Fecalith in the Proximal Area of the Appendix is a Predictor of Failure of Nonoperative Treatment for Complicated Appendicitis in Adults.

BACKGROUND: The management of complicated appendicitis remains controversial, since this disease has various clinical presentations and is associated with high rates of adverse events. Although initial nonoperative treatment is generally employed for complicated appendicitis, its clinical presentation and the predictors of nonoperative treatment failure are unclear. METHODS: Patients diagnosed with complicated appendicitis in our hospital between April 2015 and March 2020 were enrolled. In total, 113 patients were classified into three categories: emergency appendectomy, failure of nonoperative treatment and successful nonoperative treatment. The primary outcome was the rate of failure of nonoperative treatment, as assessed by logistic regression analysis. The secondary outcomes were the operative procedures and postoperative courses of the three groups. RESULTS: Of 113 patients, 45 (40%) underwent emergency appendectomy, 25 (22%) failed nonoperative treatment, and 43 (38%) had successful nonoperative treatment. Among these successful cases, 38 patients (88%) underwent interval appendectomy. In multivariate analyses, the presence of a fecalith in the proximal area of the appendix was an independent risk factor for failure of nonoperative treatment (odds ratio, 20.5; 95% confidence interval, 4.37-95.7, P < 0.001). Postoperative outcomes were more unfavorable in cases of failed nonoperative treatment than in cases of emergency and interval appendectomy. CONCLUSIONS: The presence of a fecalith in the proximal area of the appendix is an independent predictor for failure of nonoperative treatment for complicated appendicitis in adults. Patients with this risk factor should be considered candidates for surgical treatment.

Assembly and Function of a Bioengineered Human Liver for Transplantation Generated Solely from Induced Pluripotent Stem Cells.

The availability of an autologous transplantable auxiliary liver would dramatically affect the treatment of liver disease. Assembly and function in vivo of a bioengineered human liver derived from induced pluripotent stem cells (iPSCs) has not been previously described. By improving methods for liver decellularization, recellularization, and differentiation of different liver cellular lineages of human iPSCs in an organ-like environment, we generated functional engineered human mini livers and performed transplantation in a rat model. Whereas previous studies recellularized liver scaffolds largely with rodent hepatocytes, we repopulated not only the parenchyma with human iPSC-hepatocytes but also the vascular system with human iPS-endothelial cells, and the bile duct network with human iPSC-biliary epithelial cells. The regenerated human iPSC-derived mini liver containing multiple cell types was tested in vivo and remained functional for 4 days after auxiliary liver transplantation in immunocompromised, engineered (IL2rg-/-) rats.

Generation of Human Fatty Livers Using Custom-Engineered Induced Pluripotent Stem Cells with Modifiable SIRT1 Metabolism.

The mechanisms by which steatosis of the liver progresses to non-alcoholic steatohepatitis and end-stage liver disease remain elusive. Metabolic derangements in hepatocytes controlled by SIRT1 play a role in the development of fatty liver in inbred animals. The ability to perform similar studies using human tissue has been limited by the genetic variability in man. We generated human induced pluripotent stem cells (iPSCs) with controllable expression of SIRT1. By differentiating edited iPSCs into hepatocytes and knocking down SIRT1, we found increased fatty acid biosynthesis that exacerbates fat accumulation. To model human fatty livers, we repopulated decellularized rat livers with human mesenchymal cells, fibroblasts, macrophages, and human SIRT1 knockdown iPSC-derived hepatocytes and found that the human iPSC-derived liver tissue developed macrosteatosis, acquired proinflammatory phenotype, and shared a similar lipid and metabolic profiling to human fatty livers. Biofabrication of genetically edited human liver tissue may become an important tool for investigating human liver biology and disease.

Laparoscopic total gastrectomy for remnant gastric cancer: A single-institution experience.

INTRODUCTION: The incidence of remnant gastric cancer is increasing because of past use of subtotal gastrectomy to treat peptic ulcer and increased survival rates after radical gastrectomy for gastric cancer. The feasibility and advantages of laparoscopic total gastrectomy (LTG) for remnant gastric cancer remain unclear. Therefore, we aimed to investigate the safety, feasibility, and clinical short-term outcomes of LTG for remnant gastric cancer. METHODS: Patients who underwent completion total gastrectomy for remnant gastric cancer between April 2007 and October 2017 were divided into two groups: the open total gastrectomy (OTG) group and the LTG group. Clinicopathological data and short-term outcomes were analyzed. RESULTS: A total of 31 remnant gastrectomies (23 OTG, 8 LTG) were performed. Blood loss was significantly lower in the LTG group than in the OTG group (135.5 vs 568.3 mL, P = 0.013). However, there was no significant difference in the operation time, days to food intake, or length of hospital stay between the two groups. Additionally, there was no significant difference in the postoperative complications, number of retrieved lymph nodes, or pathological findings. Two LTG patients (25.0%) required conversion to open surgery. There was no mortality in either group. CONCLUSIONS: LTG for remnant gastric cancer can be a safe treatment option and may have an advantage of less blood loss than OTG.

Regeneration and Cell Recruitment in an Improved Heterotopic Auxiliary Partial Liver Transplantation Model in the Rat.

BACKGROUND: Auxiliary partial liver transplantation (APLT) in humans is a therapeutic modality used especially to treat liver failure in children or congenital metabolic disease. Animal models of APLT have helped to explore therapeutic options. Though many groups have suggested improvements, standardizing the surgical procedure has been challenging. Additionally, the question of whether graft livers are reconstituted by recipient-derived cells after transplantation has been controversial. The aim of this study was to improve experimental APLT in rats and to assess cell recruitment in the liver grafts. METHODS: To inhibit recipient liver regeneration and to promote graft regeneration, we treated recipients with retrorsine and added arterial anastomosis. Using green fluorescence protein transgenic rats as recipients, we examined liver resident cell recruitment within graft livers by immunofluorescence costaining. RESULTS: In the improved APLT model, we achieved well-regenerated grafts that could maintain regeneration for at least 4 weeks. Regarding the cell recruitment, there was no evidence of recipient-derived hepatocyte, cholangiocyte, or hepatic stellate cell recruitment into the graft. Macrophages/monocytes, however, were consistently recruited into the graft and increased over time, which might be related to inflammatory responses. Very few endothelial cells showed colocalization of markers. CONCLUSIONS: We have successfully established an improved rat APLT model with arterial anastomosis as a standard technique. Using this model, we have characterized cell recruitment into the regenerating grafts.

Postoperative Delirium in Patients after Pancreaticoduodenectomy.

BACKGROUND/AIMS: Postoperative delirium (POD) is one of the most common complications after various types of surgery. The aim of this study was to investigate the incidence and risk factors for delirium after pancreaticoduodenectomy (PD). METHODS: This was a retrospective study of 146 consecutive patients who underwent PD between April 2007 and June 2015 at Saiseikai Yokohamashi Tobu Hospital. RESULTS: Twenty-nine patients (19.9%) were diagnosed with delirium. Patients who were >70 years were divided into a delirium group (n = 24) and a non-delirium group (n = 41). Multivariate analysis showed that only the Charlson Age Comorbidity Index (CACI) (OR 1.8; 95% CI 1.067-3.036; p = 0.028) was an independent risk factor of delirium for patients >70 years. The receiver operating characteristic curve revealed an optimal cutoff value of 4.5 for the CACI score in all patients (sensitivity 62.1%; specificity 82.9%; area under the curve 0.782). The higher CACI score (≥5) is significantly different from the lower CACI score (p < 0.0001) with respect to POD occurrence. CONCLUSIONS: The CACI, especially in elderly patients, was associated with the incidence of POD. Therefore, utilizing this validated and practical tool preoperatively might be useful for POD.

[Local Control of Advanced Breast Cancer with Mohs Paste and Systemic Therapy].

Unresectable locally advanced breast cancer results in a decline in patient quality of life because of the presence of bleeding, exudates, and strong odor. The clinical application of supportive care using Mohs paste for improving quality of life has become widespread. We report 2 cases of locally advanced breast cancer treated with systemic therapy and chemosurgery. Case 1 was a Japanese woman in her fifties who had a locally advanced left breast cancer. She had continuous bleeding and exudates, and received Mohs chemosurgery and endocrine therapy. One month later, the surface healed and dried up. The bleeding, exudates, and strong odor disappeared almost completely. Case 2 was a Japanese woman in her forties who had a locally advanced left breast cancer with massive exudates and oozing blood. She underwent Mohs chemosurgery 20 times, but the exudates and bleeding were not controlled. According to pathological findings, we confirmed her breast cancer to be of the triple negative subtype. After 2 courses of therapy with 5-fluorouracil, epirubicin, and cyclophosphamide, the tumor immediately decreased in diameter by 65%. The bleeding, exudates, and strong odor disappeared. Although Mohs chemosurgery is useful for local control of locally advanced breast cancer, this alone is insufficient to treat the disease. Early introduction of systemic therapy is considered essential in breast cancer treatment.

Resetting the transcription factor network reverses terminal chronic hepatic failure.

The cause of organ failure is enigmatic for many degenerative diseases, including end-stage liver disease. Here, using a CCl4-induced rat model of irreversible and fatal hepatic failure, which also exhibits terminal changes in the extracellular matrix, we demonstrated that chronic injury stably reprograms the critical balance of transcription factors and that diseased and dedifferentiated cells can be returned to normal function by re-expression of critical transcription factors, a process similar to the type of reprogramming that induces somatic cells to become pluripotent or to change their cell lineage. Forced re-expression of the transcription factor HNF4α induced expression of the other hepatocyte-expressed transcription factors; restored functionality in terminally diseased hepatocytes isolated from CCl4-treated rats; and rapidly reversed fatal liver failure in CCl4-treated animals by restoring diseased hepatocytes rather than replacing them with new hepatocytes or stem cells. Together, the results of our study indicate that disruption of the transcription factor network and cellular dedifferentiation likely mediate terminal liver failure and suggest reinstatement of this network has therapeutic potential for correcting organ failure without cell replacement.

A switch in the source of ATP production and a loss in capacity to perform glycolysis are hallmarks of hepatocyte failure in advance liver disease.

BACKGROUND & AIMS: The cause of hepatic failure in the terminal stages of chronic injury is unknown. Cellular metabolic adaptations in response to the microenvironment have been implicated in cellular breakdown. METHODS: To address the role of energy metabolism in this process we studied mitochondrial number, respiration, and functional reserve, as well as cellular adenosine-5'-triphosphate (ATP) production, glycolytic flux, and expression of glycolysis related genes in isolated hepatocytes from early and terminal stages of cirrhosis using a model that produces hepatic failure from irreversible cirrhosis in rats. To study the clinical relevance of energy metabolism in terminal stages of chronic liver failure, we analyzed glycolysis and energy metabolism related gene expression in liver tissue from patients at different stages of chronic liver failure according to Child-Pugh classification. Additionally, to determine whether the expression of these genes in early-stage cirrhosis (Child-Pugh Class A) is related to patient outcome, we performed network analysis of publicly available microarray data obtained from biopsies of 216 patients with hepatitis C-related Child-Pugh A cirrhosis who were prospectively followed up for a median of 10years. RESULTS: In the early phase of cirrhosis, mitochondrial function and ATP generation are maintained by increasing energy production from glycolytic flux as production from oxidative phosphorylation falls. At the terminal stage of hepatic injury, mitochondria respiration and ATP production are significantly compromised, as the hepatocytes are unable to sustain the increased demand for high levels of ATP generation from glycolysis. This impairment corresponds to a decrease in glucose-6-phosphatase catalytic subunit and phosphoglucomutase 1. Similar decreased gene expression was observed in liver tissue from patients at different stages of chronic liver injury. Further, unbiased network analysis of microarray data revealed that expression of these genes was down regulated in the group of patients with poor outcome. CONCLUSIONS: An adaptive metabolic shift, from generating energy predominantly from oxidative phosphorylation to glycolysis, allows maintenance of energy homeostasis during early stages of liver injury, but leads to hepatocyte dysfunction during terminal stages of chronic liver disease because hepatocytes are unable to sustain high levels of energy production from glycolysis.

Assembly of human organs from stem cells to study liver disease.

Recently, significant developments in the field of liver tissue engineering have raised new possibilities for the study of complex physiological and pathophysiological processes in vitro, as well as the potential to assemble entire organs for transplantation. Human-induced pluripotent stem cells have been differentiated into relatively functional populations of hepatic cells, and novel techniques to generate whole organ acellular three-dimensional scaffolds have been developed. In this review, we highlight the most recent advances in organ assembly regarding the development of liver tissue in vitro. We emphasize applications that involve multiple types of cells with a biomimetic spatial organization for which three-dimensional configurations could be used for drug development or to explain mechanisms of disease. We also discuss applications of liver organotypic surrogates and the challenges of translating the highly promising new field of tissue engineering into a proven platform for predicting drug metabolism and toxicity.

[Advanced gallbladder cancer that showed complete response to gemcitabine plus S-1 chemotherapy].

A 57-year-old man with advanced gallbladder cancer and accompanying hepatic, colonic and duodenal invasion and para-aortic lymph node metastasis was referred to our hospital. Gemcitabine plus S-1 administration was chosen. Gemcitabine was administered intravenously at a dose of 1000 mg/m(2) on days 1 and 15, and repeated every 4 weeks. S-1 was administered orally at a dose of 40 mg/m(2) b.i.d. on days 1-14. Chemotherapy was effective for the primary gallbladder tumor and lymph node metastasis. The primary tumor and metastatic lymph nodes were shown to have disappeared by a FDG-PET CT study after 10 courses of chemotherapy. Informed consent was obtained prior to performing surgery of the primary lesion. Pathological examination showed fibrosis and a small focus of residual cancer in the resected gallbladder. Complete resection was achieved as all the margins were negative. The findings suggest that gemcitabine plus S-1 treatment may be effective against advanced gallbladder cancer.

[Pathological complete response in advanced gastric carcinoma by S-1/CDDP combination chemotherapy].

A59 -year-old woman was referred to our hospital for a close examination and treatment of an advanced gastric carcinoma. A physical examination and CT scan showed that the right cervical and axillar lymph nodes were swelling, and a histopathological examination of the axillar lymph node revealed metastatic growth of the gastric carcinoma (Stage IV). Then, we started S-1/CDDP combination chemotherapy. S-1 (80 mg/m2/day)was orally administered for 3 weeks followed by 2 weeks of rest, and CDDP (60 mg/m2) was administered by drip on day 8. Since the distant metastases were greatly reduced after 6 courses of combination therapy, a distal gastrectomy with lymph nodes dissection (D2) was performed. Histopathological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. The clinical course after the operation went well without any complications, and the patient is alive with no evidence of recurrence 1 year after surgery. S-1/CDDP combination chemotherapy appears to be one of the effective treatments for advanced gastric carcinoma.

Phosphorescence-assisted microvascular O(2) measurements reveal alterations of oxygen demand in human metastatic colon cancer in the liver of superimmunodeficient NOG mice.

We aimed to examine metabolism of human cancer in vivo and utilized superimmunodeficient NOG mice as an experimental model of hepatic metastasis, where human colon cancer cell line HCT116 transfected with Venus, the mutant GFP was injected intrasplenically. The mice were pretreated with Pd-porphyrin to quantify local O(2) tension through intravital phosphorescence assay. In this model, a majority of metastatic foci occurred in periportal regions but not in central regions. At 1 week after the transplantation, a PO(2) drop in periportal regions was minimal without any notable decrease in microvascular blood flow. Under these conditions, there was a negative correlation between the size of metastatic foci and the lobular O(2) consumption, suggesting that the tumor O(2) consumption is smaller than that in the residual liver. At 2 weeks, portal PO(2) was significantly smaller than controls, while the central PO(2) was not comparably decreased, indicating that metastatic foci increased the O(2) consumption, while the residual liver decreased it. These results suggest metastatic tumors derived from human colon cancer exhibit notable aerobic metabolism during their developmental process, compromising respiration of the rest of the tissue regenerated during tumor development.

Pseudoaneurysm of the cystic artery secondary to cholecystitis as a cause of hemobilia: report of a case.

Spontaneous intracholecystic bleeding is very rare. We report herein a very rare case of a pseudoaneurysm of the cystic artery due to acute cholecystitis. A 58-year-old man presented at the emergency department complaining of colicky pain in the right upper quadrant. Dynamic magnetic resonance imaging demonstrated an early-enhanced pooling of contrast material (suggestive of a pseudoaneurysm of the cystic artery) inside the neck of the gallbladder. After the proximal control of the hepatic artery, the patient underwent a cholecystectomy and a ligation of the cystic artery. The resected specimen of the gallbladder showed evidence of a massive intracholecystic hematoma. Proximal to the impacted gallstone in the neck, a 2-cm diameter saccular-type pseudoaneurysm was identified. Although a pseudoaneurysm of the cystic artery is very rare, it should be included in the differential diagnosis of hemobilia. Once the pseudoaneurysm is confirmed, its embolization before a cholecystectomy (which can be attempted laparoscopically) may be useful to ensure the safety of the patient.