Preoperative fluorescent clip marking vs. India ink tattooing for tumor identification during colorectal surgery.

PURPOSE: Identifying tumor location is important in colorectal tumor resection. Preoperative endoscopic India ink marking is a widespread practice, but local injection of ink is an unstable procedure. Although it is often invisible, the ink may be sprayed into the peritoneal cavity and contaminate the surgical field. At our hospital, we introduced fluorescent clip marking (FCM) using the Zeoclip FS®, an endoscopic clip developed using near-infrared fluorescent resin. We tested the usefulness of FCM by retrospectively comparing cases in which FCM was used with cases in which conventional ink marking was used. METHODS: We enrolled 305 patients with colorectal tumors who underwent colorectal surgery after preoperative marking from January 2017 to April 2022. We classified the patients into the FCM group (86 patients) and the India ink tattoo group (219 patients). Endoscopic marking was completed in the FCM group by the day before surgery, and fluorescence was evaluated during surgery with a fluorescent laparoscopic system. Patient backgrounds, marking visibility, adverse effects, and early postoperative results were retrospectively compared between groups. RESULTS: Marking was visually confirmed in 80 patients in the FCM group (93.02%) and in 166 patients in the India ink tattoo group (75.80%) (p = 0.0006). In the group with India ink tattoos, contamination of the surgical field was observed in seven cases (3.20%). No adverse events were observed in the FCM group. CONCLUSION: In colorectal surgery, FCM provides better visibility than the conventional India ink tattooing method and is a simple and safe marking method. CLINICAL TRIAL REGISTRATION: Examination of fluorescence navigation for laparoscopic colorectal cancer surgery. Research Ethics Committee of the Kawaguchi Municipal Medical Center (Saitama, Japan) approval number: 2020-3. https://kawaguchi-mmc.org/wp-content/uploads/clinicalresearch-r02.pdf .

Preoperative evaluation of oral hygiene may predict the overall survival of patients with esophageal cancer.

BACKGROUND: Previously, the association between tooth loss and prognosis after esophagectomy was reported; however, the presence of periodontal disease has not been assessed. This study investigated the association between the degree of oral hygiene, as evaluated by tooth loss and periodontal disease, and the prognosis of patients with esophageal cancer. METHODS: A total of 163 esophageal cancer patients who underwent surgery with perioperative oral care and examination were enrolled. We assessed the periodontal pocket depth for the presence of periodontal disease and established a periodontal pocket index, defined as the sum of the periodontal pocket depth of the remaining tooth divided by the total count of the remaining teeth. Patients were divided into three groups: Group A (tooth loss < 13 and periodontal pocket index < 3.67); Group B (tooth loss < 13 and periodontal pocket index ≥ 3.67); and Group C (tooth loss ≥ 13). Overall survival and cancer-specific survival were analyzed, and a multivariate analysis was performed. RESULTS: There was a significant difference in the 5-year overall survival rates between the groups (A:B:C = 74.8%:62.8%:50.5%; p = 0.0098), but not in the 5-year cancer-specific survival rates (A:B:C = 80.2%:64.2%:62.2%; p = 0.0849). In multivariate analysis, oral hygiene (tooth loss < 13 and periodontal pocket index ≥ 3.67 + tooth loss ≥ 13; p = 0.041) was a significant independent poor prognostic factor for overall survival. CONCLUSIONS: Oral evaluation, focusing on tooth loss and periodontal disease, is meaningful in predicting the long-term prognosis of postoperative esophageal cancer patients.

Fluorescence vessel and ureter navigation during laparoscopic lateral lymph node dissection.

BACKGROUND: Lateral lymph node metastasis in lower rectal cancer is considered a local disease in Japan, and guidelines suggest lateral lymph node dissection (LLND). However, laparoscopic procedures are relatively difficult. The ureter and hypogastric fascia must be dissected from the vesicohypogastric fascia to preserve the autonomic nerve and ureter. Additionally, lymph node dissection around the internal iliac artery is complex because many patterns of branching from the internal iliac artery exist. We investigated the utility of fluorescence ureter and vessel navigation using a near-infrared ray fluorescent ureteral catheter (NIRFUC) and indocyanine green (ICG). METHODS: Fourteen patients who underwent laparoscopic LLND using fluorescence navigation were included. Eleven patients had rectal cancer, 1 had anal cancer, and 2 exhibited recurrence of rectal cancer. Eleven patients underwent NIRFUC insertion before surgery. Fluorescence vessel navigation (FVN) was performed with intraoperative ICG injections in 14 patients, with a total of 18 sides. The outcome measures were ureter navigation visibility, detection of the branch form from the internal iliac artery with FVN, differences between the fluorescence findings and anatomy of the internal iliac artery determined after LLND, and the surgical outcome. RESULTS: In all 11 patients, the ureters were clearly identified as fluorescent before dissection around the ureter. FVN revealed the internal iliac, umbilical, and superior vesical arteries in all patients. The branch from the internal iliac artery according to the Adachi classification was revealed on 16 sides (89%). The time from intravenous ICG injection to fluorescence of the internal iliac artery was 38 (17-57) s. The time from intravenous injection to when the vessels were observed as fluorescent was 113 (65-661) s. No ureteral or vessel injuries occurred. CONCLUSIONS: Fluorescence navigation of vessels and the ureter is feasible in laparoscopic LLND and has the potential to increase safety. CLINICAL TRIAL REGISTRATION: Examination of fluorescence navigation for laparoscopic colorectal cancer surgery Research Ethics Committee of the Kawaguchi Municipal Medical Center (Saitama, Japan) approval number: 2020-3. https://kawaguchi-mmc.org/wp-content/uploads/clinicalresearch-r02.pdf.

Fluorescence angiography vs. direct palpation for bowel viability evaluation with strangulated bowel obstruction.

PURPOSE: In surgery for strangulated bowel obstruction, intestinal blood flow (IBF) is usually evaluated by observing bowel colour, peristalsis, intestinal temperature and arterial pulsations in the mesentery. We investigated whether indocyanine green (ICG) fluorescence angiography (ICG-FA) is an effective alternative to palpation. METHODS: Thirty-eight patients who underwent emergency surgery for strangulated bowel obstruction from January 2017 to April 2021 were divided into two groups: (i) the ICG + group, in which ICG was used during laparoscopic surgery (n = 16), and (ii) the ICG - group, in which palpation without ICG was used during open surgery (n = 22). Starting in July 2019, ICG and laparoscopic surgery were applied in all cases except emergency cases when the fluorescence laparoscope was not ready. Surgical outcomes and patient characteristics were compared. RESULTS: Patient characteristics, the operative duration and postoperative hospitalization duration did not significantly differ between the groups. Bowel resection was performed in 4 cases (25%) among ICG + patients and 11 cases (50%) among ICG - patients. The ratios of pathological findings (ischaemia:mucosal necrosis:transmural necrosis) were 0:2:2 and 1:6:4 in the two groups, respectively. Blood loss was measured with gauze and suction tubes and was 1 (0-5) mL in the ICG + group and 12.5 (0-73) mL in the ICG - group (p = 0.002). Postoperative complications occurred in 1 case (6.3%) in the ICG + group and 9 cases (40.9%) in the ICG - group (p = 0.025). CONCLUSION: Although there were few intestinal resections in the ICG + group, the rate of pathological necrosis tended to be high, and no complications due to ineligibility were noted in the intestinal preservation group. During laparoscopic surgery, ICG-FA is useful as a substitute for palpation and has the potential to improve surgical outcomes. CLINICAL TRIAL REGISTRATION: Research Ethics Committee of the Kawaguchi Municipal Medical Center (Saitama, Japan) approval number: 2019-40.

CD36 Expression Is Associated with Cancer Aggressiveness and Energy Source in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. CD36, a long-chain fatty acid (FA) receptor, can initiate metastasis in human oral squamous cell carcinoma (SCC), and its expression is associated with poor prognosis in several cancers. The clinical significance of CD36 expression and its function in ESCC remain unknown. METHODS: We examined the clinical significance of CD36 expression in 160 ESCC samples using immunohistochemical staining. Functional analysis was performed to determine the association between CD36 and ESCC characteristics (proliferative ability, invasive ability, and energy source dependency). RESULTS: Thirty (18.8%) ESCC cases showed high CD36 expression, indicating a significant association with progression. CD36 suppression inhibited proliferation and invasiveness in ESCC cells. ESCC cells with CD36 suppression used specific essential amino acids (EAAs) as energy sources. Cell viability depended on FAs under CD36 expression. The viability of ESCC cells with CD36 suppression depended on EAAs but not FAs. CONCLUSIONS: CD36 may be a good biomarker and therapeutic target in ESCC. Our data provide new insights into the basic mechanism of CD36-dependent energy utilization for ESCC survival. CD36 might be a key regulator of the dependency of FAs as energy source in ESCC cells.

High L-Type Amino Acid Transporter 1 Levels Are Associated with Chemotherapeutic Resistance in Gastric Cancer Patients.

INTRODUCTION: We investigated whether the expression of L-type amino acid transporter 1 (LAT-1) in clinical gastric cancer (GC) patients could predict patient therapeutic response to postoperative adjuvant chemotherapy. METHODS: Immunohistochemistry was used to investigate LAT-1, CD98, and phosphorylated-mammalian target of rapamycin (p-mTOR) expression in 111 GC patients. To clarify whether LAT-1 influences the therapeutic effects of chemotherapy, the correlation between disease-free survival rates and LAT-1 was determined in 2 groups: 59 patients who did not undergo postoperative adjuvant chemotherapy and 52 patients who did undergo postoperative adjuvant chemotherapy. RESULTS: LAT-1 was significantly correlated with CD98 and p-mTOR expressions. We did not find any statistically significant correlation between LAT-1 and recurrence in the nontreated group. In contrast, a significant association was found between LAT-1 expression and disease-free survival in the chemotherapy group. Moreover, multivariate regression analysis demonstrated that LAT-1 was an independent predictor of disease-free survival in the postoperative adjuvant chemotherapy group (p = 0.012). CONCLUSION: Our findings demonstrate that LAT-1 is a useful predictive marker for a successful postoperative adjuvant chemotherapy treatment.

Chest Pain after Endoscopic Submucosal Dissection for Esophageal Cancer: The Simple and Clinically Useful Surrogate Marker for Transmural Thermal Injury by Electrocoagulation.

BACKGROUND: Endoscopic submucosal dissection (ESD) of early esophageal cancer (EC) is becoming more widespread. Post-ESD coagulation syndrome (CS) has been proposed as temporary inflammatory signs that occur during the post-ESD period caused by transmural thermal injury by electrocoagulation. This retrospective study aimed to evaluate the association between chest pain and abnormal levels of inflammatory markers during the post-esophageal ESD period. We also investigate the clinical importance of chest pain to define the post-esophageal ESD CS. METHODS: We examined 42 patients with thoracic EC who underwent ESD. RESULTS: The incidence of chest pain after esophageal ESD is 35.7% and associated with elevation of WBC count on postoperative day 1 (WBC day 1) (p = 0.022). Multivariate logistic regression analysis using the procedure-related factors revealed that WBC day 1 was an independent predictive factor for chest pain (p = 0.034). The elevation of WBC count is associated with the resected esophageal circumference (p for trend = 0.018), specimen size (p = 0.031), and procedural time (p = 0.004). The incidence of post-esophageal ESD CS was estimated ranging from 11.9 to 54.8% using previously reported criteria. CONCLUSIONS: The incidence of chest pain after ESD was only associated with postoperative elevation of WBC day 1. In considering the elevation of WBC count associated with procedure-related factors, chest pain possibly reflected transmural thermal injury by electrocoagulation during ESD. Post-esophageal ESD chest pain is a simple and clinically useful surrogate marker for transmural thermal injury and is a vital sign of post-esophageal ESD CS.

Ureteral navigation using a fluorescent ureteral catheter during laparoscopic colorectal surgery.

BACKGROUND: Ureteral injury is the most common urological complication of pelvic surgery, with a reported incidence during colon resection of 0.3-1.5%. Ureteral stenting is commonly performed preoperatively to prevent ureteral injury. Because tactile sensation is not reliable during laparoscopic surgery, the effect of the ureteral stent is considered limited. Recently, fluorescence imaging has been used in laparoscopic surgery. The Near-Infrared Ray Catheter (NIRC™) fluorescent ureteral catheter (NIRFUC) is a new catheter with built-in NIR fluorescent resin. This pilot study was performed to evaluate the utility of fluorescence ureteral navigation using the NIRFUC during laparoscopic colorectal surgery. METHODS: We evaluated the intraoperative utility of the NIRFUC and the short-term outcomes in 20 patients treated with colorectal surgery at Kawaguchi Municipal Medical Center between February and July 2020. In all, 18 patients with malignant tumors and 2 patients with benign disease, i.e., a sigmoid colovesical fistula, were included. Ten patients developed preoperative intestinal obstruction. One patient experienced preoperative perforation. Nine patients developed preoperative peritumoral abscesses. Laparoscopic surgery was performed with the VISERA ELITE2 system. RESULTS: In all cases, the ureters were very clearly identified as fluorescent without the need for dissection. In all cases, only a moment was required to identify the ureter by fluorescence observation. In all cases, R0 resection was performed. The mean surgical duration was 334 min (161-1014), the mean blood loss was 10 ml (1-500), and the mean postoperative hospital stay was 11 days (8-47). There were no cases of ureteral injury. CONCLUSION: The NIRFUC was very clearly identified as fluorescent in a moment during surgery without dissection around the ureter. Fluorescence ureteral navigation using the NIRFUC may make colorectal surgery easier and facilitate completion of complex minimally invasive surgery, especially during surgery in patients with invasion of the surrounding tissue or a history of pelvic surgery or radiation.

Uptake of positron emission tomography tracers reflects the tumor immune status in esophageal squamous cell carcinoma.

The relationship between the local immune status and cancer metabolism regarding 18 F-FDG and 18 F-FAMT uptake in esophageal squamous cell carcinoma (ESCC) remains unknown. The present study examined the correlations between tumor immune status, clinicopathological factors, and positron emission tomography (PET) tracer uptake in ESCC. Forty-one ESCC patients who underwent 18 F-FDG PET and 18 F-FAMT PET before surgery were enrolled in the study. Immunohistochemistry was conducted for programmed death 1 (PD-1), CD8, Ki-67, CD34, GLUT1 (18 F-FDG transporter) and LAT1 (18 F-FAMT transporter). ESCC specimens with high tumoral PD-L1 and high CD8-positive lymphocytes were considered to have "hot tumor immune status." High PD-L1 expression (53.7%) was significantly associated with tumor/lymphatic/venous invasion (P = 0.028, 0.032 and 0.018), stage (P = 0.041), CD8-positive lymphocytes (P < 0.001), GLUT1 (P < 0.001), LAT1 expression (P = 0.006), Ki-67 labelling index (P = 0.009) and CD34-positive vessel counts (P < 0.001). SUVmax of 18 F-FDG was significantly higher in high PD-L1 cases than in low PD-L1 cases (P = 0.009). SUVmax of 18 F-FAMT was significantly higher in high PD-L1 (P < 0.001), high CD8 (P = 0.012) and hot tumor groups (P = 0.028) than in other groups. High SUVmax of 18 F-FAMT (≥4.15) was identified as the only predictor of hot tumor immune status. High PET tracer uptake was significantly associated with cancer aggressiveness and hot tumor immune status in ESCC. PET imaging may be an effective tool to predict tumor immune status in ESCC with respect to immune checkpoint inhibitor sensitivity.

Elucidation of the Anatomical Mechanism of Nodal Skip Metastasis in Superficial Thoracic Esophageal Squamous Cell Carcinoma.

BACKGROUND: Lymph node metastasis (LNM) is a standard mechanism of cancer progression in esophageal squamous cell carcinoma (ESCC). We aimed to clarify the anatomical mechanism of skip nodal metastasis to mediastinal zones by analyzing the relationship between LNM to sentinel zones and lymphatic vessel counts in the muscle layer adjacent to the outer esophagus. METHODS: We examined the surgical records of 287 patients with ESCC who underwent potentially curative surgery (three-field lymphadenectomy) and whole esophagi, including pharynges and stomachs from 10 cadavers, to determine the number of lymphatic vessels in the intra-outer longitudinal muscle layer adjacent to the outer esophagus of the cervical (Ce), upper thoracic, middle thoracic (Mt), lower thoracic (Lt), and abdominal esophagi (Ae). RESULTS: The frequency of LNM to the middle mediastinal and supraclavicular zones, including the Mt and Ce, respectively, was lower than to the upper and lower mediastinal and abdominal zone in patients with superficial and advanced thoracic ESCC. In cadavers, the lymphatic vessel counts of the intra-outer longitudinal muscle layer in the Mt and Ce were significantly lower than those of the Lt and Ae, suggesting that lymphatic flow toward the outside of the Mt and Ce was not more abundant than to other sites. CONCLUSION: Our anatomical data suggested that the absence of intra-muscle lymphatic vessels in the middle mediastinal and supraclavicular zones causes skip LNM in patients with thoracic ESCC. Thus, standard esophagectomy with lymph node dissection, including distant zones, may be appropriate for treating patients with superficial thoracic ESCC.

18F-FAMT PET Is Useful to Distinguish between Specific Uptake and Nonspecific Uptake Compared to 18F-Flourodeoxyglucose Position Emission Tomography in Esophageal Cancer Patients.

BACKGROUND: L-[3-18F]-α-methyltyrosine (18F-FAMT) solely accumulates in tumor cells via an amino acid transport system. This selective uptake pattern results in a very high tumor-to-background ratio, enabling clear delineation of the tumor. The purpose of the present study was to assess the significance of 18F-FAMT PET, which shows little nonspecific uptake compared to 18F-flourodeoxyglucose position emission tomography (FDG PET) in esophageal cancer patients. METHODOLOGY: PET-CT studies with 18F-FAMT and 18F-FDG were performed as part of pretreatment work-up in 82 patients with histologically confirmed esophageal cancer. We evaluated nonspecific uptakes of 18F-FDG and 18F-FAMT PET. RESULTS: The nonspecific uptake of 18F-FAMT PET was lower than that of 18F-FDG PET (p = 0.282). In the operation group, 26.1% demonstrated nonspecific uptake in 18F-FDG PET, whereas only 2.38% (1 case) demonstrated nonspecific uptake in 18F-FAMT PET (p = 0.433). In the inoperable group, 47.5% showed nonspecific uptake in 18F-FDG PET, whereas 5.0% showed nonspecific uptake in 18F-FAMT PET (p = 0.079). CONCLUSION: A crucial point for the diagnostic value of PET is distinguishing specific and nonspecific uptake. 18F-FAMT-PET is a very superior modality with regard to the lower rate of nonspecific uptake in esophageal cancer.

[High-resolution Manometry for Esophageal Motility Disorders].

High-resolution manometry (HRM) has significant contribution in the field of esophageal motility disorders recently. The development of HRM has categorized various esophageal motility disorders focusing on patterns of esophageal motor function. Additionally, the Chicago classification criteria are widely used for manometric diagnosis. HRM provides functional imaging of the esophagus. HRM has closely spaced pressure sensors and displays pressure variations as pressure topography plots. In the analysis of HRM according to the Chicago classification, a hierarchical categorization of motility disorders is made after evaluation of the individual swallow patterns. First the lower esophageal sphincter (LES) function, and subsequently the esophageal pressure patterns are used to make a diagnosis. The hierarchical flow-chart has 4 groups; (1) incomplete LES relaxation( achalasia or esophagogastric junction outflow obstruction), (2) major motility disorders, (3) minor motility disorders, (4) normal esophageal motility. HRM is the gold standard for diagnosis of esophageal motility disorders.

Utility of double endoscopic intraluminal operation for esophageal cancer.

OBJECTIVES: Endoscopic submucosal dissection (ESD) is a more difficult technique for esophageal cancer than for gastric cancer because the working space for esophageal ESD is small. Further, the difficulty level gradually increases depending on the size of the carcinoma. To overcome these difficulties, double endoscopic intraluminal operation (DEILO), which enables the resection of mucosal lesions using two fine endoscopes and monopolar shears, was reported previously. Here, we report the utility of DEILO for esophageal cancer. METHODS: A total of 26 esophageal cancer patients (19 men and seven women) with 26 lesions treated using DEILO between 2011 and 2014 at Gunma University Hospital were included. We evaluated the utility and safety of DEILO for early esophageal cancer. RESULTS: For all patients (100%), the DEILO procedure was performed successfully, and en bloc resection was achieved. The median operation time, postoperative hospital stay, and the longitudinal dimension of resected specimens were 123 min (range 45-236 min), 5 days, and 32 mm, respectively. Perioperative perforation, pneumothorax, and mediastinal emphysema were not recognized. Only one patient was diagnosed with a postoperative hemorrhage, but the bleeding was successfully treated by bleeding vessel coagulation. CONCLUSION: DEILO has good utility as a technique of ESD for early esophageal cancers. Additional improvement and advancement of the procedure will increase the indication of DEILO.

Impact of the Level of Anastomosis on Reflux Esophagitis Following Esophagectomy with Gastric Tube Reconstruction.

BACKGROUND: Among patients who undergo gastric tube reconstruction after esophagectomy, it is generally accepted that the incidence of reflux esophagitis (RE) is significantly lower in patients with neck anastomosis than in those with intrathoracic anastomosis. However, the true impact of the level of anastomosis on RE currently remains unclear. METHODS: We examined 53 patients with thoracic esophageal cancer underwent radical esophagectomy with gastric tube reconstruction and neck anastomosis. The level of anastomosis was assessed by measuring the distance from the sternal notch to the stapled ring by computed tomography. The relative level of anastomosis was calculated by the distance from the sternal notch to the most caudal side of the stapled ring (mm)/height (cm). RESULTS: The relative level of anastomosis in 30 (56.6%) patients showed <0, which indicated that anastomosis in these patients was located at a lower level than the sternal notch. The mean relative level of anastomosis was significantly lower in patients with RE (grade A to D) than in those without RE (grade N) (-0.062 vs. -0.012 mm/cm, respectively; p = 0.043). RE was more severe with a lower relative level of anastomosis (p for trends = 0.044). CONCLUSIONS: The level of anastomosis in patients with gastric tube reconstruction following esophagectomy was associated with the incidence of RE. The displacement of anastomosis into the thoracic cavity was detected in approximately half of the patients with neck anastomosis. RE was more severe with a lower level of anastomosis, even in patients with neck anastomosis.

TGFBI Expression in Cancer Stromal Cells is Associated with Poor Prognosis and Hematogenous Recurrence in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Esophageal squamous cell carcinoma (ESCC) is an important cause of cancer-related death worldwide. To improve prognoses in patients with ESCC, we evaluated the potential of transforming growth factor-beta-induced protein (TGFBI), which is overexpressed in ESCC, as a therapeutic candidate. METHODS: We examined the clinical significance of TBFBI in 102 ESCC samples using real-time RT-PCR. Immunohistochemical studies were conducted to examine the localization of TGFBI. Knockdown of TGFBI in cocultured fibroblasts was performed to determine the roles of TGFBI in migration and invasion. RESULTS: The level of TGFBI in ESCC tissues was higher than that in normal tissues. The high TGFBI expression group (n = 16) had higher TGFB1 expression and more frequent hematogenous recurrence than the low-expression group (n = 86). High TGFBI expression was an independent prognostic factor in patients with ESCC. TGFBI was mainly localized in stromal cells of ESCC. Moreover, suppression of TGFBI in fibroblasts inhibited the migration and invasion capacity of TE8 ESCC cells. CONCLUSIONS: High TGFBI expression in ESCC tissues could be a powerful biomarker of poor prognosis and hematogenous recurrence. TGFBI in stromal cells might be a promising molecular target for ESCC treatment.

Nuclear PRMT1 expression is associated with poor prognosis and chemosensitivity in gastric cancer patients.

BACKGROUND: Metastatic and refractory gastric cancer (GC) are associated with a poor prognosis; therefore, the identification of prognostic factors and chemosensitivity markers is extremely important. Protein arginine methyltransferase 1 (PRMT1) may play a role in chemosensitivity/apoptosis induction via activation of the tumor suppressor forkhead box O1 (FOXO1). The purpose of this study was to clarify the expression of and relationship between PRMT1 and FOXO1 to evaluate the applicability of PRMT1 as a prognostic marker and a therapeutic tool in GC. METHODS: We investigated the clinical and functional significance of PRMT1 and FOXO1 in 195 clinical GC samples using immunohistochemistry. We performed suppression analysis of PRMT1 using small interfering RNA to determine the biological roles of PRMT1 in chemosensitivity. RESULTS: PRMT1 and FOXO1 in GC samples were predominantly expressed in the nucleus. Patients with lower PRMT1 expression (n = 131) had suppressed nuclear accumulation of FOXO1, higher recurrence after adjuvant chemotherapy, and poorer prognosis than those with higher PRMT1 expression (n = 64). PRMT1 downregulation in GC cells by RNA interference inhibited cisplatin and 5-fluorouracil sensitivity. The expression of phosphorylated FOXO1 and phosphorylated BCL-2 antagonist of cell death was upregulated in PRMT1 small interfering RNA groups. CONCLUSION: Our data suggest that the evaluation of PRMT1 expression in GC is a useful predictor of poor prognosis and recurrence after adjuvant chemotherapy. Moreover, these data suggest that PRMT1 is a promising therapeutic tool for overcoming refractory GC.

Nuclear PROX1 is Associated with Hypoxia-Inducible Factor 1α Expression and Cancer Progression in Esophageal Squamous Cell Carcinoma.

BACKGROUND: Transcription factor prospero homeobox 1 (PROX1) has been identified as a master regulator of lymphangiogenesis associated with metastasis. Although PROX1 expression has been investigated in several cancers, its clinical significance remains controversial and needs further validation. In this study, we investigated the clinical and functional significance of PROX1 and PROX1 regulator hypoxia-inducible factor 1α (HIF1α) in esophageal squamous cell carcinoma (ESCC). METHODS: A total of 117 samples from ESCC patients were analyzed for PROX1, HIF1α, and E-cadherin expression by immunohistochemistry; correlation with clinicopathological characteristics was determined. PROX1 function was evaluated in PROX1 small interfering RNA (siRNA)-transfected human ESCC cells in vitro by assessing cell proliferation and migration. RESULTS: PROX1 expression was higher in ESCC than in normal tissues. Patients with higher PROX1 expression (n = 26) had increased nuclear accumulation of HIF1α (p = 0.004) and more advanced metastasis, both lymph node (N factor; p = 0.09) and hematogenous (M factor; p = 0.04), than those with lower PROX1 expression (n = 91). In addition, high PROX1 and HIF1α expression correlated with low levels of E-cadherin, an epithelial cell marker. Analysis of overall and cancer-specific survival indicated that elevated PROX1 expression was significantly correlated with poor prognosis (p = 0.0064). PROX1 downregulation in ESCC cells inhibited cellular proliferation and migration (p < 0.05). Hypoxia restored PROX1 levels that were reduced by PROX1-specific siRNA. CONCLUSION: Our data suggest that high expression of PROX1 in ESCC could be used as an indicator of poor prognosis, and that PROX1 is a promising candidate molecular target for ESCC treatment.

Usefulness of 18f-Fluorodeoxyglucose Positron Emission Tomography for Predicting the Pathological Response of Neoadjuvant Chemoradiotherapy for T4 Esophageal Squamous Cell Carcinoma.

BACKGROUND/AIMS: The purpose of this study is to assess the efficacy of 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET) in predicting the pathological response of neoadjuvant chemoradiation (CRT) for clinically diagnosed T4 esophageal squamous cell carcinoma (SCC). METHODOLOGY: We examined 32 patients with T4 thoracic esophageal SCC who received neoadjuvant CRT followed by surgery. RESULTS: Pathological complete response (pCR) was achieved in 7 patients (21.9%). pCR was significant correlated with standardized uptake value (SUV) after neoadjuvant CRT (P = 0.034) and SUV decrease (%) (P = 0.030). The optimal cut-off values to predict pCR were 2.25 for SUV after neoadjuvant CRT and 79.3 for SUV decrease (%). Of note, no patients who did not reach both cut-off values achieved pCR. Conclusions: SUV after CRT and SUV decrease (%) in FDG-PET of the primary tumor are useful tools to predict pathological response of neoadjuvant CRT for T4 esophageal SCC.

Effectiveness of Combination Chemotherapy With Docetaxel, Nedaplatin, and 5-Fluorouracil for Advanced and Recurrent Esophageal Cancer.

BACKGROUND/AIM: Chemotherapy and immunotherapy have been recently developed as potentially useful first-line treatments for unresectable, advanced, or recurrent esophageal cancer. We performed a retrospective study of the therapeutic effectiveness of triplet chemotherapy with docetaxel, nedaplatin, and 5-fluorouracil therapy for advanced, recurrent, and unresectable advanced esophageal cancer at our hospital and compared the regimen's results with those of current and possible future treatment options. PATIENTS AND METHODS: The study cohort comprised 101 patients who received docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer at Gunma University from May 2008 to December 2017. We retrospectively evaluated the results of this combination chemotherapy and postulated future treatment strategies. RESULTS: The overall response and disease control rates, the latter including stable disease, for docetaxel, nedaplatin, and 5-fluorouracil were 33.6% and 61.4%, respectively. The median overall survival and progression-free survival were 12.26 months and 5.1 months, respectively. In patients with recurrence, the median overall and progression-free survivals were 14.97 months (449 days) and 5.1 months (152 days), respectively. No study patients developed acute kidney injury and there were no treatment-related deaths. However, leukopenia and neutropenia were frequent hematologic toxicities. CONCLUSION: Treatment with docetaxel, nedaplatin, and 5-fluorouracil for advanced or recurrent esophageal cancer is particularly useful for recurrent cases and has the advantage of not causing severe renal dysfunction.