Advances in three-dimensional tumor models for colorectal cancer / 中华肿瘤杂志

Conventional tumor culture models include two-dimensional tumor cell cultures and xenograft models. The former has disadvantages including lack of tumor heterogeneity and poor clinical relevance, while the latter are limited by the slow growth, low engraftment successful rate, and high cost. In recent years, in vitro three-dimensional (3D) tumor models have emerged as the tool to better recapitulate the spatial structure and the in vivo environment of tumors. In addition, they preserve the pathological and genetic features of tumor cells and reflect the complex intracellular and extracellular interactions of tumors, which have become a powerful tool for investigating the tumor mechanism, drug screening, and personalized cancer treatment. 3D tumor model technologies such as spheroids, organoids, and microfluidic devices are maturing. Application of new technologies such as co-culture, 3D bioprinting, and air-liquid interface has further improved the clinical relevance of the models. Some models recapitulate the tumor microenvironment, and some can even reconstitute endogenous immune components and microvasculature. In recent years, some scholars have combined xenograft models with organoid technology to develop matched in vivo/in vitro model biobanks, giving full play to the advantages of the two technologies, and providing an ideal research platform for individualized precision therapy for specific molecular targets in certain subtypes of tumors. So far, the above technologies have been widely applied in the field of colorectal cancer research. Our research team is currently studying upon the application of patient-derived tumor cell-like clusters, a self-assembly 3D tumor model, in guiding the selection of postoperative chemotherapy regimens for colorectal cancer. A high modeling success rate and satisfactory results in the drug screening experiments have been achieved. There is no doubt that with the advancement of related technologies, 3D tumor models will play an increasingly important role in the research and clinical practice of colorectal cancer.

Quality of life of patients with locally advanced rectal cancer after neoadjuvant therapy and sphincter-preserving surgery / 中华胃肠外科杂志

Objective: To investigate quality of life (QoL) of patients with locally advanced rectal cancer (LARC) who underwent low anterior resection with protective stoma under neoadjuvant therapy mode, and to explore the changes of QoL of patients from before neoadjuvant therapy to 12 months after stoma reversal. Methods: A descriptive case series study was carried out. A retrospective study was performed on patients with mid and low LARC who received complete neoadjuvant long course radiotherapy and chemotherapy, followed by radical low anterior resection (LAR) combined with protective stoma at Peking Union Medical College Hospital from December 2017 to January 2020. Inclusion criteria: (1) patients with rectal MRI assessment of mT3-4b or mN1-2 without distant metastasis (M0) before neoadjuvant therapy; (2) distance from tumor lower margin to the anal verge <12 cm; (3) rectal adenocarcinoma confirmed by biopsy before neoadjuvant therapy; (4) complete cycle of neoadjuvant therapy; (5) patients undergoing radical LAR with sphincter preservation and protective ostomy; (6) patients receiving follow-up for more than 12 months after stoma reversal. Exclusion criteria: (1) patients as grade Ⅳ to Ⅴclassified by the American Society of Anesthesiologists (ASA); (2) patients with multiple primary colorectal cancer; (3) patients with history of other malignant tumors in the past 5 years; (4) patients of emergency surgery; (5) pregnant or lactating women; (6) patients with history of severe mental illness; (7) patients with contraindication of MRI, radiotherapy, chemotherapy, or surgical treatment. A total of 83 patients were enrolled, including 51 males and 28 females with median age of 59 years and mean BMI of (24.4±3.1) kg/m(2). EORTC QLQ-CR29, international erectile function index (IIEF), Wexner constipation score and low anterior resection syndrome (LARS) score were applied to investigate the QoL of the patients before neoadjuvant therapy, 3 and 12 months after ostomy reversal, including rectal anal function and sexual function. M (P25, P75) was used for the scores of the scale. Results: (1) EORTC QLQ-CR29 score showed that before neoadjuvant therapy, before surgery, 3 months and 12 months after ostomy reversal, anxiety [64.4 (52, 0, 82.5), 75.3 (66.0, 89.5), 82.6 (78.5, 90.0), 83.6 (78.0, 91.0)] and concern about body image [76.8 (66.0, 92.0), 81.1 (76.5, 91.5), 85.5 (82.5, 94.0), 86.1 (82.0, 92.0)] were improved (all P<0.01); pelvic pain [5.4 (2.0, 8.0), 5, 0 (2.0, 7.8), 3.9 (1.0, 5.0), 3.0 (1.0, 5.0)], urinary incontinence [15.7 (7.0, 22.0), 11.1 (0, 17.5), 10.0 (0, 17.0), 9.9 (0, 16.0)], impotence [14.3 (4.2, 19.0), 12.2 (0, 16.8), 5.6 (0, 10.0), 5.2 (0.2, 8.0)], urinate [26.4 (13.0, 38.5), 13.9 (0, 20.0), 13.4 (2.5, 21.5), 13.2 (2.0, 20.0)] and mucous bloody stool [4.7 (3.0, 6.0), 2.6 (0, 5.0), 2.2 (0, 5.0), 1.9 (0, 4.0)] were improved as well (all P<0.01). The scores fluctuated in the improvement of male sexual function, abdominal pain, dry mouth, worry about body mass change, skin pain and dyspareunia, but the symptoms were significantly improved after ostomy reversal compared with before neoadjuvant therapy (all P<0.05). There were no significant changes in female sexual function, dysuria, dysgeusia and fecal incontinence after ostomy reversal compared with before neoadjuvant therapy (all P>0.05). (2) IIEF scale showed that all scores were similar before and after neoadjuvant therapy (all P>0.05). (3) Rectal and anal function scale revealed that before neoadjuvant therapy, before operation, 3 months and 12 months after stoma reversal, gas incontinence [3.1 (0, 4.0), 2.3 (0, 4.0), 1.8 (0, 4.0), 1.2 (0, 3.0)] and urgent defecation [7.2 (0, 11.0), 5.2 (0, 11.0), 2.9 (0, 9.0), 1.7 (0, 0)] were improved (all P<0.001). In terms of improving incomplete emptying sensation, the symptoms fluctuated, but the symptoms improved significantly after ostomy reversal compared with before neoadjuvant therapy (all P<0.05). While the symptoms of assistance with defecation [0 (0, 0), 0.7 (0, 1.0), 0.6 (0, 1.0), 0.7 (0, 1.0)] and defecation failure [0.2 (0, 0), 1.0 (0, 2.0), 0.8 (0, 1.5), 0.8 (0, 1.0)] showed a worsening trend (all P<0.001). Stratified analysis was performed on patients with different efficacy of neoadjuvant therapy to compare the changes in QoL before and after neoadjuvant therapy. Patients with less sensitive and more sensitive neoadjuvant therapy showed similar changes in function and symptoms. Patients with less sensitive therapy showed significant improvement in dysuria, urinary incontinence, skin pain and dyspareunia (all P<0.05), and the symptom of defecation frequency in more sensitive patients was significantly improved (P<0.05). Conclusions: For patients with LARC, neoadjuvant radiochemotherapy combined with radical LAR and protective stoma can improve QoL in many aspects. It is noted that patients show a worsening trend in the need for assistance with defecation and in defecation failure.

Protective colostomy and protective ileostomy for the prevention of anastomotic leak in patients with rectal cancer after neoadjuvant chemoradiotherapy and radical surgery / 中华胃肠外科杂志

Objective: To investigate whether protective colostomy and protective ileostomy have different impact on anastomotic leak for rectal cancer patients after neoadjuvant chemoradiotherapy (nCRT) and radical surgery. Methods: A retrospectively cohort study was conducted. Inclusion criteria: (1) Standard neoadjuvant therapy before operation; (2) Laparoscopic rectal cancer radical resection was performed; (3) During the operation, the protective enterostomy was performed including transverse colostomy and ileostomy; (4) The patients were followed up regularly; (5) Clinical data was complete. Exclusion criteria: (1) Colostomy and radical resection of rectal cancer were not performed at the same time; (2) Intestinal anastomosis is not included in the operation, such as abdominoperineal resection; (3) Rectal cancer had distant metastasis or multiple primary colorectal cancer. Finally 208 patients were included in this study. They suffered from rectal cancer and underwent protective stoma in radical surgery after nCRT at our hospital from January 2014 to December 2018. There were 148 males and 60 females with age of (60.5±11.1) years. They were divided into protective transverse colostomy group (n=148) and protective ileostomy group (n=60). The main follow up information included whether the patient has anastomotic leak and the type of leak according to ISREC Grading standard. Besides, stoma opening time, stoma flow, postoperative hospital stay, stoma related complications and postoperative intestinal flora were also collected. Results: A total of 28 cases(13.5%) suffered from anastomotic leak and 26 (92.9%) of them happened in the early stage after surgery (less than 30 days) . As for these early-stage leak, ISREC Grade A happened in 11 cases(42.3%), grade B in 15 cases(57.7%) and no grade C occurred. There was no significant difference in the incidence [12.8% (19/148) vs. 15.0% (9/60) , χ(2)=0.171, P=0.679] or type [Grade A: 5.4%(8/147) vs. 5.1%(3/59); Grade B: 6.8%(10/147) vs. 8.5%(5/59), Z=0.019, P=1.000] of anastomotic leak between the transverse colostomy group and ileostomy group (P>0.05), as well as operation time, postoperative hospital stay, drainage tube removal time or stoma reduction time (P>0.05). There were 10 cases (6.8%) and 24 cases (40.0%) suffering from intestinal flora imbalance in protective transverse colostomy and protective ileostomy group, respectively (χ(2)=34.503, P<0.001). Five cases (8.3%) suffered from renal function injury in the protective ileostomy group, while protective colostomy had no such concern (P=0.002). The incidence of peristomal dermatitis in the protective colostomy group was significantly lower than that in the protective ileostomy group [12.8% (9/148) vs. 33.3%(20/60), χ(2)=11.722, P=0.001]. Conclusions: It is equally feasible and effective for rectal cancer patients after nCRT to carry out protective transverse colostomy or ileostomy in radical surgery. However, we should pay more attention to protective ileostomy patients, as they are at high risk of intestinal flora imbalance, renal function injury and peristomal dermatitis.

Prognosis and complications of local excision for rectal cancer after neoadjuvant chemoradiotherapy / 中华胃肠外科杂志

Objective: To investigate the prognosis and postoperative complications of local excision for rectal cancer after neoadjuvant chemoradiotherapy (nCRT). Methods: A descriptive case series study was carried out. Patient inclusion criteria: (1) patients who underwent local excision by transanal endoscopic microsurgery (TEM) after nCRT; (2) magnetic resonance evaluated tumor regression grade (mrTRG) as 1, 2 after nCRT;(3) American Society of Anesthesiologists class I to III. Patient exclusion criteria: (1) with multiple primary colorectal cancers; (2) with other malignant tumors within five years; (3) with emergency surgicery indications like digestive tract obstruction, perforation or bleeding. Clinicopathological and follow-up data of rectal cancer patients with obvious tumor regression after nCRT who underwent local excision in Peking Union Medical College Hospital from January 2010 to August 2019 were retrospectively collected. Outcome measures included disease-free survival (DFS), short-term postoperative complications, and at postoperative 1-year during follow up, gas continence, fecal continence, and quality of life (using the EORTC QLQ-CR29 scale, higher score indicated worse quality of life) at postoperative 1-year. Results: A total of 40 patients were included in this study. There were 27 males and 13 females with an average age of (66.7±12.3) years. Preoperative rectal ultrasound and other imaging examinations indicated that the tumor was located in the anterior wall in 16 cases, the lateral wall in 12 cases, and the posterior wall in 12 cases. The distance between the lower margin of the tumor and the anal verge was (4.3±1.2) cm before nCRT and (5.1±0.9) cm after nCRT. According to mrTRG, 31 cases were assessed as mrTRG 1 and 9 cases as mrTRG 2. All the patients received local extended excision of rectal cancer using TEM platform. A total of 19 cases(47.5%) suffered from complications within one month postoperatively. Clavien-Dindo grade I complications happened in 14 cases, grade II in 3 patients, and grade III in 2 cases, who all were healed by conservative treatment. Except that 2 patient presented severe low anterior resection syndrome (LARS) at 1 year postoperatively, no severe anal dysfunction was found in this cohort patients. EORTC QLQ CR29 scale results for quality of life showed that at 1 year after TEM excision, except taste (Z=-1.968, P=0.049), anxiety (Z=-3.624, P<0.001) and skin irritation (Z=-2.420, P=0.023) were worse than the situation before neoadjuvant therapy, there were no statistically significant differences in other assessment results between pre-operation and post-operation (all P>0.05). Postoperative pathological results indicated complete tumor regression (pTRG0) in 17 cases, moderate remission (pTRG1) in 13, and mild remission (pTRG2) in 10. During the follow-up of (49.1±29.6) months, 3 patients had local recurrence and 4 had distant metastasis (3 patients with liver metastasis and 1 patient with lung metastasis followed by liver metastasis). No death was found and the 5-year disease-free survival (DFS) was 84.3%. Conclusions: Local excision through TEM following nCRT not only can be adopted as an important means to accurately determine complete clinical remission (cCR), but also has high therapeutic value for rectal cancer patients presenting cCR or near cCR, with little impact on defecatory function and quality of life. However, the morbidity of complication of TEM excision after nCRT is relatively high and there is a risk of recurrence and metastasis. Therefore, it is still necessary to strictly select the indications of local excision.