Risk Factors for Postoperative Paralytic Ileus in Advanced-age Patients after Laparoscopic Colorectal Surgery: A Retrospective Study of 124 Consecutive Patients.

Objectives: Postoperative paralytic ileus (POI) is one of the most common and troublesome complications following colorectal surgery. However, to date, the risk factors for POI remain unclear. This study aimed to identify the risk factors for POI following laparoscopic colorectal surgery in advanced-age patients. Methods: The clinical data of 124 patients aged ≥75 years who underwent curative colorectal surgery from January 2018 to December 2020 were retrospectively reviewed. The relationship between POI and clinicopathological data including sarcopenia and visceral fat obesity was then assessed. Sarcopenia was defined as a low skeletal muscle mass index; visceral obesity, visceral fat with an area ≥100 cm2 on computed tomography at the level of the third lumbar vertebra; and sarcobesity, sarcopenia with visceral obesity. Results: The rate of POI was 9% (12/124 patients), and all the affected patients improved with conservative treatment. In the univariate and multivariate analyses, sarcopenia and sarcobesity were significant predictive factors for POI. Conclusions: Sarcopenia and sarcobesity may be risk factors for POI in patients aged ≥75 years after laparoscopic colorectal surgery.

Disturbed passage of jejunal limb near esophageal hiatus after overlapped esophagojejunostomy following laparoscopic total gastrectomy.

BACKGROUND: Overlapped esophagojejunostomy (OEJ) is a secure purely laparoscopic reconstruction after laparoscopic total gastrectomy (LTG). However, long-term surgical results have not been documented well. AIM: In this paper, we report unusual patients who manifested jejunal limb stricture near the esophageal hiatus without anastomotic stenosis during long-term observation after surgery. METHODS: From April 2009 until May 2020, we retrospectively reviewed 211 patients underwent LTG following by OEJ for gastric carcinoma and took a standard surveillance program. We aimed to characterize a novel complicated disorder observed in these patients to assist treatment and prevention. RESULTS: Five patients (2.4%) had unusual jejunal limb stricture after LTG and OEJ, occurring at a mean of 10 mo after initial radical LTG. All five patients had disturbed oral intake and marked weight loss, and two had aspiration pneumonia. Various diagnostic modalities and intraoperative findings in each patient revealed an intact anastomosis, bent or tortuous jejunal limb resulting from loose fibrous adhesions on the left crus at the esophageal hiatus and no cancer recurrence. All five patients were successfully treated by reoperation for adhesiolysis, division of the left crus and rearrangement of the jejunal limb. CONCLUSION: Disturbed passage through the jejunal limb near the hiatus can occur after some types of OEJ following LTG. We speculate that it may result from a short remnant esophagus, excessive mobilization of the jejunal limb that permits bending or tortuosity and adhesions on the left crus at the hiatus. Prevention for this complication is possible during the original LTG procedure.

Initial Learning Curve and Stereotypical Use of Extra Arm During da Vinci Chest Procedures of McKeown Esophagectomy.

Objective: McKeown esophagectomy facilitates extensive lymphadenectomy for the optimal management of esophageal cancer. Robot-assisted esophagectomy (RAE) was introduced in an attempt to reduce the incidence of postoperative complications. The da Vinci System has 3 active robotic arms in addition to the camera scope, and an extra robotic arm (ERA) is generally used to maintain a fine and stable operative field. However, the optimal use of an ERA has not been documented. In addition, the learning curve of the RAE using the da Vinci System remains controversial. In this study, we aimed to determine the optimal use of an ERA in association with the initial learning curve of robotic McKeown esophagectomy with extremely extensive lymphadenectomy. Methods: We reviewed 81 consecutive patients who underwent RAE. To determine whether stereotypical use of an ERA after establishment of its optimal use accounted for the learning curve, we measured the duration of 14 steps and the duration when performed with optimal use of an ERA in the corresponding step by reviewing video-recorded procedures. We then calculated the ratio as the degree of stereotypical use of the ERA during the da Vinci chest procedures. Results: The cumulative sum method showed that the learning curve required 27 cases of RAE. In addition, stereotypical use of the ERA was significantly associated with the learning curve of RAE. Conclusions: Establishment of optimal use of an ERA could help to accelerate the learning curve in da Vinci chest procedures during McKeown esophagectomy with extensive lymphadenectomy.

Matrix metalloproteinase­1 expression is regulated by HIF­1­dependent and epigenetic mechanisms and serves a tumor­suppressive role in gastric cancer progression.

The matrix metalloproteinase (MMP) family is associated with degradation of the extracellular matrix and is known to promote cancer invasion. The present study aimed to investigate the biological role of MMP­1 in gastric cancer cells and analyze the association between MMP­1 expression and the clinical outcomes of gastric cancer patients. In the present study, hypoxia accelerated invasion, accompanied by elevated MMP­1 expression in the gastric cancer cell line 58As9. Additionally, hypoxia­inducible factor­1α (HIF­1α) knockdown in 58As9 cells reduced MMP­1 expression under hypoxic conditions. Treatment with 5­aza­2­deoxycytidine and trichostatin A restored MMP­1 expression in the MMP­1­deficient cell lines MKN45 and MKN74. These results indicated that MMP­1 expression was controlled by both HIF­1α­dependent and epigenetic mechanisms in gastric cancer cell lines. In addition, MMP­1 knockdown impaired the hypoxia­induced invasiveness of 58As9 cells, implicating MMP­1 in the elevated invasion. By contrast, knockdown enhanced the proliferative ability of 58As9 cells, whereby expression of cell cycle­related genes was subsequently altered. In nude mouse models, the knockdown accelerated the growth of xenograft tumor and the development of peritoneal dissemination. In an immunohistochemical study using 161 surgically resected cancer tissues, the Ki67 score was significantly higher in the group with low MMP­1 expression (P<0.001). Disease­free survival (DFS) and disease­specific survival (DSS) were both significantly reduced in patients with low MMP­1 expression (log­rank test; DFS: P=0.005; DSS: P=0.022). Multivariate analysis demonstrated that MMP­1 expression was an independent prognostic factor for DFS and DSS [DFS: HR=2.11 (1.22­3.92) P=0.005, DSS: HR=2.90 (1.23­8.50) P=0.012]. In conclusion, the present study indicated that MMP­1 may serve as a tumor­suppressive factor that inhibits gastric cancer progression, although it promoted invasion in vitro.

Antitumor effects of low-dose tipifarnib on the mTOR signaling pathway and reactive oxygen species production in HIF-1α-expressing gastric cancer cells.

Farnesyltransferase inhibitors (FTIs) suppress tumor aggressiveness in several malignancies by inhibiting Ras signaling. However, treatment of cells with a low dose of the FTI tipifarnib suppresses the expression of hypoxia-inducible factor-1α (HIF-1α) and results in antitumor effects without inhibiting the Ras pathway. Although we previously reported that elevated HIF-1α expression is associated with an aggressive phenotype in gastric cancer (GC), little is known about the antitumor effects of FTIs on GC. In this study, we examined the relationship between the antitumor effects of low-dose tipifarnib and HIF-1α expression in GC cells. Under normoxic conditions, HIF-1α was expressed only in MKN45 and KATOIII cells. The inhibitory effect of tipifarnib on HIF-1α was observed in HIF-1α-positive cells. Low-dose tipifarnib had antitumor effects only on HIF-1α-positive cells both in vitro and in vivo. Furthermore, low-dose tipifarnib inactivated ras homolog enriched in brain (Rheb)/mammalian target of rapamycin (mTOR) signaling and decreased intracellular reactive oxygen species (ROS) levels in HIF-1α-positive GC cells. Our results that the antitumor effects of low-dose tipifarnib are at least partially mediated through suppression of mTOR signaling and HIF-1α expression via inhibition of Rheb farnesylation and reduction in ROS levels. These findings suggest that low-dose tipifarnib may be capable of exerting an antitumor effect that is dependent on HIF-1α expression in GC cells. Tipifarnib may have potential as a novel therapeutic agent for HIF-1α-expressing GC exhibiting an aggressive phenotype.

Colon perforation caused by transanal decompression tube after laparoscopic low anterior resection: A case report.

INTRODUCTION: The effectiveness of transanal decompression tube (TDT) to prevent anastomotic leakage after rectal surgery has been widely accepted in recent years. However, a rare complication of intestinal perforation due to TDT has been also reported. PRESENTATION OF CASE: A 88-year-old woman underwent laparoscopic low anterior resection for rectal cancer. An abdominal drainage tube adjacent to the colorectal anastomosis and a TDT were placed. The patient experienced abdominal pain, nausea and elevated inflammatory markers on postoperative day 6. Enema and computed tomography demonstrated colonic perforation due to the TDT, and emergency laparotomy was performed. Perforation of the anterior sigmoid colon located at the proximal side of the colorectal anastomosis was seen, and the TDT was exposed to the abdominal cavity. Therefore, primary closure of the perforation site, peritoneal lavage, drainage tube placement and transverse colostomy was performed. DISCUSSION: In our case, TDT seemed to compress the anterior wall of the colon and lead to perforation. The looseness of the remaining oral intestinal tract depressed in the pelvis was compressed by the TDT. CONCLUSION: TDTs should be very carefully placed to avoid complication. The length and looseness of the oral intestine and the relationship between the TDT to be inserted might be important.

Retrospective Risk Analysis for Anastomotic Leakage Following Laparoscopic Rectal Cancer Surgery in a Single Institute.

PURPOSE: Anastomotic leakage (AL) is one of the most serious complications after laparoscopic low anterior resection (LALAR) for rectal cancer. The aim of the present study was to investigate the risk factors for AL after LALAR. METHODS: A retrospective study was conducted of 103 patients who underwent LALAR in a single institute between October 2008 and January 2018. Univariate and multivariate analyses were performed to determine the clinicopathological factors associated with AL. RESULTS: The overall incidence of AL was 9.7% (10/103). After anastomosis using the double-stapling technique, a transanal tube was placed in 88 patients (85.4%). A diverting stoma was created in 26 patients (25.2%). The univariate analysis showed that a younger age (P = 0.014), higher stage (P = 0.048), deeper depth of tumor invasion (P = 0.028), larger tumor circumference (P = 0.024), longer operation time (P = 0.015), and early postoperative diarrhea (P = 0.002) were associated with AL. The multivariate logistic regression analysis revealed early postoperative diarrhea (odds ratio [OR] 16.513, 95% confidence interval [CI] 2.393-113.971, P = 0.004) a younger age (10-year increments; OR 0.351, 95% CI 0.147-0.839, P = 0.019), operative time (10-min increments; OR 1.089, 95% CI 1.012-1.172, P = 0.022), and higher stage (OR 10.605, 95% CI 1.279-87.919, P = 0.029) were independent risk factors for AL CONCLUSION: Our findings suggest that tumor progression accompanied by a high stage, long operative time, and insufficient bowel preparation and early postoperative diarrhea due to a large tumor circumference may be risk factors of AL after LALAR for rectal cancer.

Mieap-induced accumulation of lysosomes within mitochondria (MALM) regulates gastric cancer cell invasion under hypoxia by suppressing reactive oxygen species accumulation.

Mitochondrial quality control (MQC) protects against potentially damaging events, such as excessive generation of mitochondrial reactive oxygen species (mtROS). We investigated the contribution of the two major MQC processes, namely, mitophagy and Mieap-induced accumulation of lysosomes within mitochondria (MALM), to the response to hypoxia of two human gastric cancer (GC) cell lines. We found that hypoxia increased mtROS generation and cell invasion in 58As9, but not in MKN45, although the transcription factor hypoxia-inducible factor 1α was induced in both cell lines. Colocalisation of lysosomes with mitochondria was found only in hypoxic MKN45 cells, suggesting that hypoxia-induced MQC functions normally in MKN45 but may be impaired in 58As9. Hypoxia did not lead to decreased mitochondrial mass or DNA or altered appearance of autophagosomes, as judged by electron microscopy, suggesting that mitophagy was not induced in either cell line. However, western blot analysis revealed the presence of the MALM-associated proteins Mieap, BNIP3 and BNIP3L, and the lysosomal protein cathepsin D in the mitochondrial fraction of MKN45 cells under hypoxia. Finally, Mieap knockdown in MKN45 cells resulted in increased mtROS accumulation and cell invasion under hypoxia. Our results suggest that hypoxia-induced MALM suppresses GC cell invasion by preventing mtROS generation.

Hypoxia-induced ANGPTL4 sustains tumour growth and anoikis resistance through different mechanisms in scirrhous gastric cancer cell lines.

Patients with scirrhous gastric cancer (SGC) frequently develop peritoneal dissemination, which leads to poor prognosis. The secreted protein angiopoietin-like-4 (ANGPTL4), which is induced by hypoxia, exerts diverse effects on cancer progression. Here, we aimed to determine the biological function of ANGPTL4 in SGC cells under hypoxia. ANGPTL4 levels were higher in SGC cells under hypoxia than in other types of gastric cancer cells. Hypoxia-induced ANGPTL4 mRNA expression was regulated by hypoxia-inducible factor-1α (HIF-1α). Under hypoxic conditions, monolayer cultures of ANGPTL4 knockdown (KD) 58As9 SGC (58As9-KD) cells were arrested in the G1 phase of the cell cycle through downregulation of c-Myc and upregulation of p27, in contrast to control 58As9-SC cells. Moreover, the ability of 58As9-KD xenografts to form tumours in nude mice was strongly suppressed. When 58As9-KD cells were cultured in suspension, hypoxia strongly increased their susceptibility to anoikis through suppression of the FAK/Src/PI3K-Akt/ERK pro-survival pathway, followed by activation of the apoptotic factors caspases-3, -8 and -9. The development of peritoneal dissemination by 58As9-KD cells was completely inhibited compared with that by 58As9-SC cells. In conclusion, ANGPTL4 is uniquely induced by hypoxia in cultured SGC cells and is essential for tumour growth and resistance to anoikis through different mechanisms.

Repeated changes of the molecular subtype in gastric metastasis from breast cancer: A case report.

Gastric metastasis from breast cancer is clinically diagnosed rarely. The present study described an interesting and valuable case of gastric metastasis from breast cancer, which showed repeated changes of the molecular subtype with an impact on the choice of treatment. A 42-year-old woman underwent mastectomy with axillary lymph node dissection for an invasive lobular carcinoma of the left breast. The patient received gastroscopy due to an epigastric pain during the adjuvant chemotherapy. The endoscopic examination revealed an erosive lesion at the posterior wall of the gastric body. The gastric lesion was immunohistochemically diagnosed as a metastatic disease from the breast cancer. The patient initially received hormone therapy, according to the subtype of the primary and the metastatic diseases. The gastric lesion initially disappeared; however, a relapsed lesion transformed into luminal human epidermal growth factor receptor 2 type from luminal type. Subsequently, the metastatic lesions underwent repeated subtype changing, which created difficultly when deciding the treatment strategy. The molecular profile of breast cancer can change during the treatment, resulting in the treatment resistance observed in certain cases. Therefore, the optimal treatment must be selected, according to the changed subtype.

Total synthesis of (-)-haouamine B pentaacetate and structural revision of haouamine B.

The enantiocontrolled total synthesis of (-)-haouamine B pentaacetate was accomplished via an optically active indane-fused ß-lactam, which was prepared by a newly developed Friedel-Crafts reaction. Subsequent cleavage of the ß-lactam and an intramolecular McMurry coupling reaction provided the core indane-fused tetrahydropyridine, which led to the elucidation of the structure, as proposed by Trauner and Zubía.