Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients.

BACKGROUND: RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described. AIM: To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC. METHODS: We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression. RESULTS: The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors. CONCLUSION: This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.

Prognostic impact of tumor deposits on overall survival in colorectal cancer: Based on Surveillance, Epidemiology, and End Results database.

BACKGROUND: In colorectal cancer, tumor deposits (TDs) are considered to be a prognostic factor in the current staging system, and are only considered in the absence of lymph node metastases (LNMs). However, this definition and the subsequent prognostic value based on it is controversial, with various hypotheses. TDs may play an independent role when it comes to survival and addition of TDs to LNM count may predict the prognosis of patients more accurately. AIM: To assess the prognostic impact of TDs and evaluate the effect of their addition to the LNM count. METHODS: The patients are derived from the Surveillance, Epidemiology, and End Results database. A prognostic analysis regarding impact of TDs on overall survival (OS) was performed using Cox regression model, and other covariates associating with OS were adjusted. The effect of addition of TDs to LNM count on N restaging was also evaluated. The subgroup analysis was performed to explore the different profile of risk factors between patients with and without TDs. RESULTS: Overall, 103755 patients were enrolled with 14131 (13.6%) TD-positive and 89624 (86.4%) TD-negative tumors. TD-positive patients had worse prognosis compared with TD-negative patients, with 3-year OS rates of 47.3% (95%CI, 46.5%-48.1%) and 77.5% (95%CI, 77.2%-77.8%, P < 0.0001), respectively. On multivariable analysis, TDs were associated poorer OS (hazard ratio, 1.35; 95%CI, 1.31-1.38; P < 0.0001). Among TD-positive patients, the number of TDs had a linear negative effect on disease-free survival and OS. After reclassifying patients by adding TDs to the LNM count, 885 of 19 965 (4.4%) N1 patients were restaged as pN2, with worse outcomes than patients restaged as pN1 (3-year OS rate: 78.5%, 95%CI, 77.9%-79.1% vs 63.2%, 95%CI, 60.1%-66.5%, respectively; P < 0.0001). CONCLUSION: TDs are an independent prognostic factor for OS in colorectal cancer. The addition of TDs to LNM count improved the prognostic accuracy of tumor, node and metastasis staging.

Predictive value of serum alpha-fetoprotein for tumor regression after preoperative chemotherapy for rectal cancer.

BACKGROUND: Preoperative therapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, there are few indicators that can predict the effect of preoperative chemotherapy accurately. AIM: To investigate whether the increase in serum α-fetoprotein (AFP) can predict better efficacy of preoperative chemotherapy. METHODS: This was a retrospective study. We analyzed 125 patients admitted between 2017 and 2019 with locally advanced rectal cancer. All patients received six cycles of preoperative chemotherapy (mFOLFOX6 every 2 wk). Serum AFP of 26 patients rose slightly after three or four cycles of chemotherapy, and fell to normal again within 2 mo. The other 99 patients had a normal level of serum AFP during chemotherapy. Patients were divided into two groups (AFP risen and AFP normal). According to postoperative pathology, we compared tumor regression and complete response rate between the two groups. The primary outcome measure was the tumor regression grade (TRG) after chemotherapy. The difference in pathological complete response between the two groups was also investigated. RESULTS: There were no tumor progression and distant metastasis in both groups during preoperative chemotherapy. Patients in the AFP risen group achieved better TRG 0/1 than those in the AFP normal group (61.5% vs 39.4%). The increase in AFP was a significant predictor for better tumor regression [χ 2 = 4.144, odds ratio (OR) = 2.666, P = 0.04]. In the AFP risen group, the complete response rate was 30.8%, which was higher than in the AFP normal group (30.8% vs 12.1%, χ 2 = 4.542, OR = 3.251, P = 0.03). CONCLUSION: Patients with a slight increase in serum AFP can achieve better tumor regression during preoperative chemotherapy, and are more likely to achieve pathological complete response.

Tumor mutation burden in blood predicts benefit from neoadjuvant chemo/radiotherapy in locally advanced rectal cancer.

Distant metastasis has been the major concern of prognosis in patients with locally advanced rectal cancer (LARC). The purpose of this study was to investigate the prognostic value of TMB in blood (bTMB) in LARC patients after receiving neoadjuvant chemoradiotherapy (nCRT) and surgery. Using targeted ctDNA sequencing, we revealed that bTMB level at baseline was positively correlated with recurrence-free survival (RFS). Following nCRT, the patients with decreasing TMB tends to have a longer median RFS. bTMB level after surgery was negatively correlated with RFS. The serum cytokines including IFNγ, IFNα2, IL-1ß, IL-2 and MIP-1ß were significantly higher in pre-nCRT serum with higher bTMB group than that of lower bTMB group. Clonal evolution analysis showed that the pre- and post-nCRT ctDNAs of most cases had shared mutations. In conclusion, we presume that bTMB could potentially improve pre- and post-treatment risk assessment and facilitate individualized therapy for patients with LARC.

Surgical treatment of massive stoma site tumors after a curative operation for rectal cancer.

OBJECTIVE: This study aimed to evaluate the clinical and oncological outcomes of selected rectal cancer patients with massive stoma site tumors who underwent radical resection and reconstruction. METHODS: We reviewed 8 cases of massive stoma site tumors in patients who had permanent gastrointestinal stoma in the abdominal wall following radical resection of rectal cancer between March 2013 and May 2018 at the Peking University Cancer Hospital and Peking University Shougang Hospital. RESULTS: There were seven males and one female patient, with a median age of 50.6 years. The average time between the initial surgery and the development of a malignant tumor at the stoma site was 5 years (range, 0.5-14 years). The average diameter of the stoma site tumors was 8.1 cm, and the diameter of the largest tumor was 12 cm. After tumor resection, the area of the largest abdominal wall defect was about 15 × 14 cm2. Abdominal wall repair included the use of a tensor fasciae latae muscle flap, local fasciocutaneous rotational flap, and pedicled anterolateral thigh flap. No patient died in the 30 days following surgery. The longest follow-up period was 81 months, and 5 patients died. CONCLUSIONS: Multidisciplinary clinical management fosters positive outcomes in treating massive stoma site tumors. Local R0 resection and abdominal wall reconstruction are safe and feasible, and function to removes local disease, allowing patients to live a higher quality of life.

Surgical complications after different therapeutic approaches for locally advanced rectal cancer.

BACKGROUND: Preoperative radiochemotherapy is widely used in locally advanced rectal cancer. It can improve local control of rectal cancer. However, some researchers believe it increases the incidence of surgical complications. They doubt its safety. Patients with locally advanced rectal cancer receive three different treatments in our hospital, including long-course radiochemotherapy, short-course radiotherapy, and surgery directly. We can compare their differences in postoperative complications. AIM: To investigate surgical complications caused by different preoperative radiotherapy regimens. METHODS: We retrospectively analyzed 1197 patients admitted between 2008 and 2010 with locally advanced rectal cancer. Three hundred and forty-six patients were treated with preoperative long-course radiochemotherapy (25 × 2 Gy) followed by total mesorectal excision (TME) 6-8 wk later, and 259 patients received short-course radiotherapy (10 × 3 Gy) and subsequently TME 7-10 d later. The remaining 592 patients underwent TME alone without neoadjuvant therapy. According to Clavien-Dindo classification, surgical complications were evaluated for up to 30 d after discharge from hospital. RESULTS: There were no deaths in 30 d in all groups after treatment. The major complications were anastomotic leakage and perineal wound complications. The results suggested that both long-course [odds ratio (OR) = 3.624, 95% confidence interval (CI): 1.689-7.775, P = 0.001] and short-course (OR = 5.150, 95%CI: 1.828-14.515, P = 0.002) radiotherapy were associated with anastomotic leakage. Temporary ileostomy was a protective factor for anastomotic leakage (OR = 6.211, 95%CI: 2.525-15.385, P < 0.001). The severity of anastomotic leakage did not increase in patients following preoperative radiotherapy (P = 0.411). Compared with TME alone, short-course radiotherapy was associated with an increase in perineal wound complications (OR = 5.565, 95%CI: 2.203-14.057, P < 0.001), but long-course radiotherapy seemed safe regarding this complication (OR = 1.692, 95%CI: 0.651-4.394, P = 0.280). Although the severity of perineal wound complications increased in patients following short-course radiotherapy (P < 0.001), additional intervention was not necessary. CONCLUSION: Radiotherapy increased the incidence but not severity of anastomotic leakage. Short-course radiotherapy was also accompanied with perineal wound complications, but intervention appeared unnecessary to ameliorate the complications.

Somatic Mutations and Immune Alternation in Rectal Cancer Following Neoadjuvant Chemoradiotherapy.

Checkpoint blockade therapy triggers tumor-specific immune responses in a variety of cancer types. We presumed that rectal cancer patients could have become sensitive to immunotherapy after receiving neoadjuvant chemoradiotherapy (nCRT). In this study, we report immune alternation in post-nCRT patients compared with pretreatment conditions from gene-expression omnibus (GEO) data. Whole-exome sequencing of 14 locally advanced rectal cancer (LARC) patient samples showed that nCRT induced new mutations compared with the paired pretreatment biopsies, evidenced by appearance of a neoantigen landscape. An association was identified between mutation burden and enrichment of immune activation-related pathways. Animal experiment results further demonstrated that radiotherapy enhanced the efficacy of anti-PD-1. Mutation burden and the neoantigens of LARC patients were associated with response to nCRT. The mRNA expression profiling of 66 pretreatment biopsy samples from LARC patients showed that immune activation-related pathways were enriched in response to nCRT. PD-L1 expression was negatively correlated with disease-free survival in the CD8-low expression patient group who received nCRT in a cohort of 296 samples. Thus, nCRT was able to alter immune function in LARC patients, which may be associated with the appearance of neoantigens. Neoantigens could make rectal cancer patients potential candidates to receive checkpoint blockade immunotherapy, and mutation burden could be a useful biomarker to stratify patients into responding and nonresponding groups for immunotherapy. Cancer Immunol Res; 6(11); 1401-16. ©2018 AACR.

[Predictive value of serum carcinoembryonic antigen level in efficacy and prognosis for patients with rectal cancer following preoperative radiochemotherapy].

OBJECTIVE: To examine the association of preoperative carcinoembryonic antigen (CEA) level with the efficacy of neoadjuvant radiochemotherapy and postoperative metastasis and relapse in patients with rectal cancer. METHODS: Between January 2011 and January 2014, 325 patients with local advanced rectal cancer underwent preoperative radiochemotherapy and radical operation in Department of Colorectal Cancer Surgery, Beijing University Cancer Hospital, including 194 males and 131 females. According to preoperative MRI, all the patients suffered from clinical T3-4 tumors or positive lymph nodes. Their Zubrod-ECOG-WHO score was 0-1. These patients received preoperative intensity modulated radiotherapy which consisted of 50.6 Gy in 22 fractions (IMRT GTV 50.6 Gy/CTV 41.8 Gy/22 f) with capecitabine(825 mg/m2, twice per day) as radiosensitizer. According to the preoperative serum CEA level, patients were divided into high group (125 cases) and normal group (200 cases). In high group, serum CEA level decreased into normal range in 60 patients (high-normal group) after radiochemotherapy, while it was still in high level in other 65 patients (high-high group). The differences in sensitivity to radiochemotherapy and 3-year disease free survival (DFS) of these patients were both evaluated. RESULTS: In high group and normal group, the complete response rates were 18.4% (23/125) and 17.5% (35/200) (χ2=0.319, P=0.660); the percentages of tumor regression grade(TRG) 0-1 patients were 68.0%(85/125) and 67.5%(135/200)(χ2=0.009, P=0.925); the T downstage rates were 63.2%(79/125) and 70.0%(140/200)(χ2=1.266, P=0.274), respectively, whose differences were all not significant. The 3-year DFS rate in high group was 62.4%, which was significantly lower than 93.5% in normal group (χ2=53.147, P=0.000). There were 65 patients in high-high group, accounting for 52% (65/125) of high group. Among these 65 patients, 44(67.7%) presented recurrence and metastasis within 3 years and the 3-year DFS was 32.3%, which was much lower than 95.0% of 60 patients in high-normal group(χ2=182.085, P=0.000). CONCLUSIONS: Preoperative serum CEA level may not be used to predict tumor response of rectal cancer patients who receive preoperative radiochemotherapy. However, the prognosis of patients with high CEA level is worse. Recurrence and metastasis are more likely to occur in patients with high CEA level after radiochemotherapy.

[Clinical characteristics and prognosis of colon cancer patient with extremely elevated carcinoembryonic antigen level].

OBJECTIVE: To explore the clinicopathological characteristics and prognosis of colon cancer patients with extremely elevated serum carcinoembryonic antigen(CEA) level before operation(>50 µg/L). METHODS: Clinicopathological and follow-up data of 1250 patients with colonic adenocarcinoma undergoing primary tumor resection between January 2001 and December 2011 were retrospectively analyzed. All the patients were divided into three groups according to the preoperative serum CEA levels as normal group (0-5 µg/L, 721 cases), elevated group(5-50 µg/L, 408 cases) and extremely elevated(>50 µg/L, 121 cases). Kaplan-Meier method was used to analyze the overall survival and disease-free survival. Log-rank test was used to compare the survival between groups. Cox regression was used to screen the independent prognostic factors of colon cancer. RESULTS: Compared with normal and elevated groups, patients with extremely elevated CEA had more advanced T,N,M stages (P<0.01), more palliative surgery (P<0.01) and more lymphovascular invasion(P<0.01). During the follow-up, patients with extremely elevated CEA demonstrated significantly higher ratio of distant metastases and liver metastases (both P=0.001). After radical surgery, 5-year overall survival rate of patients with normal, elevated and extremely elevated CEA levels was 70.1%, 54.4% and 42%, respectively, with statistically significant difference among three groups (P<0.001). Multivariate analysis showed that tumor differentiation, TNM staging, preoperative CEA levels, lymphovascular invasion and adjuvant chemotherapy were independent prognostic factors for colon cancer (all P<0.01). CONCLUSIONS: Colon cancer patients with extremely elevated preoperative CEA levels are associated with more unfavorable pathological factors, advanced TNM stage and more distant metastases (especially the liver metastases) during the follow-up. The elevated degree of preoperative CEA level is an independent poor prognostic factor of patients with colon cancer.

[Comparison of postoperative outcomes between hand-assisted laparoscopic and conventional sigmoidectomy: a prospective non-randomized controlled trial].

OBJECTIVE: To compare the perioperative safety and efficacy between hand-assisted laparoscopic surgery(HALS) and conventional open sigmoidectomy. METHODS: A total of 291 patients with sigmoid colon cancer who underwent surgery in our hospital from January 2010 to June 2013 were seperated into (HALS) group (n=200) and conventional open surgery (COS) group (n=91) with a non-randomized method. The perioperative safety and efficacy of two groups and perioperative outcomes were compared. RESULTS: These two groups were comparable in operative time, lymph node harvest, and postoperative complications. However, HALS group had less intraoperative bleeding [(57.9±28.3) ml vs. (82.5±47.6) ml, P=0.000], shorter time to flatus [(3.0±1.4) d vs. (3.3±0.9) d, P=0.000], and shorter hospital stay [(7.3±4.2) d vs. (8.9±4.4) d, P=0.004]. There werer no significant differences in overall survival time and disease-free survival time between the two groups during 6 months to 3 years follow-up. CONCLUSIONS: HALS results in similar outcomes of conventional open surgery for sigmoidectomy with the advantage of minimal invasiveness.

Unprecedented laser action from energy transfer in multichromophoric BODIPY cassettes.

A cassette molecule, featuring direct integration of two donor BODIPY units to one acceptor BODIPY unit, was conveniently developed as the first highly "through-bond energy transfer" (TBET) laser dye. This multicolor absorbing dye exhibited highly efficient and photostable laser action under drastic pumping conditions.

Development of excellent long-wavelength BODIPY laser dyes with a strategy that combines extending π-conjugation and tuning ICT effect.

By comparison and combination of two strategies, extending π-conjugation and tuning Intramolecular Charge Transfer (ICT) effect, new long-wavelength BODIPY dyes have been efficiently synthesized. The new chromophores exhibit good optical properties: high fluorescence quantum yields, exceptionally large molar extinction coefficients, narrow red-emission bands, and relatively large Stokes shifts etc., in polar or apolar solvents. Besides, the new dyes, under transversal pumping at 532 nm, exhibit highly efficient and stable laser emission tunable from the green to NIR spectral region (570-725 nm). Moreover, one of these new BODIPY derivatives shows cell membrane permeability and bright intracellular red fluorescence. These advantageous characteristics assure the potential of these dyes for biophotonic applications.

Bulky 4-tritylphenylethynyl substituted boradiazaindacene: pure red emission, relatively large Stokes shift and inhibition of self-quenching.

Bulky 4-tritylphenylethynyl substituted boradiazaindacene with pure red emission, relatively large Stokes shift, high fluorescence quantum yield, and low self-quenching was efficiently synthesized and qualified as a potential EL dopant.