Therapeutic Efficacy and Adverse Events of Tacrolimus in Patients with Crohn's Disease: Systematic Review and Meta-Analysis.

BACKGROUND: Only a few randomized controlled trials (RCTs) and some uncontrolled trials have reported the efficacy and adverse events (AEs) of tacrolimus (Tac) in patients with refractory Crohn's disease (CD). The aim of this study was to undertake a systematic review and meta-analysis of the therapeutic efficacy and AEs of Tac in patients with CD. METHODS: We investigated studies reporting the therapeutic efficacy of Tac in patients with CD from 1950 until December 2017. Study subjects were categorized into three groups: systemic administration of Tac for patients with luminal CD (Group 1); systemic administration of Tac for patients with perianal CD (Group 2); and topical administration of Tac for patients with localized CD (Group 3). The primary endpoint of this study was the remission rate. Secondary endpoints were partial response rate, factors related to remission, and the incidence of AEs. RESULTS: The remission rate of Group 1, 2, and 3 was 37.1, 32.0, and 22.7%, respectively. The partial response rate of those was 42.3, 42.9, and 44.3%, respectively. In addition, the incidence of AEs of those was 50.9, 65.5, and 40.0%, respectively. No life-threatening AEs were observed in any study. CONCLUSION: This systematic review and meta-analysis demonstrated that Tac therapy was effective for subpopulation of CD patients and that the incidence of AEs was tolerable. Therefore, Tac therapy should be considered an option for patients with CD. However, there have been few well-designed RCTs on this subject and further studies are required.

Systemic amyloidosis with gastrointestinal involvement: Diagnosis from endoscopic and histological views.

Amyloid tends to deposit in the gastrointestinal tract, which, being easily accessible, is often the target organ for a pathological diagnostic examination. Although a mucosal biopsy is necessary for a definitive diagnosis and several studies have reported positive results for each possible biopsy site, there remain many unclear features in various aspects. This review focuses on the current literature to determine a better understanding of the diagnosis from endoscopic and histological views in patients with systemic amyloidosis with gastrointestinal involvement. A literature search was performed using PubMed to identify relevant studies; linked references were also reviewed. Endoscopic findings vary based on the organ and the depositing amyloids. A fine granular appearance or polypoid protrusions are likely to occur in the duodenum. AL, Aß2M, and ATTR amyloids are likely to deposit submucosally, while AA amyloid is easily deposited in the superficial layer of the mucous membrane. Furthermore, it is necessary to consider the collection of biopsy specimens from the duodenum, which has high positive biopsy rates. However, the difference in the positive biopsy rates depends on whether endoscopic findings are available or whether the appropriate number has not been fully elucidated. A duodenal biopsy is strongly recommended to confirm the deposition of amyloid in patients with systemic amyloidosis having gastrointestinal involvement. Because amyloidosis is a disease with a poor prognosis, early diagnosis and treatment are required; gastroenterologists and endoscopists play important roles.

Osteopontin attenuates acute gastrointestinal graft-versus-host disease by preventing apoptosis of intestinal epithelial cells.

BACKGROUND AND AIMS: Acute graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic stem cell transplantation, which often targets gastrointestinal (GI) tract. Osteopontin (OPN) plays an important physiological role in the efficient development of Th1 immune responses and cell survival by inhibiting apoptosis. The role of OPN in acute GI-GVHD is poorly understood. In the present study, we investigated the role of OPN in donor T cells in the pathogenicity of acute GI-GVHD. METHODS: OPN knockout (KO) mice and C57BL/6 (B6) mice were used as donors, and (C57BL/6 × DBA/2) F1 (BDF1) mice were used as allograft recipients. Mice with acute GI-GVHD were divided into three groups: the control group (BDF1→BDF1), B6 group (B6→BDF1), and OPN-KO group (OPN-KO→BDF1). Bone marrow cells and spleen cells from donors were transplanted to lethally irradiated recipients. Clinical GVHD scores were assessed daily. Recipients were euthanized on day 7 after transplantation, and colons and small intestines were collected for various analyses. RESULTS: The clinical GVHD score in the OPN-KO group was significantly increased compared with the B6 and control groups. We observed a difference in the severity of colonic GVHD between the OPN-KO group and B6 group, but not small intestinal-GVHD between these groups. Interferon-γ, Tumor necrosis factor-α, Interleukin-17A, and Interleukin-18 gene expression in the OPN-KO group was differed between the colon and small intestine. Flow cytometric analysis revealed that the fluorescence intensity of splenic and colonic CD8 T cells expressing Fas Ligand was increased in the OPN-KO group compared with the B6 group. CONCLUSION: We demonstrated that the importance of OPN in T cells in the onset of acute GI-GVHD involves regulating apoptosis of the intestinal cell via the Fas-Fas Ligand pathway.

The Phagocytic Function of Macrophage-Enforcing Innate Immunity and Tissue Homeostasis.

Macrophages are effector cells of the innate immune system that phagocytose bacteria and secrete both pro-inflammatory and antimicrobial mediators. In addition, macrophages play an important role in eliminating diseased and damaged cells through their programmed cell death. Generally, macrophages ingest and degrade dead cells, debris, tumor cells, and foreign materials. They promote homeostasis by responding to internal and external changes within the body, not only as phagocytes, but also through trophic, regulatory, and repair functions. Recent studies demonstrated that macrophages differentiate from hematopoietic stem cell-derived monocytes and embryonic yolk sac macrophages. The latter mainly give rise to tissue macrophages. Macrophages exist in all vertebrate tissues and have dual functions in host protection and tissue injury, which are maintained at a fine balance. Tissue macrophages have heterogeneous phenotypes in different tissue environments. In this review, we focused on the phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis for a better understanding of the role of tissue macrophages in several pathological conditions.

Is Osteopontin a Friend or Foe of Cell Apoptosis in Inflammatory Gastrointestinal and Liver Diseases?

Osteopontin (OPN) is involved in a variety of biological processes, including bone remodeling, innate immunity, acute and chronic inflammation, and cancer. The expression of OPN occurs in various tissues and cells, including intestinal epithelial cells and immune cells such as macrophages, dendritic cells, and T lymphocytes. OPN plays an important role in the efficient development of T helper 1 immune responses and cell survival by inhibiting apoptosis. The association of OPN with apoptosis has been investigated. In this review, we described the role of OPN in inflammatory gastrointestinal and liver diseases, focusing on the association of OPN with apoptosis. OPN changes its association with apoptosis depending on the type of disease and the phase of disease activity, acting as a promoter or a suppressor of inflammation and inflammatory carcinogenesis. It is essential that the roles of OPN in those diseases are elucidated, and treatments based on its mechanism are developed.

5-Aminosalicylic acid.

Despite the emergence of new biological therapies that aim for mucosal healing as a new therapeutic target, the importance of 5-ASA formulations in the standard treatment for inflammatory bowel diseases, particularly ulcerative colitis, remains unchanged. With a growing number of patients suffering from inflammatory bowel diseases in Japan, general physicians are also increasingly prescribing 5-ASA formulations. In order to obtain the maximum efficacy of 5-ASA formulations when treating inflammatory bowel diseases, it is essential that the dosage and administration are appropriate.

A case of adenosquamous carcinoma of the lower bile duct diagnosed preoperatively via transpapillary biopsy.

A 78-year-old man presented to our hospital with fever and brownish urine. Upon thorough examination, a diagnosis of obstructive jaundice and acute cholangitis associated with a lower bile duct tumor was made. Endoscopic retrograde cholangiopancreatography revealed entire circumferential stenosis of the lower bile duct. Examination of a transpapillary biopsy specimen of the lesion suggested adenosquamous carcinoma. The patient underwent subtotal stomach-preserving pancreaticoduodenectomy. Histopathological examination revealed adenocarcinoma of the lower bile duct and squamous cell carcinoma components;a case of adenosquamous carcinoma was accordingly diagnosed. The lower bile duct tumor directly extended into the pancreatic parenchyma for approximately 1mm. We performed radical surgery and administered adjuvant chemotherapy with gemcitabine because of advanced neural invasion after consulting with the patient. There was no sign of recurrence 46 months after surgery. As adenosquamous carcinoma of the extrahepatic bile duct is rare, it is difficult to preoperatively diagnose the condition. Only a few cases have been reported till date.

[mFOLFOX6 chemotherapy enabling curative resection in a patient with locally advanced duodenal adenocarcinoma and lymph node metastases].

A 65-year-old man was referred to our hospital with a primary complaint of unintentional weight loss. Upper gastrointestinal endoscopy showed a large duodenal tumor, and computed tomography (CT) showed tumor invasion of the pancreatic head, associated with lymph node swelling around the tumor and abdominal aorta. After 4 courses of chemotherapy with 5-fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6), follow-up upper gastrointestinal endoscopy and biopsy showed no evidence of a duodenal tumor. However, follow-up CT showed persistent lymph node swelling near the superior mesenteric artery. The patient therefore underwent pancreaticoduodenectomy with curative intent. At 18 months after the surgery, there were no findings suggestive of tumor recurrence.

[Four cases of 5-fluorouracil-related hyperammonemia in patients with large intestinal cancer and multiple liver metastases, including a case of hyperammonemia treated using hemodialysis].

Systemic chemotherapy based on 5-fluorouracil (5-FU) is a standard treatment for unresectable or recurrent large intestinal cancer. Although hyperammonemia is a known side effect of 5-FU that can cause serious pathological conditions, only a few cases have been reported. We describe 4 cases of 5-FU-related hyperammonemia with impairment of consciousness in patients who received 5-FU chemotherapy for large intestinal cancer with multiple liver metastases. Hemodialysis was effective in 1 severe case. There have been no detailed reports on the use of hemodialysis for hyperammonemia caused by 5-FU. Renal dysfunction is considered to be a risk factor for hyperammonemia caused by 5-FU and it is necessary to pay particular attention in patients with renal dysfunction who receive chemotherapy with 5-FU. Here we summarize our cases together with 16 previously reported cases of hyperammonemia caused by 5-FU in Japan.

[A case of hypercalcemia associated with parathyroid hormone-related protein produced by the recurrence of B-cell lymphoma of the pancreas].

An 87-year-old woman was diagnosed with primary diffuse large B-cell lymphoma of the pancreas by endoscopic ultrasonography-guided fine needle aspiration. Complete remission was achieved after treatment with six courses of R-CHOP chemotherapy. However, two and a half years later, she was readmitted because of weakness during walking. At this time, laboratory tests revealed hypercalcemia associated with high plasma levels of parathyroid hormone-related protein (PTHrP), but bone lesions were not detected. Although computed tomography only revealed splenomegaly, we suspected a recurrence of her malignant lymphoma because she also had marked elevation of soluble interleukin-2 receptor and lactate dehydrogenase levels. Bone marrow examination revealed the involvement of Burkitt's lymphoma cells with malignant transformation. Immunohistochemical analysis confirmed that hypercalcemia was caused by a paraneoplastic syndrome related to PTHrP-producing B-cell lymphoma cells. Unfortunately, the patient's general condition rapidly deteriorated, and she died soon after admission. Our case is unusual because of the presentation of bone marrow relapse of malignant lymphoma.

A case of carcinosarcoma of the duodenum.

A 59-year-old man was admitted to the hospital because of upper abdominal pain. Endoscopic examination and computed tomography showed a polypoid tumor located in the 2nd portion of the duodenum with invasion to the pancreas head, and biopsy findings suggested a gastrointestinal stromal tumor. He underwent a pancreaticoduodenectomy, and the tumor, which measured 6.5×6.5 cm, was resected. Histologically, the tumor contained two divergent components: differentiated tubular adenocarcinoma and sarcomatoid tissue composed of spindle tumor cells. The tumor directly extended to the pancreas head and metastasized to multiple lymph nodes. The adenocarcinoma cells were positive for AE1/3 and cytokeratin 7 and negative for vimentin. In contrast, the sarcomatoid tissue was negative for epithelial markers and positive for vimentin. The tumor was finally diagnosed as duodenal carcinosarcoma. Duodenal carcinosarcoma is very rare, and only seven cases have been reported to date.

[A case of a collision tumor comprising mucosa-associated lymphoid tissue lymphoma and early gastric cancer].

A 60-year-old woman underwent upper gastrointestinal endoscopy for an abnormality identified during routine examination. The lower gastric corpus showed a type 0-I elevated lesion with a faded mucosa and an area of converging mucosal folds in contact with the lesion. Biopsy indicated the former to be a high-grade adenoma and the latter to be a mucosa-associated lymphoid tissue (MALT) lymphoma. At the same time, Helicobacter pylori infection was diagnosed. Eradication therapy was administered to manage the MALT lymphoma; this resulted in improvement after 3 months. Endoscopic submucosal dissection was performed for the elevated lesion, and subsequent histopathology showed contact between the MALT lymphoma and gastric cancer. Therefore, the patient was diagnosed with a collision tumor. Concurrent cancers are increasingly reported and should be considered during examination.

Use of Tumguide® in the Insertion of a Nasogastric Tube Into the Stomach of a Patient With Creutzfeldt-Jakob Disease in a Nursing Home: A Case Report.

A 77-year-old woman exhibited a rapid progression of dementia and declining physical function and, over a period of about four months, reached a state of akinetic mutism. A final diagnosis of Creutzfeldt-Jakob disease (CJD) was made. A nasogastric tube was inserted into the stomach, and then it was confirmed on X-ray that the end of the tube was in the correct position. She was discharged to a nursing home, where she received home medical care after discharge. One month after the nasogastric tube insertion, Tumguide® was used to assist in replacing the tube at this home. In home care settings where an X-ray machine may not be available, Tumguide® may assist with nasogastric tube insertion.

Clinical Features of Hypoxemia Due to Infection Under Home-Based Medication During the COVID-19 Pandemic Period.

BACKGROUND: Despite the growing demand for home-based medication during the COVID-19 pandemic period, there remains scarce evidence of hypoxemic infection in home-care settings. In this study, we investigated the clinical features of hypoxemic respiratory failure due to infection during the period under home-based medication (defined as 'home-care-acquired infection'). METHODS: This retrospective observational study enrolled patients with home-care-acquired infection, other than COVID-19, in two home-care clinics in Sapporo, Japan, between April 2020 and May 2021 (the early phase of the COVID-19 pandemic). The participants were divided into two groups according to whether they required additional home oxygen therapy, and were compared to assess the predictors of hypoxemic respiratory failure. Furthermore, the clinical features were compared with those in patients aged >60 years with COVID-19 who were admitted to Toyama University Hospital during the same period. RESULTS: A total of 107 patients with home-care-acquired infections were included in the study (median age, 82 years). Twenty-two patients required home oxygen therapy, and 85 did not. Thirty-day mortality rates were 32% and 8%. Among the patients in the hypoxemia group, none had desired a care-setting transition, following the advanced care planning. Multivariable logistic regression analysis showed that initial antibiotic treatment failure and malignant disease were independently associated with hypoxemic respiratory failure (odds ratio, 7.28 and 7.10; p=0.023 and p<0.005, respectively). In comparison with hypoxemia in the COVID-19 cohort, the lower incidence of febrile co-habitants and earlier onset of hypoxemia were significant in those due to home-care-acquired infection. CONCLUSION: This study demonstrated that hypoxemia due to home-care-acquired infection was characterized by distinct features, possibly different from those due to COVID-19 in the early pandemic period.

HOPS-R01 phase II trial evaluating neoadjuvant S-1 therapy for resectable pancreatic adenocarcinoma.

Although neoadjuvant therapy (Nac) is recommended for high-risk resectable pancreatic cancer (R-PDAC), evidence regarding specific regimes is scarce. This report aimed to investigate the efficacy of S-1 Nac for R-PDAC. In a multicenter phase II trial, we investigated the efficacy of Nac S-1 (an oral fluoropyrimidine agent containing tegafur, gimeracil, and oteracil potassium) in R-PDAC patients. The protocol involved two cycles of preoperative S-1 chemotherapy, followed by surgery, and four cycles of postoperative S-1 chemotherapy. Two-year progression-free survival (PFS) rates were the primary endpoint. Overall survival (OS) rates and median survival time (MST) were secondary endpoints. Forty-nine patients were eligible, and 31 patients underwent resection following Nac, as per protocol (31/49; 63.3%). Per-protocol analysis included data from 31 patients, yielding the 2-year PFS rate of 58.1%, and 2-, 3-, and 5-year OS rates of 96.8%, 54.8%, and 44.0%, respectively. MST was 49.2 months. Intention-to-treat analysis involved 49 patients, yielding the 2-year PFS rate of 40.8%, and the 2-, 3-, and 5-year OS rates of 87.8%, 46.9%, and 33.9%, respectively. MST was 35.5 months. S-1 single regimen might be an option for Nac in R-PDAC; however, the high drop-out rate (36.7%) was a limitation of this study.