Designer umbilical cord-stem cells induce alveolar wall regeneration in pulmonary disease models.

Background: Researchers are focusing on cellular therapy for chronic obstructive pulmonary disease (COPD) using mesenchymal stem cells (MSCs), with human bone marrow-derived MSCs (hBM-MSCs) leading the way. However, BM-MSCs may not be as optimal as therapeutic cells owing to their low growth potential, invasive harvesting, and high expression of aging-related genes with poor differentiation potential. Consequently, umbilical cord-derived MSCs (hUC-MSCs), which have many excellent features as allogeneic heterologous stem cells, have received considerable attention. Allogeneic and heterologous hUC-MSCs appear to be promising owing to their excellent therapeutic properties. However, MSCs cannot remain in the lungs for long periods after intravenous infusion. Objective: To develop designer hUC-MSCs (dUC-MSCs), which are novel therapeutic cells with modified cell-adhesion properties, to aid COPD treatment. Methods: dUC-MSCs were cultured on type-I collagen gels and laminin 411, which are extracellular matrices. Mouse models of elastase-induced COPD were treated with hUC-MSCs. Biochemical analysis of the lungs of treated and control animals was performed. Results: Increased efficiency of vascular induction was found with dUC-MSCs transplanted into COPD mouse models compared with that observed with transplanted hUC-MSCs cultured on plates. The transplanted dUC-MSCs inhibited apoptosis by downregulating pro-inflammatory cytokine production, enhancing adhesion of the extracellular matrix to alveolar tissue via integrin ß1, promoting the polarity of M2 macrophages, and contributing to the repair of collapsed alveolar walls by forming smooth muscle fibers. dUC-MSCs inhibited osteoclastogenesis in COPD-induced osteoporosis. hUC-MSCs are a promising cell source and have many advantages over BM-MSCs and adipose tissue-derived MSCs. Conclusion: We developed novel designer cells that may be involved in anti-inflammatory, homeostatic, injury repair, and disease resistance processes. dUC-MSCs repair and regenerate the alveolar wall by enhancing adhesion to the damaged site. Therefore, they can contribute to the treatment of COPD and systemic diseases such as osteoporosis.

Timing of Mesenchymal Stromal Cell Therapy Defines its Immunosuppressive Effects in a Rat Lung Transplantation Model.

Cell therapy using mesenchymal stromal cells (MSCs) is being studied for its immunosuppressive effects. In organ transplantation, the amount of MSCs that accumulate in transplanted organs and other organs may differ depending on administration timing, which may impact their immunosuppressive effects. In vitro, adipose-derived mesenchymal stem cells (ADMSCs) suppress lymphocyte activation under cell-to-cell contact conditions. However, in vivo, it is controversial whether ADMSCs are more effective in accumulating in transplanted organs or in secondary lymphoid organs. Herein, we aimed to investigate whether the timing of ADMSC administration affects its immunosuppression ability in a rat lung transplantation model. In the transplantation study, rats were intramuscularly administered half the usual dose of tacrolimus (0.5 mg/kg) every 24 h after lung transplantation. ADMSCs (1 × 106) were administered via the jugular vein before (PreTx) or after (PostTx) transplantation. Cell tracking using quantum dots was performed. ADMSCs accumulated predominantly in the lung and liver; fewer ADMSCs were distributed in the grafted lung in the PreTx group than in the PostTx group. The rejection rate was remarkably low in the ADMSC-administered groups, particularly in the PostTx group. Serum tumor necrosis factor-α (TNF-α), interferon-γ, and interleukin (IL)-6 levels showed a greater tendency to decrease in the PreTx group than in the PostTx group. The proportion of regulatory T cells in the grafted lung 10 days after transplantation was higher in the PostTx group than in the PreTx group. PostTx administration suppresses rejection better than PreTx administration, possibly due to regulatory T cell induction by ADMSCs accumulated in the transplanted lungs, suggesting a mechanism different from that in heart or kidney transplantation that PreTx administration is more effective than PostTx administration. These results could help establish cell therapy using MSCs in lung transplantation.

Adipose-Derived Mesenchymal Stem Cells Attenuate Immune Reactions Against Pig Decellularized Bronchi Engrafted into Rat Tracheal Defects.

Decellularized scaffolds are promising biomaterials for tissue and organ reconstruction; however, strategies to effectively suppress the host immune responses toward these implants, particularly those without chemical crosslinking, remain warranted. Administration of mesenchymal stem cells is effective against immune-mediated inflammatory disorders. Herein, we investigated the effect of isogeneic abdominal adipose-derived mesenchymal stem/stromal cells (ADMSCs) on xenogeneic biomaterial-induced immunoreactions. Peripheral bronchi from pigs, decellularized using a detergent enzymatic method, were engrafted onto tracheal defects of Brown Norway (BN) rats. BN rats were implanted with native pig bronchi (Xenograft group), decellularized pig bronchi (Decellularized Xenograft), or Decellularized Xenograft and ADMSCs (Decellularized Xenograft+ADMSC group). In the latter group, ADMSCs were injected intravenously immediately post implantation. Harvested graft implants were assessed histologically and immunohistochemically. We found that acute rejections were milder in the Decellularized Xenograft and Decellularized Xenograft+ADMSC groups than in the Xenograft group. Mild inflammatory cell infiltration and reduced collagen deposition were observed in the Decellularized Xenograft+ADMSC group. Additionally, ADMSC administration decreased CD8+ lymphocyte counts but increased CD163+ cell counts. In the Decellularized Xenograft+ADMSC group, serum levels of vascular endothelial growth factor and IL-10 were elevated and tissue deposition of IgM and IgG was low. The significant immunosuppressive effects of ADMSCs illustrate their potential use as immunosuppressive agents for xenogeneic biomaterial-based implants.

Prognostic Value of Repeat Hepatectomy for Hepatocellular Carcinoma Patients.

BACKGROUND/AIM: The potential for repeat hepatectomy has been increasing in hepatocellular carcinoma (HCC) patients. PATIENTS AND METHODS: To assess its significance, we examined the clinical features, surgical records, and survival of 279 HCC patients who underwent hepatectomy as primary treatment. Patients were divided into three groups: single hepatectomy without HCC relapse in 97 patients (Group 1), single hepatectomy with HCC relapse in 133 patients (Group 2) and repeat hepatectomy for HCC relapse in 49 patients (Group 3). Group 3 was divided into three subgroups. Multiple, larger size (>5 cm), and confluent nodular HCC. RESULTS: Child-Pugh B patients were significantly higher in Group 2 (p<0.01). The prevalence of histological vascular involvement was significantly higher in Group 2 than in the other groups (p<0.01). Although Group 2 showed significantly poorer survival (p<0.01), the 10-year overall survival in Groups 1 and 3 was over 70% but not different between groups. The relapse-free survival period was significantly correlated with overall survival, and patients with a cancer-free period of over 36 months showed significantly better 10-year survival rates than those with a period of less than 36 months (p<0.01). Patients undergoing 3 or more repeat hepatectomies also showed good survival periods. CONCLUSION: Careful follow-up and proper decision-making in terms of repeat hepatectomy with multimodal treatments including novel chemotherapies upon assessment of postoperative tumor relapse are important in HCC patients to prolong survival.

Relationship of immunonutritional factor with changes in liver volume after portal vein embolization.

Background: To identify predictors of changes in hepatic volumes after portal vein embolization, we examined the relationship with preoperative nutritional and immunological parameters. Patients and Methods: Ninety-three patients who underwent portal vein embolization were included. The control group comprised 13 patients who underwent right hepatectomy without portal vein embolization. Computed tomographic volumetric parameter was measured for changes in embolized and nonembolized liver. Correlation with various candidates of immunonutritional parameters was examined. Results: Difference in increased liver ratio was 9.1%. C-reactive protein levels significantly increased after portal vein embolization (P < .01), whereas albumin and total cholesterol levels significantly decreased, respectively (P < .01). The C-reactive protein/albumin ratio, prognostic nutritional index, Controlling Nutritional Status score, and modified Glasgow Prognostic Score were significantly different, respectively (P < .01). Prothrombin activity and total cholesterol level significantly correlated with the increased change in nonembolized liver (P < .05). The C-reactive protein and C-reactive protein/albumin ratio after portal vein embolization negatively correlated with hypertrophic ratio (P < .05). By comparing posthepatectomy outcomes between 64 patients undergoing portal vein embolization and 13 who did not, the prevalence of severe complications and mortality in the portal vein embolization group was not different from that in the non-portal vein embolization group. Liver activity at 15 minutes > 0.92 and increased liver volume ≥ 10% tended to correlate with lower prevalence of severe complications. Only increased intraoperative blood loss ≥ 1,500 mL was significantly associated with morbidity and mortality (P < .05). Conclusion: Contrary to our hypothesis, immunonutritional parameters, except C-reactive protein and C-reactive protein/albumin ratio, did not reflect hypertrophy after portal vein embolization. Although it is difficult to predict the hypertrophic degree, the strategy of scheduled hepatectomy should be switched in case of impaired inflammatory status after portal vein embolization.

Rare resected eight cases of duodenal adenocarcinomas.

INTRODUCTION: Duodenal adenocarcinoma is a rare malignancy; recently, it has been found to be accompanied by operative indications. METHODS: Nine consecutive rare cases were diagnosed with duodenal carcinoma (DC), in which clinicopathological characteristics were retrospectively examined. Age was ranged over middle-aged males and females. No clinical onset with severe symptoms was observed, and the specific treatment for accompanied diseases or habits was not found. OUTCOMES: One case of two T1 stage DCs that underwent pancreas-sparing duodenectomy. Stage II DC was diagnosed in three cases, and stage III DC was diagnosed in four cases. Pancreaticoduodenectomy (PD) mainly occurred in seven patients, and duodenectomy was limited in two patients. All operations were safely performed, and the postoperative course showed no severe morbidity. Histological findings showed R0 resection in eight cases and R1 at the retroperitoneal dissecting part in one case. Five patients with advanced-stage DC underwent adjuvant chemotherapy; however, four patients showed tumor recurrence within 12 months. With additional strong chemotherapy, eight patients survived up to 84 months, and one died of liver metastasis at 43 months after surgery. Three representative cases of mucosal invasion with widespread pancreas-sparing duodenectomy and advanced-stage DC cases undergoing duodenectomy or PD are shown. CONCLUSION: In the field of upper digestive tract surgery, duodenal adenocarcinoma and various applications of surgery or adjuvant chemotherapy for long-term survival are important.

Relationship between hepatic venous anatomy and hepatic venous blood loss during hepatectomy.

PURPOSE: Predicting increased blood loss based on anatomical intervascular relationships is essential in major hepatectomy. METHODS: We assessed 63 consecutive patients undergoing anatomical hepatectomy exposing the hepatic vein (HV) trunk at two institutes. Correlations between anatomical alterations of the hepatic inferior vena cava (IVC), HV, hepatic IVC, or right atrium (RA) and the blood loss per standard weight (BLSW) or blood transfusion (n = 18) were analyzed. The results of IVC partial clamping (PC) were additionally examined. RESULTS: The BLSW in type V-up anatomical morphology was significantly higher than that in straight type (p < 0.05). The parameters associated with an increased BLSW (> 13.5 mL/kg) were tumor size (> 4 cm), prothrombin activity (< 87%), CVP (> 7 mmHg), area of suprahepatic IVC (< 360 mm2), IVC-RA gap (> 28 mm), longitudinal angle of IVC (< 160°), and axial angle of the MHV (< 55°). A multivariate analysis revealed that a high IVC-RA gap was a significant independent risk factor (odds ratio; 4.32, p < 0.05). Among 25 patients undergoing IVC-PC, only three showed a remarkable decrease in hepatic venous bleeding. No other statistically significant differences in the surgical records were observed in most cases. CONCLUSION: The IVC-RA gap might be a promising novel predictive parameter reflecting increased blood loss leading to blood transfusion in anatomical hepatectomy.

[Clinical Investigation of Surgical Cases for Pulmonary Aspergillosis].

INTRODUCTIONS: The number of cases requiring surgical resection for pulmonary aspergillosis has increased in recent years. PATIENTS AND METHODS: From April 2008 to March 2019, 10 patients underwent pulmonary resection for chronic pulmonary aspergillosis(CPA) in our hospital. RESULTS: Five patients were diagnosed with simple pulmonary aspergilloma (SPA) and 5 were diagnosed with chronic progressive pulmonary aspergillosis( CPPA). The median age was 73 years, and 8 patients were men. A history of tuberculosis was present in 2 cases, diabetes was present in 3 cases, and prednisolone( PSL) administration was performed in 3 cases. The operative procedures included 1 pneumonectomy, 4 lobectomies, 1 segmentectomy, and 4 wedge resections. The median surgery time was 220.5 minutes, and the median blood loss was 301 ml, requiring perioperative transfusion in 2 cases. Postoperative pneumonia was observed in 2 cases. The median postoperative observation period was 11.5 months, and 6 out of 8 patients did not show postoperative recurrences. CONCLUSIONS: Although patients with pulmonary aspergillosis have a high rate of underlying disease and it is necessary to pay attention to postoperative complications, it has been shown that surgery can be performed safely on these patients by selecting appropriate cases and surgical procedures.

Prognostic value of the preoperative prognostic nutritional index in oldest-old patients with colorectal cancer.

BACKGROUND: The prognostic nutritional index (PNI), which is calculated using serum albumin and the peripheral lymphocyte count, is a simple and useful score for predicting the prognosis in patients with various cancers. The correlation between the preoperative PNI and long-term outcomes is unclear in oldest-old patients with colorectal cancer. METHODS: A total of 84 consecutive patients ≥ 85 years old who underwent resection for primary colon adenocarcinoma at our institution between April 2008 and March 2017 were retrospectively reviewed. The cut-off value of the PNI for predicting the relapse-free survival (RFS) was 42.4 on a receiver operating characteristic curve analysis. The clinical characteristics and markers of systemic inflammation were then compared between patients with a low PNI (PNI < 42.4, n = 33) and a high PNI (PNI ≥ 42.4, n = 51). RESULTS: A low PNI was associated with systemic inflammation marker levels, including a low neutrophil-to-lymphocyte ratio (p = 0.048), a low platelet-to-lymphocyte ratio (p = 0.006), and a high lymphocyte-to-monocyte ratio (p < 0.001). The median follow-up period of this cohort was 34 months (1-151 months). The 5-year RFS, overall survival (OS), and cancer-specific survival were significantly worse in the low-PNI group than in the high-PNI group (p = 0.032, p = 0.004, p = 0.049, respectively). In the multivariate analysis, a low PNI was an independent predictor for both the RFS (HR 3.188, p = 0.041) and OS (HR 3.953, p = 0.027). CONCLUSIONS: A low-preoperative PNI was significantly associated with a poor prognosis in oldest-old colorectal cancer patients. Perioperative nutritional support may be important for prolonging the survival.

Utility of thoracic cage width in assessing surgical difficulty of minimally invasive esophagectomy in left lateral decubitus position.

BACKGROUND: This study aimed to assess the surgical difficulty of minimally invasive esophagectomy in the left lateral decubitus position for patients with esophageal cancer from the perspective of short-term outcomes, including operation time, blood loss, and morbidity. MATERIALS AND METHODS: The initial 44 consecutive patients with esophageal cancer who underwent minimally invasive esophagectomy were statistically analyzed retrospectively. Thoracic cage area was measured from preoperative computed tomography as a factor affecting the surgical difficulty of minimally invasive esophagectomy, as well as other patient characteristics. Correlations with short-term outcomes including chest operation time, blood loss, and morbidity rate were then examined. RESULTS: In univariate analyses, smaller area of the upper thoracic cage width correlated with prolonged thoracic procedure time (p = 0.0119) and greater blood loss during thoracic procedures (p = 0.0283), but area of the lower thoracic cage showed no correlations. History of respiratory disease was associated with thoracic procedure time (p < 0.0001), but not blood loss. In multivariate analysis, small area of the upper thoracic cage was independently associated with prolonged thoracic procedure time (p = 0.0253). Small upper thoracic cage area was not directly correlated with morbidity rate, but prolonged thoracic procedure time was associated with increased blood loss (p < 0.0001) and morbidity rate (p = 0.0204). Empirical time reduction (p = 0.0065), but not blood loss, was associated with thoracic procedure time. However, area of the upper thoracic cage did not correlate with empirical case number. In multivariate analysis, area of the upper thoracic cage (p = 0.0317) and empirical case number (p = 0.0193) correlated independently with thoracic procedure time. CONCLUSION: A small area of the upper thoracic cage correlated significantly with prolonged thoracic procedure time and increased thoracic blood loss for minimally invasive esophagectomy in the left lateral decubitus position, suggesting the surgical difficulty of minimally invasive esophagectomy in the left lateral decubitus position.

Significance of the preoperative regional maximal removal rate of technetium-99m-galactosyl human serum albumin in the future remnant liver: a sequential study of regional maximal removal rate of technetium-99m-galactosyl human serum albumin in the whole liver.

BACKGROUND: The relationship between posthepatectomy complications and liver functional parameters was preliminary reported in a pilot study. The present study sequentially evaluated the clinical significance of maximal removal rate of technetium-99m-galactosyl human serum albumin (GSARmax) in the future remnant liver (rGSARmax) in patients to predict posthepatectomy complications. METHODS: Between 2010 and August 2017, GSARmax, rGSARmax, their difference (Dif), and the rGSARmax to GSARmax ratio were examined in 247 additional patients who underwent hepatectomy for liver and biliary diseases. Hepatectomy-related postoperative complications (i.e. long-term ascites, intra-abdominal infection, and hepatic failure) occurred in 73 (29.6%) patients. RESULTS: The median and mean preoperative GSARmax values were 0.477 and 0.498±0.166 mg/min, respectively; rGSARmax values were 0.341 and 0.366±0.145 mg/min, respectively; Dif values were 0.105 and 0.132±0.111 mg/min, respectively; and the rGSARmax to GSARmax ratio values were 0.774 and 0.746±0.177, respectively. Among these, the GSARmax and rGSARmax values were significantly correlated with the liver functional parameters ICGR15, LHL15, HH15, prothrombin activity, serum hyaluronic acid level, and platelet count (all P<0.01). The rGSARmax values were significantly lower in patients with long-term ascites (P<0.05), and the predictive cutoff values of rGSARmax were 0.290 mg/min; however, the multivariate logistic regression analysis showed that rGSARmax was not independently related to long-term ascites. CONCLUSION: When accompanied by other functional liver reserve parameters, rGSARmax seemed to be an alternative liver functional parameter related to ascites.

Drainage Tubeless (DRESS) Bypass Surgery as the Best Palliative Care for Unresectable Thoracic Esophageal Cancer with and without Esophago-Respiratory Fistula.

Approximately half of the patients with esophageal cancer are diagnosed at an advanced stage with inoperable disease. The technique of bypass surgery, which is one of the palliative procedures for esophageal cancer, usually requires the insertion of a drainage tube for clearing secretions from the blind remnant esophagus. Since the artificial drainage tube is sometimes problematic for the patient after discharge from the hospital, drainage tubeless (DRESS) surgery might be preferable. The authors demonstrated the utility of DRESS bypass surgery by adding esophagostomy in the right supraclavicular region in three patients with unresectable esophageal cancer with and without esophago-respiratory fistula. All patients had been able to take per-orally and discharged the hospital. Two of three patients are alive with per-oral intake at 1 year later. This DRESS bypass surgery technique, which has not hardly reported in the literature, could release the patients from the tube trouble after the discharge from the hospital and give the patients the better quality of life.

A case of separation surgery with drainage tube-less (DRESS) esophagostomy for advanced cancer with a respiratory fistula.

INTRODUCTION: An esophagorespiratory fistula (ERF) can cause severe pneumonia or a lung abscess which progresses to life-threatening sepsis. A case of a patient with esophageal cancer and an esophagopulmonary fistula (EPF) who underwent separation surgery with drainage tube-less (DRESS) esophagostomy and was promptly started on definitive chemoradiotherapy (CRT) is reported. PRESENTATION OF CASE: A 79-year-old man visited a clinic with a month-long history of dysphagia. Esophageal cancer at the middle thoracic esophagus was detected, and invasion of the left main bronchus and lower lobe of the right lung was seen on contrast-enhanced computed tomography (CT). Three weeks later, the patient was transferred to our hospital. CT showed a lung abscess in the lower lobe of the right lung that continued into the adjacent esophageal cancer. Due to the EPF, the patient underwent emergency surgery that consisted of esophageal separation surgery and double bilateral esophagostomy and enterostomy. Definitive CRT for the esophageal cancer was started from postoperative day 25. At six-month follow-up, the patient achieved relapse-free survival. DISCUSSION: Separation surgery with a DRESS esophagostomy provides good control of inflammation because of division of the respiratory tract from the alimentary tract, which allows prompt initiation of CRT. Alternatively, a DRESS esophagostomy allows patients to be free from any tube trouble. CONCLUSION: Separation surgery with a DRESS esophagostomy for an ERF is a promising method to improve patient quality of life that is less invasive, controls inflammation, and facilitates subsequent definitive CRT.