditions in immunocompromised patients including those with primary immunodeficiency. We describe a case of X-linked chronic granulomatous disease presenting with mesenteric abscess caused by a coinfection with Bacillus Calmette-Guérin (BCG) and Phialemonium sp. The patient received BCG vaccination at 5 months old. He developed left axillary BCG lymphadenitis at 17 months of age, and 3 months later mesenteric abscess occurred. Concomitant use of rifampicin and itraconazole at 17 months of age might have reduced serum itraconazole concentrations and led to superinfection with Phialemonium sp. in our patient, which was susceptible to itraconazole and voriconazole in vitro. The patient was successfully treated with a combination of isoniazid, rifampicin, streptomycin, ciprofloxacin, prednisolone, interferon-γ, and an increased dose of itraconazole, followed by hematopoietic stem cell transplantation. Our results suggest that clinician need to be aware of rifampicin drug interactions, and that precise detection and identification of pathogens are essential to appropriate treatment.

Verification of Resectability Status for Pancreatic Cancer: Radiological and Pathological Analysis of Patients Undergoing Pancreatoduodenectomy With Combined Resection of the Superior Mesenteric Artery.

OBJECTIVES: Resectability status is considered an important indicator for progression of pancreatic cancer. We verified the superior mesenteric artery (SMA) factors of resectability status by radiological and pathological analysis in patients who underwent pancreatoduodenectomy with combined resection of the SMA. METHODS: We enrolled 22 patients who underwent pancreatoduodenectomy with combined resection of the SMA. Patients were divided into 3 groups according to the contact angle between the tumor and the SMA in preoperative computed tomography images (no contact, R-sma; contact within 180 degrees, BR-sma; contact more than 180 degrees, UR-sma). We pathologically evaluated cancer progression toward the SMA. RESULTS: There were 3 patients with R-sma, 12 with BR-sma, and 7 with UR-sma. The median distance (mm) between the cancer and the SMA was 7.0 with R-sma, 1.0 with BR-sma, and 0 with UR-sma (P = 0.0003). Invasion to the superior mesenteric nerve plexus was positive in none with R-sma, 11 with BR-sma, and 7 with UR-sma (P < 0.0001). Invasion to the SMA was positive in none with R-sma and BR-sma, and 7 with UR-sma (P < 0.0001). CONCLUSIONS: Superior mesenteric artery factors of resectability status are reliable indicator for cancer progression toward the SMA.

Wavy Floating Greater Omentum Findings Are Useful for Differentiating the Etiology of Fetal Ascites.

The greater omentum is an apron-like peritoneal mesothelial sheet that was described by ultrasound as a floating fluid-filled viscus in ascites during the fetal period. To examine the association between the etiology of fetal ascites and ultrasound findings of the greater omentum, a retrospective study was conducted. Ultrasound findings of fetal omentum were defined as follows: (1) a cyst-like shape with a thin membrane observed as wavy in the ascites, (2) beside the stomach and below the liver, and (3) no blood flow noted on color Doppler. Eleven pregnancies had fetal ascites. A fetal greater omentum was confirmed in eight cases in which ascites were caused by non-peritonitis: fetal hydrops (n = 4), congenital cytomegalovirus infection (n = 2), idiopathic chylous ascites (n = 1), and unknown cause (n = 1). Of these eight cases, no abdominal surgical management was required in three live babies. However, a fetal greater omentum was not confirmed in all three cases of meconium peritonitis. It was suggested that the finding of the greater omentum can be an important clue for estimating the pathophysiological etiology of fetal ascites and helping with postnatal management. It should be reasonable to add the finding of the greater omentum to the detailed ultrasound examination checklist.

Effect of Japanese Kampo medicine, eppikajutsuto, in patients with lymphatic malformation: A retrospective observational study.

ABSTRACT: Lymphatic malformations (LMs) are congenital malformations of the lymphatic system that cause considerable cosmetic and functional complications. In this study, we present 8 children with LM who were treated with the Kampo medicine eppikajutsuto (EKJT).Between 2001 and 2020, 8 children (male: 4, female: 4) with LMs who underwent magnetic resonance imaging (MRI) evaluation both before and after treatment or observation were selected for investigating the effect of EKJT. Two patients were observed without any treatment for 24 and 60 months. EKJT was evaluated based on percentage reduction, defined as the percentage of total lesions that decreased in size, confirmed by radiological examination after initiating treatment with EKJT or determined by observation alone. Volumetric analysis of LMs on MRI was performed using the Digital Imaging and Communications in Medicine viewer.Six patients were treated with EKJT. The mean observational period was 13.2 months (range: 6-24 months). The mean reduction in LM volume on MRI was 73.0% in treated patients and -66.3% in observed patients. Two of the 6 lesions exhibited complete reduction, 2 exhibited marked (>90%) reduction, 1 exhibited moderate reduction, and 1 exhibited a small response. The treatment was well-tolerated, with no severe adverse events.This preliminary study demonstrated the beneficial effects of EKJT. Prospective evaluations of this promising therapeutic modality are warranted based on the results of this study.

Study protocol for daiobotanpito combined with antibiotic therapy for treatment of acute diverticulitis: a study protocol for a randomized controlled trial.

BACKGROUND: Colonic diverticular disease has been increasing in prevalence due to the rapidly aging global population, but standard treatment has not changed dramatically in recent years. Daiobotanpito (DBT; Da Huang Mu Dan Tang in Chinese) has been used in medical treatment of acute abdominal abscesses, such as appendicitis or diverticulitis in traditional Japanese (Kampo) medicine for many years, based on more than 3000 years of experience. Prior to this study, a retrospective open-label trial was conducted to compare patients with acute diverticulitis who received oral DBT combined with intravenous antibiotics with those who received intravenous antibiotic alone; it showed a positive effect of DBT on acute diverticulitis. We aim to investigate whether moderate to severe acute diverticulitis shows greater improvement with intravenous antibiotics plus orally administered DBT compared with intravenous antibiotics plus placebo. METHODS: This is a two-group, randomized, double-blind, placebo-controlled, multi-center trial, which is designed to evaluate the efficacy and safety of DBT in patients with moderate to severe diverticulitis treated with intravenous antibiotics. Eligible participants will be randomized to either a treatment group receiving a 10-day oral DBT regimen plus conventional therapy or a control group receiving a 10-day placebo regimen plus conventional therapy. The primary outcome will be success in treating diverticulitis: the success rate will be defined as elimination of abdominal pain within 4 days in all patients, and in patients with fever (body temperature ≧ 37.5 °C) on inclusion into this study, fever relief with reduction in body temperature to < 37.5 °C within 3 days. Secondary endpoints will include the number of hospitalization days, changes in inflammatory response (C-reactive protein (CRP), white blood cell (WBC) and neutrophil counts), fever type, number of days before beginning food intake, recurrence rate (observation for 1 year after registration), and adverse event expression rate. Assessments will be performed at baseline and on the day of discharge. The recurrence rate will be recorded at 1 year after registration. DISCUSSION: This study is expected to provide evidence to support the clinical benefits of DBT in the treatment of acute diverticulitis. It may also provide evidence on the efficacy and safety of DBT in the recurrence of acute diverticulitis. TRIAL REGISTRATION: UMIN-CTR: UMIN000027381. Registered on 27 April 2017. https://upload.umin.ac.jp/cgi-bin/ctr/ctr_view_reg.cgi?recptno=R000031377, and changed to jRCTs041180063, registered on 30 July 2019; as a result of the revision of the domestic law in 2018 in Japan.

Pretreatment with a Phosphodiesterase-3 Inhibitor, Milrinone, Reduces Hepatic Ischemia-Reperfusion Injury, Minimizing Pericentral Zone-Based Liver and Small Intestinal Injury in Rats.

BACKGROUND Severe pericentral zone (zone 3)-based liver injury (LI) may become intractable, with allograft dysfunction after liver transplantation. The phosphodiesterase-3 inhibitor, milrinone, has been reported to attenuate hepatic ischemia-reperfusion injury (IRI). This study clarified how hepatic IRI involved zone 3-based LI, in which zone milrinone was effective, and whether milrinone could improve small intestinal injury (SII) with hepatic IRI. MATERIAL AND METHODS Rats were divided into sham, ischemia-reperfusion (IR), or IR+milrinone groups (n=13 per group). Milrinone was administered intraportally via intrasplenic injection, and whole hepatic ischemia was induced for 30 min. Five hours after reperfusion, serum chemistry and histopathological findings were compared. Expression of CD34 for the detection of altered sinusoidal endothelium as sinusoidal capillarization and cleaved caspase-3 as an apoptosis marker were analyzed via immunohistochemistry. Survival rates were examined after 45 min of whole hepatic ischemia. RESULTS Serum aspartate aminotransferase and direct bilirubin levels were significantly decreased in the IR+milrinone group compared with those of the IR group. The degree of LI, sinusoidal capillarization and apoptosis at zone 3 in the IR group was significantly increased compared with those at the periportal zone (zone 1). These findings at zone 3 in the IR group were improved in the IR+milrinone group. SII with villus congestion and apoptosis in the IR group was significantly attenuated in the IR+milrinone group. The 7-day survival rate was significantly elevated in the IR+milrinone group as compared with that of the IR group. CONCLUSIONS A hepatic IRI model caused zone 3-based LI and SII, which were attenuated by intraportal administration of milrinone.

Interactions Between Neutrophils and Platelets in the Progression of Acute Pancreatitis.

OBJECTIVE: Severe acute pancreatitis is a serious disease, but its detailed mechanism has not yet been elucidated. We aimed to clarify the interaction between neutrophils and platelets in the pathogenesis of acute pancreatitis. METHODS: We induced acute pancreatitis in rats by injection of sodium taurocholate into the biliopancreatic duct and killed them over time. We observed the histological changes in pancreatic tissue with special attention to the dynamics of neutrophils and platelets. We also measured the concentrations of neutrophil- and platelet-derived factors in pancreatic tissue and blood samples. RESULTS: Neutrophils and platelets in the pancreatic tissue showed a similar pattern of migration. They initially spread in the interlobular connective tissue and finally into the lobules. The concentration of myeloperoxidase gradually increased in the inflamed pancreas until 24 hours and the concentration of thromboxane B2, plasminogen activator inhibitor 1, and CD41 also increased with time. Finally, the concentration of serum myeloperoxidase, citrullinated histone H3, and high-mobility group box 1 increased over time. CONCLUSIONS: The interaction between neutrophils and platelets in pancreatic tissue plays an important role in the mechanism of advancing severity in acute pancreatitis. Circulating damage-associated molecular patterns induced by excessive local inflammation may lead to other organ injuries.

Impact of Extravasated Platelet Activation and Podoplanin-positive Cancer-associated Fibroblasts in Pancreatic Cancer Stroma.

BACKGROUND/AIM: The aim of the study was to evaluate the status of extravasated platelet activation (EPA) surrounding podoplanin (PDPN)-positive cancer-associated fibroblasts (CAFs) in pancreatic cancer stroma by neoadjuvant chemotherapy. PATIENTS AND METHODS: A total of 74 patients were enrolled in this study. We investigated CD42b and PDPN expression in the groups of untreated, gemcitabine (GEM) alone, GEM plus S-1 (GS) and GEM plus nab-paclitaxel (GnP). RESULTS: CD42b expression in surrounding CAFs was observed in 58% patients. CD42b expression was significantly correlated with PDPN expression. CD42b-positive cases were significantly lower in the group treated with GnP than in the untreated group and groups treated with GEM alone or GS. PDPN expression was reduced in the GnP group, as revealed by markedly disorganized collagen and a low density of PDPN-positive fibroblasts. There was a significantly lower CD42b expression and fewer PDPN-positive fibroblasts in the GnP group than in untreated, GEM alone, and GS groups, but there was no significant difference between the latter three groups. CONCLUSION: There is a significant association between EPA and PDPN-positive CAFs in pancreatic cancer stroma. Our data suggest that the GnP regimen decreases EPA through PDPN-positive CAF depletion.