Right gastroepiploic artery length determined anastomotic leakage after minimally invasive esophagectomy for esophageal cancer: a prospective cohort study.

BACKGROUND: This prospective cohort study, conducted at a high-volume esophageal cancer center from July 2019 to July 2022, aimed to investigate the link between the right gastroepiploic artery (RGEA) length and anastomotic leakage (AL) rates following minimally invasive esophagectomy (MIE). Real-world data on stomach blood supply in the Chinese population were examined. MATERIALS AND METHODS: A total of 516 cases were enrolled, categorized into two groups based on the Youden index-determined optimal cut-off value for the relative length of RGEA (length of RGEA/length of gastric conduit, 64.69%) through ROC analysis: Group SR (short RGEA) and Group LR (long RGEA). The primary observation parameter was the relationship between AL incidence and the ratio of direct blood supply from RGEA. Secondary parameters included the mean length of the right gastroepiploic artery, greater curvature, and the connection type between right and left gastroepiploic vessels. Patient data were prospectively recorded in electronic case report forms. RESULTS: The study revealed median lengths of 43.60 cm for greater curvature, 43.16 cm for the gastric conduit, and 26.75 cm for RGEA. AL, the most common postoperative complication, showed a significant difference between groups (16.88 vs. 8.84%, P =0.01). Multivariable binary logistic regression identified Group SR and LR (odds ratio: 2.651, 95% CI: 1.124-6.250, P =0.03) and Neoadjuvant therapy (odds ratio: 2.479, 95% CI: 1.374-4.473, P =0.00) as independent predictors of AL. CONCLUSIONS: The study emphasizes the crucial role of RGEA length in determining AL incidence in MIE for esophageal cancer. Preserving RGEA and fostering capillary arches between RGEA and LGEA are recommended strategies to mitigate AL risk.

Concurrent radiotherapy cannot provide superiority of surgical oncological outcome and long-term survival rate in locally advanced esophageal squamous cell carcinoma patients receiving neoadjuvant chemotherapy followed by minimally invasive esophagectomy.

BACKGROUND: To evaluate effectiveness of concurrent radiotherapy in esophageal cancer patient treated with neoadjuvant therapy. METHODS: The data of 1026 consecutive esophageal squamous cell carcinoma (ESCC) patients who underwent minimally invasive esophagectomy (MIE) were retrospectively collected. The main inclusion criteria were patients with locally advanced (cT2-4N0-3M0) ESCC who underwent neoadjuvant chemoradiotherapy (NCRT) or neoadjuvant chemotherapy (NCT) followed by MIE, and divided into two groups according to different neoadjuvant strategies. Propensity score matching was performed to improve the comparability between the two groups. RESULTS: After exclusion and matching, 141 patients were enrolled retrospectively: 92 received NCT, and 49 received NCRT. No difference in clinicopathologic characteristics or incidence of adverse events between groups. A shorter operation time (215.7 ± 35.5 min) (p < 0.001), less blood loss (111.2 ± 67.7 ml) (p = 0.0007) and a greater number of lymph nodes retrieved (33.8 ± 11.7) (p = 0.002) were observed in NCT group than in NCRT group. The incidence of postoperative complications was similar between groups. Although patients in NCRT group had better pathological complete response (16, 32.7%) (p = 0.0026) and ypT0N0 (10, 20.4%) (p = 0.0002) rates, there was no significant difference in 5-year progression-free survival (p = 0.1378) or disease-specific survival (p = 0.1258) between groups. CONCLUSIONS: Compared with NCRT, NCT has certain advantages in that it can simplify the surgical procedure and decrease the surgical technique required without compromising the surgical oncological outcomes and long-term survival of patients.

Safety and feasibility of three-dimensional McKeown minimally invasive esophagectomy.

BACKGROUND: To compare the perioperative outcomes from McKeown minimally invasive esophagectomy (MIE) when performed in three-dimensional versus two-dimensional visualization system, and investigate the learning curve of a single surgeon who implemented three-dimensional McKeown MIE. METHODS: A total of 335 consecutive cases (three-dimensional or two-dimensional) were identified. Perioperative clinical parameters were compared and cumulative sum learning curve was plotted. Propensity score matching was used to reduce selection bias from confounding factors. RESULTS: Patients in three-dimensional group were associated with more chronic obstructive pulmonary disease (23.9% vs 3.0%, p < 0.01). After propensity score matching (108 matched patients in each groups), this finding was no longer statistically significant. Comparing to two-dimensional group, significant improvement in total retrieved lymph nodes (28 vs 33, p = 0.003) was observed in three-dimensional group. In addition, more lymph nodes around the right recurrent laryngeal nerve were harvested in three-dimensional group than that in two-dimensional group (p = 0.045). However, there were no significantly differences were found between the two groups in terms of other intraoperative parameters (e.g., operative time) and postoperative relevant outcomes (e.g., lung infection). Furthermore, the change point in the cumulative sum learning curves for intraoperative blood loss and thoracic procedure time was 33 procedures, respectively. CONCLUSION: Three-dimensional visualization system appears to be superior in performing lymphadenectomy during McKeown MIE to that of a two-dimensional technique. For surgeons proficient in performing two-dimensional McKeown MIE, the learning curve for a three-dimensional procedure appears to begin near proficiency after more than 33 cases.

Effect of pleural adhesions on short- and long-term outcomes after minimally invasive esophagectomy: a propensity score matching analysis.

BACKGROUND: The extent to which the presence of pleural adhesions affects the surgical and oncological outcomes of patients undergoing McKeown minimally invasive esophagectomy (MIE) for esophageal cancer (EC) has not previously been studied. METHODS: Data of consecutive EC patients undergoing McKeown MIE by a single surgeon in the Department of Thoracic Surgery at Daping Hospital from November 2015 to December 2020 were collected. Patients were grouped according to the presence or absence of pleural adhesions when entering the chest cavity. Propensity score matching (PSM) was used to reduce selection bias from confounding factors. Kaplan-Meier was used to assess the survival differences. RESULTS: A total of 617 consecutive EC patients underwent McKeown MIE were enrolled. There were 116 patients with pleural adhesions (Group A) and 501 patients without pleural adhesions (Group B). Patients in Group A were more likely to be older than those of patients in Group B: (66.26 vs. 63.27, P = 0.001). In addition, Group A had more patients with chronic obstructive pulmonary disease (COPD) (24.1% vs. 16.8%, P = 0.04). After propensity score matching (102 matched patients in Group A and 185 matched patients in Group B), these findings were no longer statistically significant. Postoperative pulmonary infection occurred in 57 patients in Group A and in 15 patients in Group B (53.9% vs. 13.0%, P < 0.001). In addition, the presence of pleural adhesions was significantly associated with the prolonged operation time (232 min vs. 210 min, P < .001), length of stay (12 days vs. 10 days, P = 0.001), and hydrothorax requiring drainage (12.7% vs. 5.4%, P = 0.04). However, the disease-specific survival and disease-free survival rates were comparable between the two groups (P = 0.40 and 0.13, respectively). CONCLUSIONS: The presence of pleural adhesions predicted an increased operation time, length of stay, postoperative pneumonia, and hydrothorax requiring drainage of EC patients undergoing McKeown MIE, but did not exert unfavourable effect on long-term survival.

Lymphovascular invasion predicts disease-specific survival in node-negative esophageal squamous cell carcinoma patients after minimally invasive esophagectomy.

Introduction: Lymphovascular invasion (LVI) is reported to be a potential prognostic predictor in esophageal squamous cell carcinoma (ESCC) patients. Aim: To investigate the prognostic value of LVI in ESCC node-negative patients after minimally invasive esophagectomy (MIE). Material and methods: 1406 consecutive ESCC patients who underwent MIE were reviewed retrospectively. After exclusion, 880 patients were enrolled, and 298 node-negative patients were used for the further analysis. The Kaplan-Meier method was used to examine the survival difference. Univariate and multivariate analyses were performed to identify prognostic predictors. Results: LVI was observed in 29.4% of all patients. Totally, the proportion of LVI was increased with advanced T (p < 0.01) and N (p < 0.01) stage and poor tumor differentiation (p < 0.01). In the node-negative patients, a similar result was obtained in T stage (p = 0.0252) and tumor differentiation (p = 0.0080). In survival analysis, the disease-specific survival (DSS) (p = 0.0146) rate was significantly lower in node-negative patients with LVI than in those without. The difference was absent when calculating disease-free survival (DFS) (p = 0.0796). Additionally, the presence of LVI was associated with lower DSS (p = 0.0187) but not DFS (p = 0.0785) in univariate analysis in node-negative patients. Moreover, in multivariate Cox regression analysis, the presence of LVI was identified as an independent prognostic factor only in DSS (p = 0.0496) but not in DFS (p = 0.5670) in node-negative patients. Conclusions: LVI is associated with shorter DSS and an independent prognostic factor in ESCC node-negative patients after MIE.

Does high body mass index influence the postoperative complications and long-term survival in patients with esophageal squamous cell carcinoma after minimally invasive esophagectomy?

Introduction: The prognostic value of high body mass index (BMI) in patients with esophageal squamous cell carcinoma (ESCC) is still controversial. Aim: To evaluate the impact of high BMI on postoperative complications and survival after minimally invasion esophagectomy (MIE) for ESCC patients. Material and methods: Three hundred and fourteen consecutive ESCC patients were used to analyze the potential association between high BMI and postoperative complications and survival. Results: Patients were divided into two groups. There was no significant difference between high and low BMI groups in terms of postoperative complications, including respiratory disease (p = 0.8362), pneumothorax (p = 0.6058), anastomotic leakage (p = 0.8678), chylothorax (p = 0.9062), cardiovascular disease (p = 0.5763), vocal cord paresis (p = 0.8349), wound infection (p = 0.5763) and perioperative death (p = 0.7179). Patients in the high BMI group had a longer operative time (p = 0.003) and more blood loss (p = 0.002) than in the low BMI group. There was no difference in number of retrieved lymph nodes between the two groups (p = 0.728). Patients could not benefit from high BMI in overall survival (OS) (p = 0.2459). High BMI was not an independent prognostic factor for survival (p = 0.1735, HR = 0.776 and 95% CI: 0.5386-1.1180). Conclusions: High BMI is associated with prolonged operative time and increased blood loss in MIE. However, high BMI is not associated with postoperative complications and not an independent prognostic factor for survival in ESCC patients who undergo MIE.

Solitary Celiac Lymph Node Metastasis Has a Better Long-Term Survival Compared With Solitary Mediastinal Lymph Node Metastasis in Esophagectomy of Esophageal Squamous Cell Cancer: A Propensity Score Matching Analysis.

Background: The prognostic benefit of extensive lymphadenectomy remains controversial in esophageal squamous cell carcinoma (ESCC). The purpose of this retrospective study was to investigate the potential effect of solitary mediastinal (SM) lymph node metastasis and solitary celiac (SC) lymph node metastasis on the short- and long-term outcomes for patients who underwent minimally invasive McKeown esophagectomy. Methods: From September 2009 to December 2020, a total of 934 cases were diagnosed with ESCC and underwent minimally invasive McKeown esophagectomy in our department; 223 cases met the inclusion and exclusion criteria. Propensity score matching (PSM) was utilized to contrast the postoperative results and long-term survival of Group 1 (SM) and Group 2 (SC). Univariate and multivariate Cox proportional hazards regression analyses were used on possible predictors of survival. Results: One hundred forty-seven patients were available for outcome comparison after PSM. The postoperative results were not significantly different between the two groups. In terms of long-term survival, the 5-year disease-free survival (DFS) was 37.6% and 57.3% (p = 0.191) and 5-year disease-specific survival (DSS) was 39.7% and 68.4% (p = 0.028) for Group 1 (SM) and Group 2 (SC), respectively. Univariate and multivariate Cox proportional hazards regression analyses showed that body mass index (BMI), pathologic stage (pStage), and SC/SM grouping had significant hazard ratios (HRs), which suggested that SC is associated with better DSS. Conclusion: This cohort study showed that SC lymph node metastasis has a better long-term survival compared with SM lymph node metastasis in esophagectomy of ESCC. The results challenge the current understanding and need confirmation in further research.

Learning Curve and Associated Prognosis of Minimally Invasive McKeown Esophagectomy.

BACKGROUND: The implementation of McKeown minimally invasive esophagectomy (MIE) is associated with a steep learning curve. However, there is no consensus on the number of cases required before effective and safe McKeown MIE can be achieved. METHODS: Data on consecutive patients with esophageal carcinoma who underwent esophagectomy performed by a single surgeon in the Department of Thoracic Surgery at Daping Hospital in Chongqing, China from September 2009 to June 2019 were collected. The cumulative sum learning curve was plotted on the basis of the learning associated parameters. Propensity score matching was used to reduce selection bias from confounding factors. The Kaplan-Meier method was used to assess the survival differences. RESULTS: The learning curve was divided into the ascending period (cases 1-197), the plateau period (198-314), and the descending period (315-onward). After 197 cases, significant improvements in operative time (300 minutes vs 210minutes; P < .001), retrieved lymph nodes (17 vs 20; P = .004), hospital length of stay (18 days vs 13 days; P = .001), major postoperative complications (38.6% vs 32.5%; P < .001), vocal cord palsy (6.1% vs 0.9%; P = .04), and pulmonary complications (31.5% vs 17.1%; P = .005) were observed. In addition, after 314 cases, significant decreases in blood loss (200 mL vs 100 mL; P < .001), anastomotic leak (24.8% vs 14.8%; P = .02), and chylothorax (4.3% vs 0%; P = .001) were observed. After propensity score matching, the overall and disease-free survival rates were significantly improved during the experienced period (P = .02 and .03, respectively). CONCLUSIONS: The initial learning phase of McKeown MIE consisted of 197 procedures in 51 months. Moreover, the surgeon's experience did have a direct impact on the long-term outcomes in patients with esophageal carcinoma.

U three protein 14a (UTP14A) promotes tumour proliferation and metastasis via the PERK/eIF2a/GRP78 signalling pathway in oesophageal squamous cell carcinoma.

Metastasis and malignant proliferation are major obstacles to the treatment of oesophageal squamous cell carcinoma (ESCC), and UTP14A is associated with poor prognosis in ESCC. However, its mechanisms have not been fully elucidated. The TCGA and GEO databases were used to identify candidate target genes and possible downstream targets. Then, the effects were determined in vitro and in vivo through knockdown and overexpression techniques, and the mechanism was explored. UTP14A was significantly higher in the tumour tissue of ESCC patients than in normal tissue. Knockdown of UTP14A significantly suppressed the migration and proliferation of ESCC cells. The PERK/eIF2a signalling pathway was positively regulated by UTP14A, and its tumour-promoting effect was further activated by overexpression of UTP14A. In conclusion, UTP14A might promote the proliferation and metastasis of ESCC cells by inducing PERK/eIF2a signalling pathway expression.

Effect of surgical start time on short- and long-term outcomes after minimally invasive esophagectomy: a propensity-score matching analysis.

There is growing focus on the relationship between surgical start time and postoperative outcomes. However, the extent to which the operation start time affects the surgical and oncological outcomes of patients undergoing esophagectomy has not previously been studied. The purpose of this retrospective study was to investigate the potential effect of surgical start time on the short- and long-term outcomes for patients who underwent thoracoscopic-laparoscopic McKeown esophagectomy. From September 2009 to June 2019, a total of 700 consecutive patients suffering from esophageal cancer underwent thoracoscopic-laparoscopic McKeown esophagectomy in the Department of Thoracic Surgery at Daping Hospital. Among these patients, 166 esophagectomies were performed on the same day and were classified as the first- or second-start group. Patients in the first-start group were more likely to be older than those in the second-start group: (64.73 vs. 61.28, P = 0.002). In addition, patients with diabetes mellitus were more likely to be first-start cases (8.4 vs. 1.2%). After propensity score matching (52 matched patients in first-start cases and 52 matched patients in second-start cases), these findings were no longer statistically significant. There was no difference in the incidence rate of peri- or postoperative adverse events between the first- and second-start groups. The disease-specific survival rates and disease-free survival rates were comparable between the two groups (P = 0.236 and 0.292, respectively). On the basis of the present results, a later start time does not negatively affect the short- or long-term outcomes of patients undergoing minimally invasive McKeown esophagectomy.

Vascular NRP2 triggers PNET angiogenesis by activating the SSH1-cofilin axis.

BACKGROUND: Angiogenesis is a critical step in the growth of pancreatic neuroendocrine tumors (PNETs) and may be a selective target for PNET therapy. However, PNETs are robustly resistant to current anti-angiogenic therapies that primarily target the VEGFR pathway. Thus, the mechanism of PNET angiogenesis urgently needs to be clarified. METHODS: Dataset analysis was used to identify angiogenesis-related genes in PNETs. Immunohistochemistry was performed to determine the relationship among Neuropilin 2 (NRP2), VEGFR2 and CD31. Cell proliferation, wound-healing and tube formation assays were performed to clarify the function of NRP2 in angiogenesis. The mechanism involved in NRP2-induced angiogenesis was detected by constructing plasmids with mutant variants and performing Western blot, and immunofluorescence assays. A mouse model was used to evaluate the effect of the NRP2 antibody in vivo, and clinical data were collected from patient records to verify the association between NRP2 and patient prognosis. RESULTS: NRP2, a VEGFR2 co-receptor, was positively correlated with vascularity but not with VEGFR2 in PNET tissues. NRP2 promoted the migration of human umbilical vein endothelial cells (HUVECs) cultured in the presence of conditioned medium PNET cells via a VEGF/VEGFR2-independent pathway. Moreover, NRP2 induced F-actin polymerization by activating the actin-binding protein cofilin. Cofilin phosphatase slingshot-1 (SSH1) was highly expressed in NRP2-activating cofilin, and silencing SSH1 ameliorated NRP2-activated HUVEC migration and F-actin polymerization. Furthermore, blocking NRP2 in vivo suppressed PNET angiogenesis and tumor growth. Finally, elevated NRP2 expression was associated with poor prognosis in PNET patients. CONCLUSION: Vascular NRP2 promotes PNET angiogenesis by activating the SSH1/cofilin/actin axis. Our findings demonstrate that NRP2 is an important regulator of angiogenesis and a potential therapeutic target of anti-angiogenesis therapy for PNET.

Primary hypothyroidism and isolated ACTH deficiency induced by nivolumab therapy: Case report and review.

RATIONALE: Nivolumab is a monoclonal IgG antibody blocking programmed death receptor-1 (PD1), leading to restoration of the natural T-cell-mediated immune response against the cancer cells. However, it also causes plenty of autoimmune-related adverse events, which often involves endocrine system. PATIENT CONCERNS: A 54-year-old male with renal clear cell carcinoma was treated with nivolumab intravenously. Routine monitoring showed elevated thyroid-stimulating hormone and low free thyroxine after the 6th administration of nivolumab. After the 12th administration, he developed general fatigue, recurrent hypoglycemia, and relative hypotension. Laboratory tests showed low sodium, low morning cortisol without correspondence increase of corticotrophin (ACTH). Other pituitary hormones were normal. MRI showed no space-occupying lesions, but heterogeneous enhancement of the pituitary gland. DIAGNOSES: Primary hypothyroidism and isolated ACTH deficiency. The etiologies were assumed to be nivolumab induced autoimmune lymphocytic thyroiditis and hypophysitis, respectively. INTERVENTIONS: Hormone replacements with levothyroxine and acetate cortisone were given orally. Nivolumab was adjusted to lower dose and longer interval. OUTCOMES: The patient felt good after adequate replacement. Nivolumab was returned to routine dose and interval six months later. And the metastasis was not obviously progressed during this time. LESSONS: The present report provides the first detailed presentation of combined hypothyroidism and isolated ACTH deficiency induced by nivolumab. Adrenal deficiency often develops insidiously. We suggest routine monitoring of fasting blood-glucose, blood pressure and serum sodium as well as thyroid function during nivolumab and other cancer immunotherapies. When unexpected fatigue, hypoglycemia, hypotension or hyponatremia appeared, adrenal deficiency should be taken into consideration.

pH and DNA luminescence switching, DNA photocleavage and cytotoxic properties of two thiophene-containing ruthenium(II) complexes.

Two new Ru(II) complexes, [Ru(Htip)3]Cl2 (1) and [Ru(Htip)2(dppz)]Cl2 (2), were synthesised and were characterised. The ground- and excited-state acid-base properties of 1 and 2 were studied and demonstrated that 1 acted as a pH-induced "on-off-on" luminescence switch. The binding behaviours of 1 and 2 to calf thymus DNA were studied with absorption and emission spectroscopy, DNA viscosities and density functional theory calculations. 2 was found to act as a DNA molecular light switch and as an efficient photocleaver of pUC 18 DNA. The cytotoxicities of the complexes were evaluated with the MTT method and it was found that 1 displayed apparent anticancer activity against MCF-7 cell, whereas 2 exhibited more potent and wider-spectrum antitumor activities against all cancer cell lines tested.

pH luminescence switch, DNA binding and photocleavage, and cytotoxicity of a dinuclear ruthenium complex.

The ground- and excited-state acid-base properties of [Ru2(bpy)4(H2bipt)]Cl4 1 {bpy = 2,2'-bipyridine, H2bipt = 2,5-bis[1,10]phenanthrolin[4,5-f]-imidazol-2-yl)thiophene} are investigated by emission and UV-visible absorption spectrophotometric pH titrations. The DNA binding properties of 1 are studied by means of DNA viscosity and optical spectroscopic techniques of UV-visible absorption and emission spectral titrations, steady-state emission quenching with ferrocyanide, ethidium bromide competitive binding, and DNA thermal denaturation as well as density functional theoretical calculations. The DNA photocleavage and singlet oxygen generation properties as well as in vitro anticancer activities against five cancer cell lines are studied as well. The results demonstrated that pH-induced luminescence switching, DNA binding, and anticancer properties of 1 are much improved with respect to those of the mononuclear analog [Ru(bpy)2(Htip)]Cl2 {Htip = 2-(thiophen-2-yl)-1H-imidazo[4,5-f][1,10]phenanthroline}.

[Genetic fingerprinting of human lung squamous cancer with lymphatic metastasis].

OBJECTIVE: To identify the differentially expressed genes related to lymphatic metastasis of lung squamous cell carcinoma. METHODS: Specimens of primary lung squamous cancer tissues and regional lymph nodes were obtained from 10 patients undergoing complete surgical resection of the tumor. The samples were classified into 3 groups, namely the primary tumor with lymphatic metastasis (TxN+, n=5), primary tumor without lymphatic metastasis (TxN-, n=5) and matched tumor cells from the metastatic lymph nodes (N+, n=5). The total RNA extracted from the laser microdissected primary tumor or metastatic nodes was labeled and hybridized with the microarray containing 6 000 known human genes or ESTs. Data analysis was performed using GeneSpring(TM) 6.2 software. Immunohistochemical staining was used to detect the expression of CCL20 in the specimens. RESULTS: A total of 37 genes showed differential expressions between TxN+ and TxN- tissues, among which 8 genes were upregulated and 29 were downregulated in TxN+ group. No genes, however, showed distinct differential expressions between N+ and TxN+ tissues. The expression of CCL20 was significantly higher in TxN- than in TxN+ tissues (P<0.05). CONCLUSION: The acquisition of the metastatic phenotype may occur early in the development of lung squamous cancer. The gene expression signature of lung squamous cell carcinoma is valuable to elucidate the molecular mechanisms regarding lymphatic metastasis of the malignancy, and may provide important clues for exploring novel therapeutic targets.

A novel water-soluble gossypol derivative increases chemotherapeutic sensitivity and promotes growth inhibition in colon cancer.

Compound 1 ((-)-gossypol) has been long known as a chemical anticancer agent. With its low water solubility and toxicity, it is not widely used as a commercial drug. To overcome these disadvantages, several novel derivatives of gossypol were designed, synthesized, and analyzed. One of the derivatives, compound 7 (6-aminopenicillanic acid sodium-gossypolone), was identified with great water solubility and anticancer property, suggested by inducing a dramatically decrease in Bcl-2 and Bcl-xL protein expression level found in vitro and growth inhibition of murine colon tumor in vivo. Furthermore, it was also recognized with less toxicity than compound 1 in vivo and significantly increased chemotherapeutic sensitivity against colon cancer in combination with traditional chemotherapeutic agent 5-fluorouracil. Therefore, it is concluded that compound 7 is superior to parent compound 1, and further preclinical studies of compound 7 is necessary for colon cancer therapy.