Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction.

BACKGROUND: Whether combined transplantation of mesenchymal stem cells (MSCs) and endothelial progenitor cells (EPCs) is more effective than transplantation of a single cell type in the restoration of erectile function is unknown. AIM: To investigate the effect of combined transplantation of MSCs and EPCs on restoration of erectile function in rats with cavernous nerve injury (CNI). METHODS: MSCs were isolated from human bone marrow and EPCs were isolated from human umbilical cord blood. MSCs and EPCs were identified by flow cytometry and in vitro differentiation or immunofluorescence staining. 25 8-week-old male Sprague-Dawley rats were allocated to 1 of 5 groups: sham operation group, bilateral CNI group receiving periprostatic implantation of MSCs plus EPCs, MSCs, EPCs, or phosphate buffered saline (control group). 2 weeks after CNI and treatment, erectile function of rats was measured by electrically stimulating the CN. The penis and major pelvic ganglia were harvested for histologic examinations. RNA and protein levels of neurotrophin factors (vascular endothelial growth factor, nerve growth factor, and brain-derived neurotrophic factor) in mono- or coculture MSCs and EPCs were assessed by real-time polymerase chain reaction and enzyme-linked immunosorbent assay, respectively. OUTCOMES: Intracavernous pressure and mean arterial pressure were measured to evaluate erectile function. Histologic examinations of the penis and major pelvic ganglia and RNA and protein levels of neurotrophin factors in MSCs and EPCs were performed. RESULTS: MSCs and EPCs expressed the specified cell markers and exhibited the typical appearance and characteristics. Treatments using MSCs and/or EPCs could increase endothelial and smooth muscle contents of the corpus cavernosum, decrease caspase-3 expression and increase penile neuronal nitric oxide synthase expression, and restore the neural component of the major pelvic ganglia in rats with CNI. Combined transplantation of MSCs and EPCs had a better effect on improving erectile function than single transplantation of MSCs or EPCs. Expression levels of vascular endothelial growth factor and nerve growth factor in coculture MSCs and EPCs were significantly higher than those of primary MSCs or EPCs. CLINICAL TRANSLATION: Combined transplantation of MSCs and EPCs was more effective in restoring erectile function in CNI-related erectile dysfunction models. STRENGTHS AND LIMITATIONS: The study, for the 1st time, proved that combined transplantation of MSCs and EPCs was more effective in restoring erectile function in rats with CNI. The rat model might not represent the human condition. CONCLUSION: Combined periprostatic transplantation of MSCs and EPCs could restore erectile function in rats with CNI more effectively. MSCs might restore CN fibers by secreting neurotrophin factors such as vascular endothelial growth factor and nerve growth factor, and EPCs could enhance the paracrine activity of MSCs. Fang J-f, Huang X-n, Han X-y, et al. Combined Transplantation of Mesenchymal Stem Cells and Endothelial Progenitor Cells Restores Cavernous Nerve Injury-Related Erectile Dysfunction. J Sex Med 2018;15:284-295.

Predictive models of adjuvant chemotherapy for patients with stage ii colorectal cancer: A retrospective study.

BACKGROUND: It remains controversial whether patients with Stage II colorectal cancer would benefit from adjuvant chemotherapy after radical resection. The aim of this study was to establish two mathematical models to identify the suitable patients for adjuvant chemotherapy. METHODS: The current study comprised of two steps. In the first step, 353 patients with Stage II colorectal cancer who underwent surgical procedures at the Third Affiliated Hospital of Sun Yat-sen University between June 2006 and December 2015 were entered and followed up for 6-120 months. Their clinical data were collected and enrolled into the database. We established two mathematical models by univariate and multivariate Cox regression analysis to identify the target patients; in the second step, 230 patients under the same standard between January 2012 and December 2016 were entered and followed up for 3-62 months to verify the two models' validation. RESULTS: In the first step, totally 340 surgical patients with Stage II colorectal cancer were finally enrolled in this study. Statistical analysis showed that tumor differentiation (TD) (P < 0.001), lymphovascular invasion (LVI) (P < 0.001), uncertain or positive margins (UPM) (P < 0.001), and fewer lymph nodes (LNs) (<12) retrieved (P < 0.001) were correlated with the overall survival (OS) and disease free survival (DFS). We obtained two models: (1) OS risk score = 1.116 × TD + 2.202 × LVI + 3.676 × UPM + 1.438 × LN - 0.493; (2) DFS risk score = 0.789 × TD + 2.074 × LVI + 3.183 × UPM + 1.329 × LN - 0.432. According to the models and cutoff points [(0.07, 1.33) and (-0.04, 1.30), respectively], patients can be divided into three groups: low-risk, moderate-risk, and high-risk. Moreover, the high-risk group patients could benefit from adjuvant chemotherapy. In the second step, totally 221 patients were finally used to verify the models' validation. The results proved that the models were accurate and feasible (P< 0.05). CONCLUSIONS: According to the predictive models, patients with Stage II colorectal cancer in the high-risk group are strongly recommended for adjuvant chemotherapy, thus facilitating the individualized and precise treatment.

Endoscopy-Assisted Laparoscopic Resections for Gastric Gastrointestinal Stromal Tumors: A Retrospective Study.

OBJECTIVE: To explore the safety, feasibility, and clinical curative effect of endoscopy-assisted laparoscopic resections for gastric gastrointestinal stromal tumors (GISTs). MATERIALS AND METHODS: We retrospectively compared the general condition of 41 GIST patients undergoing endoscopy-assisted laparoscopic resections (n = 41, combined group) with those undergoing traditional open gastrectomy (n = 43, open surgery group). RESULTS: All patients survived during the surgery. The average operation time of the combined group and the open surgery group was 90 ± 40 minutes and 120 ± 60 minutes, respectively, and no significant difference (P = .088) was observed. Bleeding volume during operation was significantly lower [(50 ± 20 versus 150 ± 40) mL, P < .001] and recovery time of the gastrointestinal function was significantly shorter in the combined group [(2.02 ± 0.99) days versus (3.02 ± 1) days, P < .001]. No statistical difference was found in the postoperative complications (5% versus 12%, P = .442) or GIST recurrence (2.44% versus 2.33%, P = 1.000) between the two groups. Follow-up visit showed no death. CONCLUSION: For GIST patients who attempted to receive gastrectomy, endoscopy-assisted laparoscopic resections showed advantages on the operation time, bleeding volume, and recovery time and are suggested as a better alternative for GISTs.

Periprostatic implantation of neural differentiated mesenchymal stem cells restores cavernous nerve injury-mediated erectile dysfunction.

Mesenchymal stem cells (MSCs) have been utilized to restore erectile function in animal models of cavernous nerve injury (CNI). However, transplantation of primary MSCs may lead to unpredictable therapeutic outcomes. In this study, we investigated the efficiency of neural differentiated MSCs (d-MSCs) on the restoration of erectile function in CNI rats. Rat bone marrow MSCs (r-BM-MSCs) were treated with all-trans retinoic acid to induce neural differentiation. Rats were divided into five groups: a sham operation group; a bilateral CNI group that received an intracavernous injection of r-BM-MSCs (IC group); and three groups that received periprostatic implantation of either r-BM-MSCs (IP group), d-MSCs (IP-d group), or PBS (PBS group). The data revealed that IP injection of d-MSCs ameliorated erectile function in a similar manner to an IC injection of MSCs and enhanced erectile function compared to an IP injection of MSCs. An in vivo time course of d-MSCs survival revealed that PKH26-labled d-MSCs were detectable either within or surrounding the cavernous nerve tissue. In addition, the expression of caspase-3 significantly increased in the PBS group and decreased after treatment with MSCs, especially in the IC and IP-d groups. Furthermore, the expression levels of neurotrophic factors increased significantly in d-MSCs. This study demonstrated that periprostatic implantation of d-MSCs effectively restored erectile function in CNI rats. The mechanism might be ascribed to decreases in the frequency of apoptotic cells, as well as paracrine signaling by factors derived from d-MSCs.

Effect of preservation of Denonvilliers' fascia during laparoscopic resection for mid-low rectal cancer on protection of male urinary and sexual functions.

The aim of this study was to investigate the effect of preservation of Denonvilliers' fascia (DF) during laparoscopic resection for mid-low rectal cancer on protection of male urogenital function. Whether preservation of DF during TME is effective for protection of urogenital function is largely elusive.Seventy-four cases of male mid-low rectal cancer were included. Radical laparoscopic proctectomy was performed, containing 38 cases of preservation of DF (P-group) and 36 cases of resection of DF (R-group) intraoperatively. Intraoperative electrical nerve stimulation (INS) on pelvic autonomic nerve was performed and intravesical pressure was measured manometrically. Urinary function was evaluated by residual urine volume (RUV), International Prostatic Symptom Score (IPSS), and quality of life (QoL). Sexual function was evaluated using the International Index of Erectile Function (IIEF) scale and ejaculation function classification.Compared with performing INS on the surfaces of prostate and seminal vesicles in the R-group, INS on DF in the P-group exhibited higher increasing intravesical pressure (7.3 ±â€Š1.5 vs 5.9 ±â€Š2.4 cmH2O, P = 0.008). In addtion, the P-group exhibited lower RUV (34.3 ±â€Š27.2 vs 57.1 ±â€Š50.7 mL, P = 0.020), lower IPSS and QoL scores (7 days: 6.1 ±â€Š2.4 vs 9.5 ±â€Š5.9, P = 0.002 and 2.2 ±â€Š1.1 vs 2.9 ±â€Š1.1, P = 0.005; 1 month: 5.1 ±â€Š2.4 vs 6.6 ±â€Š2.2, P = 0.006 and 1.6 ±â€Š0.7 vs 2.1 ±â€Š0.6, P = 0.003, respectively), higher IIEF score (3 months: 10.7 ±â€Š2.1 vs 8.9 ±â€Š2.0, P = 0.000; 6 months: 14.8 ±â€Š2.2 vs 12.9 ±â€Š2.2, P = 0.001) and lower incidence of ejaculation dysfunction (3 months: 28.9% vs 52.8%, P = 0.037; 6 months: 18.4% vs 44.4%, P = 0.016) postoperatively.Preservation of DF during laparoscopic resection for selective male mid-low rectal cancer is effective for protection of urogenital function.

Comparison of laparoscopic versus open complete mesocolic excision for right colon cancer.

AIM: To explore the feasibility, safety, efficacy, and short-term oncologic outcomes of laparoscopic-assisted complete mesocolic excision (CME) for right colon cancer. METHODS: The clinical data from 102 patients with right colon cancer who underwent laparoscopic CME (n = 53; LS group) and open CME (n = 49; OS group) from June 2012 to December 2013 were retrospectively reviewed. Outcomes of the two groups were compared. RESULTS: There were no conversions to open surgery in the LS group. The operative time in the LS group was similar to that in the OS group (194 ± 57 vs. 177 ± 51 min, respectively, p = 0.118). Intraoperative blood loss was significantly less in the LS group compared with the OS group (94 ± 56 vs. 118 ± 60 ml, respectively, p = 0.039). There was no difference in the total number of harvested lymph nodes (14 ± 6 vs. 13 ± 5, respectively, p = 0.313). The time to resume liquid diet (3 ± 2 vs. 5 ± 2 d, p < 0.001) and length of hospital stay (11 ± 4 vs. 14 ± 6 d, p = 0.002) were significantly shorter in the LS group. The rate of complications was similar between the groups (4% vs. 12%, respectively, p = 0.222). No recurrences were noted in either group during follow-up (range, 6-24 months). CONCLUSION: Laparoscopic CME is a safe, feasible, and effective minimally invasive procedure for right colon cancer.

Laparoscopic resection for rectal cancer and cholecystectomy for patient with situs inversus totalis.

Situs inversus totalis (SIT) is a rare congenital anomaly presenting with complete transposition of thoracic and abdominal viscera. Laparoscopic surgery for either rectal cancer or gallbladder diseases with SIT is rarely reported in the literature. A 39-year-old woman was admitted to hospital owing to rectal cancer. She was diagnosed with SIT by performing radiography and abdominal computed tomography scan as a routine preoperative investigation. We performed laparoscopic resection for rectal cancer successfully in spite of technical difficulties caused by abnormal anatomy. One year later, she was diagnosed with cholecysticpolyp, and we performed laparoscopic cholecystectomy for her uneventfully. With this case, we believe that performance by an experienced laparoscopic surgeon, either laparoscopic resection for rectal cancer or cholecystectomy with SIT is safe and feasible.

Laparoscopy-assisted combined resection for synchronous gastrointestinal multiple primary cancers.

BACKGROUND: Synchronous gastrointestinal multiple primary cancers (SGMPC) is infrequent. This study aimed to investigate the feasibility and outcomes of laparoscopy-assisted combined resection for SGMPC. MATERIAL AND METHODS: We retrospectively reviewed 16 cases of SGMPC underwent either open or laparoscopy-assisted combined resection in the Third Affiliated Hospital of Sun Yat-sen University from Jan. 2005 to Jan. 2014. RESULTS: Sixteen cases contained synchronous colon cancers (n = 10), gastric and rectal cancer (n = 5), gastric and duodenal cancer (n = 1). Either laparoscopy-assisted or open procedure was performed. Compared with the open group, the laparoscopy group presented less blood loss (77.1 ± 46.3 ml vs. 145.0 ± 75.9 ml, P = 0.047) and shorter incision length (5.2 ± 0.7 cm vs. 16.4 ± 1.9 cm, P = 0.000), while no differences in operative time (228.3 ± 38.8 min vs. 188.8 ± 47.7 min, P > 0.05) and postoperative hospital stay (10.0 ± 3.4 days vs. 12.0 ± 4.8 days, P > 0.05). Two cases of postoperative complications occurred in the open group and one case of incision infection occurred in the laparoscopy one. Upon follow-up, 2 cases of open group (50.0%) and 8 cases of laparoscopy group (66.7%) were under status of disease free survival. CONCLUSIONS: Laparoscopy-assisted combined resection for SGMPC is feasible, safe and effective.

Laparoscopic lysis of the ligament of treitz for superior mesenteric artery syndrome.

BACKGROUND: Superior mesenteric artery (SMA) syndrome (SMAS) is a rare condition caused by compression of the third portion of the duodenum by the SMA. The effect of the laparoscopic management of SMAS remains poorly understood. This study aimed to investigate the feasibility and effect of the laparoscopic management for SMAS. METHODS: We retrospectively reviewed 19 cases of SMAS who underwent surgical interventions in The Third Affiliated Hospital of Sun Yat-sen University between June 2006 and October 2013, consisting of 8 cases of duodenojejunostomy (DJ) and 11 cases of laparoscopic lysis of the ligament of Treitz (LL-LOT). A telephone survey was conducted to collect the follow-up status. RESULTS: Either DJ or LL-LOT was performed smoothly. The median operative time of the laparoscopic procedure and DJ was 56 and 95 min, respectively. Median blood loss was 10 versus 35 ml. Median postoperative hospital stays in both were 8 days. Ten cases of the laparoscopic group recovered uneventfully, while 1 case still presented symptoms of abdominal distention. Upper gastrointestinal fluoroscopy showed marked 'to-and-fro' peristalsis. An additional DJ was performed 35 days later to resolve her symptoms. CONCLUSIONS: LL-LOT is simple, feasible, minimally invasive and effective for SMAS with no severe duodenum 'to-and-fro' peristalsis.

Epithelial-mesenchymal transition associates with maintenance of stemness in spheroid-derived stem-like colon cancer cells.

Despite earlier studies demonstrating characteristics of colon cancer stem cells (CCSCs) and the role of epithelial-mesenchymal transition (EMT) in tumor development, it remains controversial as to the relationship between CCSCs and EMT. In this study, in order to present an insight into this relationship in colon cancer, we developed HCT116 and HT29 sphere models, which are known to be the cells enriching cancer stem cells. Compared to their parental counterparts, spheroid cells displayed lower homotypic/heterotypic adhesion but higher in vitro migratory/invasive capacity, as well as higher tumorigenic and metastatic potential in vivo. The spheroid cells also demonstrated down-regulated E-cadherin and up-regulated α-SMA and Vimentin expression, which is the typical phenotype of EMT. In order to explore whether this phenomenon is associated to activation of Wnt/ß-catenin pathway, we detected several key signaling molecules. Compared with their parental cells, HCT116 and HT29 spheroid cells demonstrated down-regulated expression of GSK3ß, but up-regulated expression of Slug and Snail. And also, the up-regulation of nucleus ß-catenin in spheroid cells indicated that the free ß-catenin transferred from cytoplasm to cell nucleus. Our findings indicate that spheroid cells have the characteristics of colon cancer stem cells, and EMT may account for their stemness and malignancy. And persistent activation of Wnt/ß-catenin pathway may play an important role in the EMT of CCSCs.

[Laparoscopy-assisted combined radical resection for synchronous rectal and gastric cancer in elderly patients: report of two cases].

OBJECTIVE: To investigate the safety and feasibility of laparoscopy-assisted combined radical resection for synchronous rectal and gastric cancer in elderly patients. METHODS: Clinical data of two elderly patients undergoing laparoscopy-assisted combined radical resection for synchronous rectal and gastric cancer were analyzed retrospectively. RESULTS: The two cases were 78 and 75 years old respectively. Both were complicated with many medical conditions. One case suffered from stage II cancer in the gastric body and stage IB rectal cancer, and the other suffered from stage IIIA gastric cancer and stage IB rectal cancer. Both cases had received laparoscopy-assisted combined radical resection for synchronous rectal and gastric cancer, with 5 cm of incision. The operative time was 260 and 255 min and the intraoperative bleeding was 60 and 80 ml respectively. No complication occurred intraoperatively. Time to resume oral intake was 4 and 5 days and length of postoperative hospital stay was 13 and 14 days respectively. No postoperative complication occurred. The patients were followed up for 13 and 12 months and no postoperative recurrence or metastasis was noticed. CONCLUSION: Laparoscopy-assisted combined radical resection for elderly synchronous rectal and gastric cancer is safe and feasible when performed by surgeons with plentiful experience in laparoscopic technology, and associated with less injury and faster recovery.

Laparoscopic versus open gastrectomy with D2 lymph node dissection for gastric cancer: a meta-analysis.

BACKGROUND: Nowadays laparoscopic gastrectomy with D2 lymph node dissection (LGD2) is used for gastric cancer, which provides an alternative to open radical gastrectomy (OGD2). But it has not gained wide acceptance, and its oncological safety remains controversial. The aim of this study is to evaluate the efficiency and safety of LGD2 through a meta-analysis. MATERIALS AND METHODS: Original articles of clinical trials comparing LGD2 and OGD2 for gastric cancer, published in English language from January 2001 to April 2010 were searched in the MEDLINE, Current Contents, and Pubmed. Strict literature appraisal and data extraction were carried out independently by 2 reviewers and then a meta-analysis was performed using RevMan 4.2.5 to evaluate the items of operative time, blood loss, harvested lymph nodes, analgesic medication, first flatus day, postoperative hospital stay, postoperative complications, and cumulative survival rate. RESULTS: Ten trials were involved in the meta-analysis, concerning a total of 1039 patients (495 in LGD2 and 544 in OGD2). Compared with OGD2, LGD2 showed advantages of less blood loss during operation [weighed mean difference (WMD), -114.98; 95% confidence interval (CI), -160.44 to -69.52; P<0.00001], less postoperative pain (WMD, -0.89; 95% CI, -1.54 to -0.32; P=0.002), earlier passage of flatus (WMD, -0.84; 95% CI, -1.25 to -0.43; P<0.0001), shorter hospital stay (WMD, -3.27; 95% CI, -4.54 to -2.00; P<0.00001), and less postoperative complications [odds ratio (OR), 0.56; 95% CI, 0.32-0.59; P=0.03]; but with longer operative time [WMD, 57.14; 95% CI, 38.12-76.15; P<0.00001]. There were no significant differences between LGD2 and OGD2 in harvested lymph nodes (WMD, -2.07; 95% CI, -4.27 to -0.14; P=0.07) and overall survival rate of 11 to 60 months' follow-up (OR, 1.44; 95% CI, 0.92-2.27; P=0.11). CONCLUSIONS: The results of this meta-analysis suggest that LGD2 results in less blood loss and postoperative complications and also less pain and faster bowel function recovery, with similar harvested lymph nodes and overall survival rate comparing to OGD2. However, we also see the need for further high-quality randomized controlled trials comparing the 2 procedures.

Celecoxib increases retinoid sensitivity in human colon cancer cell lines.

Retinoid resistance has limited the clinical application of retinoids as differentiation-inducing and apoptosis-inducing drugs. This study was designed to investigate whether celecoxib, a selective COX-2 inhibitor, has effects on retinoid sensitivity in human colon cancer cell lines, and to determine the possible mechanism of said effects. Cell viability was measured using the MTT assay. Apoptosis was detected via Annexin-V/PI staining and the flow cytometry assay. PGE(2) production was measured with the ELISA assay. The expression of RARbeta was assayed via western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, but that the addition of PGE(2) did not affect the enhanced growth-inhibitory and apoptosis-inducing effects of the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA in the two cell lines. Western blotting showed that the expression of RARbeta in HT-29 cell lines was increased by celecoxib, but not by NS398, and that the addition of PGE(2) did not affect the celecoxib-induced expression of the retinoic acid receptor beta. In conclusion, celecoxib increased the expression of RARbeta and the level of cellular ATRA sensitivity through COX-2-independent mechanisms. This finding may provide a potential strategy for combination therapy.

[Expression and its significance of retinoic acid receptor-beta in colorectal cancer].

OBJECTIVE: To investigate the expression and its significance of retinoic acid receptor-beta (RAR-beta) in colorectal cancer. METHODS: RAR-beta was detected by immunohistochemistry methods and carcino-embryonic antigen (CEA) was tested by chemiluminescence immunoassay methods in normal tissues, paracancerous tissues and colorectal cancer tissues of 60 patients with colorectal cancer treated from January 2006 to January 2007. Above-mentioned data, together with the clinicopathological data of these 60 patients, were analyzed to figure out the expression and its significance of RAR-beta in colorectal cancer. RESULTS: The expression rate of RAR-beta in tumor tissues (48%) was significantly lower than those in both normal tissues (87%) and paracancerous tissues (87%) (P < 0.05). And its expression was also significant lower in patients with lymph node metastasis (32%) and patients with advanced cancer (TNM stage III and IV) (29%) than in those without lymph nodes metastasis (60%) and those with early stage cancer (stage I and II) (69%). There was no significant differences among well, mildly and poorly differentiated cancer tissues. The CEA level rose in 20 patients, and its rising rate was remarkably higher in patients with lymph node metastasis (48%) and in patients with advanced cancer (52%) than those without lymph node metastasis (23%) and in early stage(14%). CONCLUSIONS: The expression of RAR-beta decreases significantly in cancer tissues in patients with colorectal cancer, which may be related to the carcinogenesis of colorectal cancer; and its decreasing degree is correlated negatively with the lymph node metastasis and advanced clinicopathological stage. The expression level of RAR-beta may be a new prognostic indication of patients with colorectal cancer.

[Celecoxib increased cellular ATRA sensitivity of human colon cancer cell lines through COX-2-independent mechanisms].

Retinoid resistance has limited clinical activity of retinoids as differentiation-inducing and apoptosis-inducing drugs. The present study was designed to investigate whether celecoxib (selective COX-2 inhibitor) has effects on cellular retinoid sensitivity of human colon cancer cell lines and its possible mechanism. Cell viability was measured by MTT assay. Apoptosis was detected by Annexin-V/PI staining and flow cytometry assay. PGE2 production was measured by ELISA assay. Expression of RARbeta was assayed by Western blotting. The results showed that celecoxib enhanced the inhibitory effect of ATRA in both COX-2 high-expressing HT-29 and COX-2 low-expressing SW480 cell lines. Further study showed the ATRA and celecoxib combination induced greater apoptosis, and the addition of PGE2 did not affect the number of apoptotic cells induced by the combination. Moreover, NS398 (another selective COX-2 inhibitor) did not affect the inhibitory effects of ATRA on both cell lines. Western blotting showed that the expression of RARbeta in HT-29 cell lines increased in celecoxib group and combination group. And the addition of PGE2 did not affect the expression of RARbeta induced by celecoxib either. In conclusion, celecoxib increased expression of RARbeta and cellular ATRA sensitivity through COX-2-independent mechanisms, which may provide a potential strategy for combination therapy.