Laparoscopically treated bowel obstruction secondary to a lesser omental hernia resulting from a previous laparoscopic total colectomy for ulcerative colitis: A report of two cases.

Lesser omental hernias are rare; however, they should be considered in symptomatic bowel obstruction subsequent to a subtotal or total colectomy. This report describes two cases of recurrent bowel obstruction secondary to lesser omental hernias after laparoscopic total colectomies for ulcerative colitis. Initially, these patients had been treated conservatively; however, due to symptom recurrence, surgical intervention was decided on. In both cases, laparoscopic surgery revealed lesser omental hernias. The small bowel, which had entered from the dorsal aspect of the stomach, was returned to the original position, and the lesser omentum was closed. The patients were discharged uneventfully, with no recurrent bowel obstruction during the follow-up period. These cases highlight the importance of including internal hernias in the differential diagnosis relative to recurrent bowel obstruction, in patient subpopulations with a prior history of a subtotal or total colectomy. Confirmation by computed tomography is preferable.

The usefulness of the endoscopic surgical skill qualification system in laparoscopic right hemicolectomy: a single-center, retrospective analysis with propensity score matching.

PURPOSE: Recently, a new certification system called the Endoscopic Surgical Skill Qualification System (ESSQS) has been launched in Japan to improve surgical safety. This study aimed to determine whether ESSQS-qualified surgeons affect the short- and long-term outcomes of laparoscopic right hemicolectomy. METHODS: A total of 187 colon cancer patients who underwent laparoscopic right hemicolectomy at Kindai University Hospital between January 2016 and December 2020 were enrolled. These patients were divided into two groups based on surgeries performed by ESSQS-qualified surgeons (QS group) and non-ESSQS-qualified surgeons (NQS group). The short- and long-term outcomes were compared between the two groups before and after propensity score matching (PSM). RESULTS: After PSM, 43 patients from each group were included in the matched cohort. In the short-term outcomes, the total operative time was significantly longer in the NQS group than in the QS group (229 vs. 174 min, p < 0.0001). However, there were no significant differences in the two groups regarding blood loss (0 vs. 0 ml, p = 0.7126), conversion (0.0% vs. 7.0%, p = 0.0779), Clavien-Dindo ≥ 2 complications (9.3% vs. 7.0%, p = 0.6933), mortality (2.3% vs. 0.0%, p = 0.3145), and postoperative hospital stay (9 vs. 9 days, p = 0.5357). In the long-term outcomes, there were no significant differences between the two groups in the 3-year overall survival (86.6% vs. 83.0%, p = 0.8361) and recurrence-free survival (61.7% vs. 72.0%, p = 0.3394). CONCLUSION: Laparoscopic right hemicolectomy performed by ESSQS-qualified surgeons contributed to shorter operative time. Under the supervision of ESSQS-qualified surgeons, almost equivalent safety and oncological outcomes are expected even in surgeries performed by non-ESSQS-qualified surgeons.

A Narrative Review of the Usefulness of Indocyanine Green Fluorescence Angiography for Perfusion Assessment in Colorectal Surgery.

Anastomotic leakage is one of the most dreaded complications of colorectal surgery and is strongly associated with tissue perfusion. Indocyanine green fluorescence angiography (ICG-FA) using indocyanine green and near-infrared systems is an innovative technique that allows the visualization of anastomotic perfusion. Based on this information on tissue perfusion status, surgeons will be able to clearly identify colorectal segments with good blood flow for safer colorectal anastomosis. The results of several clinical trials indicate that ICG-FA may reduce the risk of AL in colorectal resection; however, the level of evidence is not high, as several other studies have failed to demonstrate a reduction in the risk of AL. Several large-scale RCTs are currently underway, and their results will determine whether ICG-FA is, indeed, useful. The major limitation of the current ICG-FA evaluation method, however, is that it is subjective and based on visual assessment by the surgeon. To complement this, the utility of objective evaluation methods for fluorescence using quantitative parameters is being investigated. Promising results have been reported from several clinical trials, but all trials are preliminary owing to their small sample size and lack of standardized protocols for quantitative evaluation. Therefore, appropriately standardized, high-quality, large-scale studies are warranted.

Effectiveness of negative pressure wound therapy with instillation and dwelling after stoma closure: a retrospective and propensity score matching analysis.

The use of temporary diverting stoma has become more common in low colorectal anastomosis to reduce anastomotic complications. Surgical site infection (SSI) at the stoma closure site has been one of the most frequent postoperative complications. The aim of this study was to compare the short-term outcomes between conventional primary suture closure and negative pressure wound therapy with instillation and dwelling (NPWTi-d) therapy following purse-string suturing, using propensity score matching analysis. We retrospectively evaluated the medical records of 107 patients who underwent stoma closure between January 2016 and October 2020. The primary outcome was the proportion of SSI. The secondary outcome was the day of postoperative length of stay. Propensity score matching with one-to-one match was performed for reducing treatment selection bias. Of a total of 107 patients, 67 patients had been treated with conventional primary closure and 40 with NPWTi-d therapy. The propensity score matching derived 37 pairs. The respective SSI proportions were 0% and 16.2% in the groups with NPWTi-d and primary closure (P = 0.025). The respective median days of postoperative hospital stay were 9.0 and 10.0 in the groups with NPWTi-d and primary closure (P = 0.453). NPWTi-d therapy with purse-string suturing was effective in reducing SSI after stoma closure.

Laparoscopic complete mesocolic excision with central vascular ligation for splenic flexure colon cancer: short- and long-term outcomes.

BACKGROUND: Complete mesocolic excision (CME) with central vascular ligation (CVL) for colon cancer is an essential procedure for improved oncologic outcomes after surgery. Laparoscopic surgery for splenic flexure colon cancer was recently adopted due to a greater understanding of surgical anatomy and improvements in surgical techniques and innovative surgical devices. METHODS: We retrospectively analyzed the data of patients with splenic flexure colon cancer who underwent laparoscopic CME with CVL at our institution between January 2005 and December 2017. RESULTS: Forty-five patients (4.8%) were enrolled in this study. Laparoscopic CME with CVL was successfully performed in all patients. The median operative time was 178 min, and the median estimated blood loss was 20 g. Perioperative complications developed in 6 patients (13.3%). The median postoperative hospital stay was 9 days. According to the pathological report, the median number of harvested lymph nodes was 15, and lymph node metastasis developed in 14 patients (31.1%). No metastasis was observed at the root of the middle colic artery or the inferior mesenteric artery. The median follow-up period was 49 months. The cumulative 5-year overall survival and disease-free survival rates were 85.9% and 84.7%, respectively. The cancer-specific survival rate in stage I-III patients was 92.7%. Recurrence was observed in 5 patients (11.1%), including three patients with peritoneal dissemination and two patients with distant metastasis. CONCLUSIONS: Laparoscopic CME with CVL for splenic flexure colon cancer appears to be oncologically safe and feasible based on the short- and long-term outcomes in our study. However, it is careful to introduce this procedure to necessitate the anatomical understandings and surgeon's skill. The appropriate indications must be established with more case registries because our experience is limited.

The technique for less infectious and earlier healing of stoma closure wound: negative pressure wound therapy with instillation and dwelling followed by primary closure.

BACKGROUND: Temporary stomas have been widely used to avoid the risk of complications such as anastomotic leakage after colorectal resection. Stoma closure is relatively easy; however, postoperative surgical site infection (SSI) may be a problem. Various methods have been used to reduce the incidence of SSI. We aimed to evaluate a new technique for stoma wound closure. METHODS: We enrolled patients who underwent stoma closure at our hospital between September 2019 and May 2020. We selected patients who lived far from our hospital and had difficulty visiting the hospital regularly and who agreed to undergo this surgical technique. We used negative pressure wound therapy with instillation and dwelling (NPWTi-d) and delayed primary closure for these patients. RESULTS: Four patients underwent NPWTi-d and delayed primary closure without the occurrence of SSI. The median postoperative hospital stay was 9 days (range: 7-14 days), and the median number of days to confirmation of epithelialization was 11.5 days (range: 10-16 days). CONCLUSION: The combined use of NPWTi-d and delayed primary closure for the stoma wound was very effective. This method may be a valuable new technique for wound management after stoma closure.

A Novel Three-Step Approach for Secure Splenectomy During Laparoscopic Total Gastrectomy for Gastric Cancer.

BACKGROUND: Splenectomy during total gastrectomy increases operative morbidity (Nakata et al. in Surgical endoscopy 7:1817-1822, 2015). Establishing a safe approach to laparoscopic splenectomy is one of the most urgent issues in the treatment of proximal advanced gastric cancer, which invades to the greater curvature (Kawamura et al. in Gastric Cancer 3:662-668, 2015). We developed a novel three-step procedure for splenectomy during laparoscopic total gastrectomy (LTG). METHODS: Splenectomy consisted of three steps. Step 1 (dorsal approach): The pancreatic tail and spleen were mobilized. This step delineates the dissection plane and the anatomy around the pancreatic tail. Step 2 (suprapancreatic approach): The suprapancreatic peritoneum was incised to fenestrate to the mobilized space. The no. 11d station was dissected. The inferior branch of the splenic artery was exposed. Step 3 (splenic hilum approach): The spleen was lifted up to straighten the splenic hilum. The aim was to prolong the splenic vasculature and enable the surgeon to transect splenic vasculatures easily despite their anatomical diversity. Division of the splenic branches promotes mobility of the pancreatic tail, enabling precise dissection and preservation of its blood supply. RESULTS: Of 45 patients with gastric cancer who underwent LTG, seven underwent concurrent splenectomy. In all cases, splenectomy was successfully accomplished. The median operation time, duration of splenectomy, blood loss, number of total retrieved lymph nodes, lymph node counts from stations 10 and 11d, and drain amylase levels on the third postoperative day were 382 min, 94 min, 30 ml, 51, 5, 5, and 158 IU/L, respectively. Postoperative morbidity more severe than Clavien-Dindo grade 2 occurred in one case, with no pancreas-related morbidity. No mortality or conversion occurred. CONCLUSIONS: This laparoscopic procedure allows adequate nodal dissection and safe splenectomy.

Enhanced anastomotic healing by Daikenchuto (TJ-100) in rats.

Daikenchuto (DKT), a traditional Japanese medicine, is widely used to treat various gastrointestinal disorders. This study aimed to investigate whether DKT could promote the anastomotic healing in a rat model. Pedicled colonic segments were made in left colon by ligation of the feeding arteries, and then intestinal continuity was restored. Colonic blood flow was analyzed by using ICG fluorescence imaging: Fmax, Tmax, T1/2, and Slope were calculated. Anastomotic leakage (AL) was found in 6 of 19 rats (31.6%) in the control group, whereas in 1 of 16 rats (6.2%) in the DKT group. The Fmax and Slope of DKT group were significantly higher than those of control group. DKT could promote the anastomotic healing, with the higher bursting pressure on postoperative day (POD) 2 and 5, the larger granulation thickness on POD 5, and neoangiogenesis on POD 5. Histological examination showed DKT exhibited a decreased inflammatory cell infiltration, enhanced fibroblast infiltration, and enhanced collagen density on POD 5. In the DKT group, the levels of TGFß1 on POD 2 and VEGFα on POD5 were significantly higher, whereas the level of TNFα on POD 2 was significantly lower. Therefore, DKT could be effective for the prevention of AL following colorectal surgery.

Laparoscopic transhiatal lymphadenectomy in the lower mediastinum for adenocarcinoma of the esophagogastric junction.

Laparoscopic transhiatal esophagogastrectomy is difficult because the lower mediastinum is so deeply located that the operative field is narrow and restricted by surrounding organs. Therefore, we performed lymphadenectomy with opening of the bilateral mediastinal pleura to maintain safety and obtain better exposure of lymph nodes and important organs. We will present our technique for laparoscopic lower mediastinal lymphadenectomy and reconstruction for cancer of the esophagogastric junction. Five abdominal ports were used. Retraction of the left lobe of the liver exposed the esophageal hiatus. A long, narrow gastric tube (3 cm wide) was formed, and regional abdominal lymph nodes (No. 1, 2, 3a, 7, 8a, 9, 19, and 20) were resected. The diaphragmatic hiatus was widely split and the opened bilateral mediastinal pleura enabled better exposure for lymph node dissection and reconstruction. The level where the inferior vena cava passed through the diaphragm into the chest was used as a landmark to identify supradiaphragmatic (No. 111) and lower thoracic paraesophageal nodes (No. 110), which were completely retrieved with this procedure. The posterior mediastinal nodes (No. 112pulR, 112pulL, and 112aoA) were also retrieved with bilateral opening of the mediastinal pleura and dissection of the inferior pulmonary ligaments. An esophagogastric tube anastomosis with pseudo-fornix was made with a no-knife linear stapler to prevent postoperative reflux esophagitis. This approach enabled safe and accurate laparoscopic lower mediastinal nodal dissection. With the advantage of a narrow gastric tube, the good working space made tension-free anastomosis possible.

Delayed anastomotic leakage following laparoscopic intersphincteric resection for lower rectal cancer: report of four cases and literature review.

BACKGROUND: Anastomotic leakage (AL) is one of the most dreadful postoperative complications because it can result in increased morbidity and mortality as well as poorer long-term prognosis. Although most studies of AL limited their investigation time to a period of 30 days postoperatively, only a few studies have shown that AL can occur after that period. Here, we report four patients of rectal cancer with delayed AL following laparoscopic intersphincteric resection (ISR) and conduct a literature review on delayed AL. CASE PRESENTATION: Case 1 was a 67-year-old male who underwent laparoscopic partial ISR in July 2009. Although the patient was asymptomatic, an anastomotic-urethral fistula was observed 57 months after ISR. Case 2 was a 44-year-old female who underwent laparoscopic partial ISR in July 2008. She presented with discharge of gas and feces from her vagina, and an anastomotic-vaginal fistula was observed 14 months after ISR. Case 3 was a 74-year-old man who underwent laparoscopic partial ISR in August 2007. He presented with pneumaturia and fecaluria, and an anastomotic-urethral fistula was observed 4 months after ISR. Case 4 was a 68-year-old woman who underwent laparoscopic subtotal ISR for rectal cancer in February 2013 and partial hepatic resection for liver metastases in March 2013. She presented with anal pain and purulent perineal discharge, and an anastomotic-perineal fistula was observed 9 months after ISR. All four cases presented with fistula formation and required reoperation (establishment of a diverting ileostomy). CONCLUSIONS: Since delayed AL is not a rare postoperative complication, surgeons need to provide long-term follow-up and remain alert to the possible development of delayed AL.

Clinical Role of ASCT2 (SLC1A5) in KRAS-Mutated Colorectal Cancer.

Mutation in the KRAS gene induces prominent metabolic changes. We have recently reported that KRAS mutations in colorectal cancer (CRC) cause alterations in amino acid metabolism. However, it remains to be investigated which amino acid transporter can be regulated by mutated KRAS in CRC. Here, we performed a screening of amino acid transporters using quantitative reverse-transcription polymerase chain reaction (RT-PCR) and then identified that ASCT2 (SLC1A5) was up-regulated through KRAS signaling. Next, immunohistochemical analysis of 93 primary CRC specimens revealed that there was a significant correlation between KRAS mutational status and ASCT2 expression. In addition, the expression level of ASCT2 was significantly associated with tumor depth and vascular invasion in KRAS-mutant CRC. Notably, significant growth suppression and elevated apoptosis were observed in KRAS-mutant CRC cells upon SLC1A5-knockdown. ASCT2 is generally known to be a glutamine transporter. Interestingly, SLC1A5-knockdown exhibited a more suppressive effect on cell growth than glutamine depletion. Furthermore, SLC1A5-knockdown also resulted in the suppression of cell migration. These results indicated that ASCT2 (SLC1A5) could be a novel therapeutic target against KRAS-mutant CRC.

Loss of SMAD4 Promotes Lung Metastasis of Colorectal Cancer by Accumulation of CCR1+ Tumor-Associated Neutrophils through CCL15-CCR1 Axis.

PURPOSE: We have reported loss of SMAD4 promotes expression of CCL15 from colorectal cancer to recruit CCR1+ myeloid cells through the CCL15-CCR1 axis, which contributes to invasion and liver metastasis. However, the molecular mechanism of lung metastasis is yet to be elucidated. Our purpose is to determine whether similar mechanism is involved in the lung metastasis of colorectal cancer. EXPERIMENTAL DESIGN: In a mouse model, we examined whether SMAD4 could affect the metastatic activity of colorectal cancer cells to the lung through the CCL15-CCR1 axis. We immunohistochemically analyzed expression of SMAD4, CCL15, and CCR1 with 107 clinical specimens of colorectal cancer lung metastases. We also characterized the CCR1+ myeloid cells using several cell-type-specific markers. RESULTS: In a mouse model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1+ cells, promoting their metastatic activities to the lung. Immunohistochemical analysis of lung metastases from colorectal cancer patients revealed that CCL15 expression was significantly correlated with loss of SMAD4, and that CCL15-positive metastases recruited approximately 1.9 times more numbers of CCR1+ cells than CCL15-negative metastases. Importantly, patients with CCL15-positive metastases showed a significantly shorter relapse-free survival (RFS) than those with CCL15-negative metastases, and multivariate analysis indicated that CCL15 expression was an independent predictor of shorter RFS. Immunofluorescent staining showed that most CCR1+ cells around lung metastases were tumor-associated neutrophil, although a minor fraction was granulocytic myeloid-derived suppressor cell. CONCLUSIONS: CCL15-CCR1 axis may be a therapeutic target to prevent colorectal cancer lung metastasis. CCL15 can be a biomarker indicating poor prognosis of colorectal cancer patients with lung metastases. Clin Cancer Res; 23(3); 833-44. ©2016 AACR.

Mechanisms underlying 18F-fluorodeoxyglucose accumulation in colorectal cancer.

Positron emission tomography (PET) with 18F-fluorodeoxyglucose (FDG) is a diagnostic tool to evaluate metabolic activity by measuring accumulation of FDG, an analogue of glucose, and has been widely used for detecting small tumors, monitoring treatment response and predicting patients' prognosis in a variety of cancers. However, the molecular mechanism of FDG accumulation into tumors remains to be investigated. It is well-known that most cancers are metabolically active with elevated glucose metabolism, a phenomenon known as the Warburg effect. The underlying mechanisms for elevated glucose metabolism in cancer tissues are complex. Recent reports have indicated the potential of FDG-PET/CT scans in predicting mutational status (e.g., KRAS gene mutation) of colorectal cancer (CRC), which suggests that FDG-PET/CT scans may play a key role in determining therapeutic strategies by non-invasively predicting treatment response to anti-epidermal growth factor receptor (EGFR) therapy. In this review, we summarize the current findings investigating the molecular mechanism of 18F-FDG accumulation in CRC.

Metabolic Alterations Caused by KRAS Mutations in Colorectal Cancer Contribute to Cell Adaptation to Glutamine Depletion by Upregulation of Asparagine Synthetase.

A number of clinical trials have shown that KRAS mutations of colorectal cancer (CRC) can predict a lack of responses to anti-epidermal growth factor receptor-based therapy. Recently, there have been several studies to elucidate metabolism reprogramming in cancer. However, it remains to be investigated how mutated KRAS can coordinate the metabolic shift to sustain CRC tumor growth. In this study, we found that KRAS mutation in CRC caused alteration in amino acid metabolism. KRAS mutation causes a marked decrease in aspartate level and an increase in asparagine level in CRC. Using several human CRC cell lines and clinical specimens of primary CRC, we demonstrated that the expression of asparagine synthetase (ASNS), an enzyme that synthesizes asparagine from aspartate, was upregulated by mutated KRAS and that ASNS expression was induced by KRAS-activated signaling pathway, in particular PI3K-AKT-mTOR pathway. Importantly, we demonstrated that KRAS-mutant CRC cells could become adaptive to glutamine depletion through asparagine biosynthesis by ASNS and that asparagine addition could rescue the inhibited growth and viability of cells grown under the glutamine-free condition in vitro. Notably, a pronounced growth suppression of KRAS-mutant CRC was observed upon ASNS knockdown in vivo. Furthermore, combination of L-asparaginase plus rapamycin markedly suppressed the growth of KRAS-mutant CRC xenografts in vivo, whereas either L-asparaginase or rapamycin alone was not effective. These results indicate ASNS might be a novel therapeutic target against CRCs with mutated KRAS.

Loss of SMAD4 Promotes Colorectal Cancer Progression by Accumulation of Myeloid-Derived Suppressor Cells through the CCL15-CCR1 Chemokine Axis.

PURPOSE: We previously reported that loss of SMAD4 promotes chemokine CCL15 expression to recruit CCR1(+) myeloid cells via the CCL15-CCR1 axis, which facilitates metastasis of colorectal cancer to the liver. The purposes of this study were to investigate whether essentially the same mechanism works in tumor invasion of the primary colorectal cancer and to evaluate the clinical importance of CCL15 expression and CCR1(+) cell accumulation. EXPERIMENTAL DESIGN: Using human colorectal cancer cell lines with reduced expression of SMAD4 or CCL15, we investigated tumor growth activities in vivo. We used immunohistochemistry (IHC) to investigate expression of SMAD4, CCL15, and CCR1 with 333 clinical specimens of primary colorectal cancer. We next characterized the CCR1(+) cells using double immunofluorescence staining with several specific cell-type markers. Finally, we determined the serum CCL15 levels in 132 colorectal cancer patients. RESULTS: In an orthotopic xenograft model, CCL15 secreted from SMAD4-deficient colorectal cancer cells recruited CCR1(+) cells, resulting in aggressive tumor growth. IHC indicated that loss of SMAD4 was significantly associated with CCL15 expression, and that CCL15-positive primary colorectal cancers recruited approximately 2.2 times more numbers of CCR1(+) cells at their invasion front than CCL15-negative colorectal cancers. Importantly, these CCR1(+) cells were of the myeloid-derived suppressor cell (MDSC) phenotype (CD11b(+), CD33(+), and HLA-DR(-)). Most CCR1(+) cells showed the granulocytic-MDSC phenotype (CD15(+)), whereas some showed the monocytic-MDSC phenotype (CD14(+)). Serum CCL15 levels in colorectal cancer patients were significantly higher than in controls. CONCLUSIONS: Blocking the recruitment of CCR1(+) MDSCs may represent a novel molecular-targeted therapy, and serum CCL15 concentration can be a novel biomarker for colorectal cancer.

Relationship Between 18F-FDG PET/CT Scans and KRAS Mutations in Metastatic Colorectal Cancer.

UNLABELLED: Several studies have shown that KRAS mutations in colorectal cancer (CRC) result in the lack of response to anti-epidermal growth factor receptor-based therapy; thus, KRAS mutational testing has been incorporated into routine clinical practice. However, 1 limitation of this test is the heterogeneity of KRAS status, which can be either intratumoral heterogeneity within an individual primary CRC or discordant KRAS status between a primary CRC and its corresponding metastases. We previously reported that (18)F-FDG accumulation was significantly higher in primary CRCs with mutated KRAS than in those with wild-type KRAS. However, the clinical utility of the previous report has been limited because endoscopic biopsy for testing KRAS status is safe and feasible only in primary CRC. The purpose of this study was to investigate whether KRAS status is associated with (18)F-FDG accumulation in metastatic CRC and whether (18)F-FDG PET/CT scans can be used to predict the KRAS status of metastatic CRC. METHODS: A retrospective analysis was performed on 55 metastatic CRC tumors that were identified by (18)F-FDG PET/CT before surgical resection. Maximum standardized uptake value (SUVmax) of the respective metastatic tumor was calculated from (18)F-FDG accumulation. RESULTS: From the analysis with the 55 tumors, no significant correlation was found between SUVmax and KRAS status. We next analyzed only tumors larger than 10 mm to minimize the bias of partial-volume effect and found that SUVmax was significantly higher in the KRAS-mutated group than in the wild-type group (8.3 ± 4.1 vs. 5.7 ± 2.4, respectively; P = 0.03). Multivariate analysis indicated that SUVmax remained significantly associated with KRAS mutations (P = 0.04). KRAS status could be predicted with an accuracy of 71.4% when an SUVmax cutoff value of 6.0 was used. CONCLUSION: (18)F-FDG accumulation into metastatic CRC was associated with KRAS status. (18)F-FDG PET/CT scans may be useful for predicting the KRAS status of metastatic CRC and help in determining the therapeutic strategies against metastatic CRC.

Adenocarcinoma arising at a colostomy site with inguinal lymph node metastasis: report of a case.

Inguinal lymph node metastasis from adenocarcinoma arising at a colostomy site is extremely rare, and the significance of surgical resection for metastatic inguinal lymph nodes has not been established. An 82-year-old woman who had undergone abdominoperineal resection 27 years earlier was admitted to our hospital complaining of bleeding from a colostomy. Physical examination revealed that a tumor at the colostomy site directly invaded into the peristomal skin, and that a left inguinal lymph node was firm and swollen. Positron emission tomography/computed tomography scan demonstrated accumulation of (18)F-fluorodeoxy glucose into both the colostomy tumor and the left swollen inguinal lymph node, while there was no evidence of metastasis to liver or lungs. She underwent open left hemicolectomy with wide local resection of the colostomy, and dissection of left inguinal lymph nodes. Histological diagnosis was a moderately differentiated adenocarcinoma that directly invaded into the surrounding skin and metastasized to the left inguinal lymph node. The patient has been followed up for >5 years without any sign of recurrence. In general, inguinal lymph node metastasis from colorectal cancers is regarded as a systemic disease with a poor prognosis, and so systemic chemotherapy and radiotherapy, but not surgical lymph node dissection, are recommended. Considering the lymphatic drainage route in the present case, inguinal lymph node metastasis does not represent a systemic disease but rather a sentinel nodal metastasis from adenocarcinoma at a colostomy site. Surgical dissection of metastatic inguinal lymph nodes should be considered to enable a favorable prognosis in the absence of distant metastasis to other organs.

Regulation of 18F-FDG accumulation in colorectal cancer cells with mutated KRAS.

UNLABELLED: KRAS gene mutations occur in approximately 40% of colorectal cancers (CRCs) and are associated with resistance to anti-epidermal growth factor receptor antibody therapy. We previously demonstrated that (18)F-FDG accumulation in PET was significantly higher in CRCs with mutated KRAS than in those with wild-type KRAS in a clinical setting. Here, we investigated the mechanisms by which mutated KRAS increased (18)F-FDG accumulation. METHODS: Using paired isogenic human CRC cell lines that differ only in the mutational status of the KRAS gene, we measured (18)F-FDG accumulation in these cells in vitro and in vivo. We also investigated the roles of proteins that have a function in (18)F-FDG accumulation. Finally, we examined the relationship among mutated KRAS, hypoxia-inducible factor 1α (HIF-1α), and maximum standardized uptake value with 51 clinical CRC samples. RESULTS: In the in vitro experiments, (18)F-FDG accumulation was significantly higher in KRAS-mutant cells than in wild-type controls under normoxic conditions. The expression levels of glucose transporter 1 (GLUT1) and hexokinase type 2 (HK2) were higher in KRAS-mutant cells, and (18)F-FDG accumulation was decreased by knockdown of GLUT1. Hypoxic induction of HIF-1α was higher in KRAS-mutant cells than in wild-type controls; in turn, elevated HIF-1α resulted in higher GLUT1 expression and (18)F-FDG accumulation. In addition, HIF-1α knockdown decreased (18)F-FDG accumulation under hypoxic conditions only in the KRAS-mutant cells. Small-animal PET scans showed in vivo (18)F-FDG accumulation to be significantly higher in xenografts with mutated KRAS than in those with wild-type KRAS. The immunohistochemistry of these xenograft tumors showed that staining of GLUT1 was consistent with that of HIF-1α and pimonidazole. In a retrospective analysis of clinical samples, KRAS mutation exhibited a significantly positive correlation with expressions of GLUT1 and HIF-1α and with maximum standardized uptake value. CONCLUSION: Mutated KRAS caused higher (18)F-FDG accumulation possibly by upregulation of GLUT1; moreover, HIF-1α additively increased (18)F-FDG accumulation in hypoxic lesions. (18)F-FDG PET might be useful for predicting the KRAS status noninvasively.

Loss of SMAD4 from colorectal cancer cells promotes CCL15 expression to recruit CCR1+ myeloid cells and facilitate liver metastasis.

BACKGROUND & AIMS: Loss of the tumor suppressor SMAD4 correlates with progression of colorectal cancer (CRC). In mice, colon tumors that express CCL9 recruit CCR1(+) myeloid cells, which facilitate tumor invasion and metastasis by secreting matrix metalloproteinase 9. METHODS: We used human CRC cell lines to investigate the ability of SMAD4 to regulate expression of CCL15, a human ortholog of mouse CCL9. We used immunohistochemistry to compare levels of CCL15 and other proteins in 141 samples of human liver metastases. RESULTS: In human CRC cell lines, knockdown of SMAD4 increased CCL15 expression, and overexpression of SMAD4 decreased it. SMAD4 bound directly to the promoter region of the CCL15 gene to negatively regulate its expression; transforming growth factor-ß increased binding of SMAD4 to the CCL15 promoter and transcriptional repression. In livers of nude mice, SMAD4-deficient human CRC cells up-regulated CCL15 to recruit CCR1(+) cells and promote metastasis. In human tumor samples, there was a strong inverse correlation between levels of CCL15 and SMAD4; metastases that expressed CCL15 contained 3-fold more CCR1(+) cells than those without CCL15. Patients with CCL15-expressing metastases had significantly shorter times of disease-free survival than those with CCL15-negative metastases. CCR1(+) cells in the metastases expressed the myeloid cell markers CD11b and myeloperoxidase, and also matrix metalloproteinase 9. CONCLUSIONS: In human CRC cells, loss of SMAD4 leads to up-regulation of CCL15 expression. Human liver metastases that express CCL15 contain higher numbers CCR1(+) cells; patients with these metastases have shorter times of disease-free survival. Reagents designed to block CCL15 recruitment of CCR1(+) cells could prevent metastasis of CRC to liver.