Efficacy and safety of neoadjuvant sintilimab in combination with FLOT chemotherapy in patients with HER2-negative locally advanced gastric or gastroesophageal junction adenocarcinoma: an investigator-initiated, single-arm, open-label, phase II study.

BACKGROUND: The addition of immune checkpoint inhibitors to neoadjuvant chemotherapy in operable advanced gastric or gastroesophageal junction (G/GEJ) cancer aroused wide interest. This study was designed to assess the efficacy and safety of neoadjuvant sintilimab, a programmed cell death protein-1 (PD-1) inhibitor, in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT) chemotherapy for HER2-negative locally advanced G/GEJ cancer. METHODS: Eligible patients with clinical stage cT4 and/or cN+M0 G/GEJ cancer were enroled in this phase II study. Patients received neoadjuvant sintilimab (200 mg every 3 weeks) for three cycles plus FLOT (50 mg/m 2 docetaxel, 80 mg/m 2 oxaliplatin, 200 mg/m 2 calcium levofolinate, 2600 mg/m 2 5-fluorouracil every 2 weeks) for four cycles before surgery, followed by four cycles of adjuvant FLOT with same dosages after resection. The primary endpoint was the pathological complete response (pCR) rate. RESULTS: Thirty-two patients were enroled between August 2019 and September 2021, with a median follow-up of 34.8 (95% CI, 32.8-42.9) months. Thirty-two (100%) patients received neoadjuvant therapy, and 29 underwent surgery with an R0 resection rate of 93.1%. The pCR (TRG0) was achieved in 5 (17.2%; 95% CI, 5.8-35.8%) patients, and the major pathological response was 55.2%. Twenty-three (79.3%) patients had T downstaging, 21 (72.4%) had N downstaging, and 19 (65.5%) had overall TNM downstaging. Six (20.7%) patients experienced recurrence. Patients achieving pCR showed better event-free survival (EFS), disease-free survival (DFS), and overall survival (OS) than non-pCR. The estimated 3-year EFS rate, 3-year DFS rate, and 3-year OS rate were 71.4% (95% CI, 57.2-89.2%), 78.8% (95% CI, 65.1-95.5%), and 70.9% (95% CI, 54.8-91.6%), respectively. The objective response rate and disease control rate were 84.4% (95% CI, 68.3-93.1%) and 96.9% (95% CI, 84.3-99.5%), respectively. Twenty-five (86.2%) received adjuvant therapy. The main grade ≥3 treatment-related adverse events (TRAEs) were lymphopenia (34.4%), neutropenia (28.1%), and leukopenia (15.6%). no patients died from TRAE. The LDH level exhibited a better predictive value to pathological responses than PD-L1 and MSI status. CONCLUSIONS: The study demonstrated an encouraging efficacy and manageable safety profile of neoadjuvant sintilimab plus FLOT in HER2-negative locally advanced G/GEJ cancer, which suggested a potential therapeutic option for this population.

Neoadjuvant Chemotherapy With CAPOX Versus Chemoradiation for Locally Advanced Rectal Cancer With Uninvolved Mesorectal Fascia (CONVERT): Initial Results of a Phase III Trial.

OBJECTIVE: To compare neoadjuvant chemotherapy (nCT) with CAPOX alone versus neoadjuvant chemoradiotherapy (nCRT) with capecitabine in locally advanced rectal cancer (LARC) with uninvolved mesorectal fascia (MRF). BACKGROUND DATA: nCRT is associated with higher surgical complications, worse long-term functional outcomes, and questionable survival benefits. Comparatively, nCT alone seems a promising alternative treatment in lower-risk LARC patients with uninvolved MRF. METHODS: Patients between June 2014 and October 2020 with LARC within 12 cm from the anal verge and uninvolved MRF were randomly assigned to nCT group with 4 cycles of CAPOX (Oxaliplatin 130 mg/m2 IV day 1 and Capecitabine 1000 mg/m2 twice daily for 14 d. Repeat every 3 wk) or nCRT group with Capecitabine 825 mg/m² twice daily administered orally and concurrently with radiation therapy (50 Gy/25 fractions) for 5 days per week. The primary end point is local-regional recurrence-free survival. Here we reported the results of secondary end points: histopathologic response, surgical events, and toxicity. RESULTS: Of the 663 initially enrolled patients, 589 received the allocated treatment (nCT, n=300; nCRT, n=289). Pathologic complete response rate was 11.0% (95% CI, 7.8-15.3%) in the nCT arm and 13.8% (95% CI, 10.1-18.5%) in the nCRT arm ( P =0.33). The downstaging (ypStage 0 to 1) rate was 40.8% (95% CI, 35.1-46.7%) in the nCT arm and 45.6% (95% CI, 39.7-51.7%) in the nCRT arm ( P =0.27). nCT was associated with lower perioperative distant metastases rate (0.7% vs. 3.1%, P =0.03) and preventive ileostomy rate (52.2% vs. 63.6%, P =0.008) compared with nCRT. Four patients in the nCT arm received salvage nCRT because of local disease progression after nCT. Two patients in the nCT arm and 5 in the nCRT arm achieved complete clinical response and were treated with a nonsurgical approach. Similar results were observed in subgroup analysis. CONCLUSIONS: nCT achieved similar pCR and downstaging rates with lower incidence of perioperative distant metastasis and preventive ileostomy compared with nCRT. CAPOX could be an effective alternative to neoadjuvant therapy in LARC with uninvolved MRF. Long-term follow-up is needed to confirm these results.

Relationships among KRAS mutation status, expression of RAS pathway signaling molecules, and clinicopathological features and prognosis of patients with colorectal cancer.

BACKGROUND: The RAS/RAF/MEK/ERK and PI3K/AKT/mTOR signaling pathways all belong to mitogen-activated protein kinase (MAPK) signaling pathways, Mutations in any one of the upstream genes (such as the RAS gene or the BRAF gene) may be transmitted to the protein through transcription or translation, resulting in abnormal activation of the signaling pathway. This study investigated the relationship between the KRAS gene mutation and the clinicopathological features and prognosis of colorectal cancer (CRC), and the effect of KRAS mutations on its associated proteins in CRC, with an aim to clarify the cause of tumor progression and drug resistance caused by mutation of the KRAS gene. AIM: To investigate the KRAS gene and RAS pathway signaling molecules in CRC and to analyze their relationship with clinicopathological features and prognosis. METHODS: Colorectal cancer tissue specimens from 196 patients were analyzed for KRAS mutations using quantitative polymerase chain reaction and for KRAS, BRAF, MEK, and ERK protein expression levels using immunohistochemistry of tumor microarrays. To analyze differences of RAS pathway signaling molecule expression levels in different KRAS gene status, the relationships between these parameters and clinicopathological features, 4-year progression-free survival, and overall survival were analyzed by independent sample t test, Kaplan-Meier plots, and the log-rank test. Predictors of overall and disease-free survival were assessed using a Cox proportional hazards model. RESULTS: Of the 196 patients, 62 (32%) carried mutations in codon 12 (53/62) or codon 13 (9/62) in exon 2 of the KRAS gene. KRAS, BRAF, ERK, and MEK protein expression was detected in 71.4%, 78.8%, 64.3%, and 50.8% of CRC tissues, respectively. There were no significant differences between KRAS mutation status and KRAS, BRAF, MEK, or ERK protein levels. Positive expression of KRAS and ERK was associated with poor tumor differentiation, and KRAS expression was also associated with age < 56 years. MEK expression was significantly associated with distant metastasis (P < 0.05). The 4-year progression-free survival rate, but not overall survival rate, was significantly higher in patients with KRAS-negative tumors than in those with KRAS-positive tumors (P < 0.05), whereas BRAF, MEK, and ERK expression was unrelated to survival. Multivariate analysis showed that only the expression of KRAS protein was a risk factor for tumor recurrence (P < 0.05). No other clinicopathological factors correlated with KRAS, BRAF, MEK, or ERK expression. CONCLUSION: KRAS gene mutations do not affect downstream protein expression in CRC. KRAS protein is associated with poor tumor differentiation, older age, and a risk of tumor recurrence.

Lysine-specific demethylase 1 activation by vitamin B2 attenuates efficacy of apatinib for proliferation and migration of gastric cancer cell MGC-803.

B vitamins play an essential role in the biosynthesis of nucleotides, replication of DNA, supply of methyl-groups, growth and repair of cells, aberrancies of which have all been implicated in carcinogenesis. Although the potential role of vitamin B in relation to the risk of cancer, including breast, and colorectal cancer, has been investigated in several observational studies, the mechanism of action is still unclear. In this study, vitamin B2 exhibited efficient activation of LSD1 by occupying the active sites where FAD stands. Interestingly, vitamin B2 significantly downregulated expression of CD86, a sensitive surrogate biomarker of LSD1 inhibition, and showed marked activation of gastric cancer cell migration and invasion. Meanwhile, vitamin B2 induced activation of LSD1 may attenuate the proliferation inhibition, and anti-migration effects of apatinib in gastric cancer cells. These findings suggested that vitamin B supplementation may interfere with the efficacy of apatinib in patients with gastric cancer.

Association of long non-coding RNA HOTTIP with progression and prognosis in colorectal cancer.

Long non-coding RNA (lncRNA) has an important role in carcinoma progression and prognosis. However, little is known about the pathological role of lncRNA HOTTIP (HOXA transcript at the distal tip) in colorectal cancer (CRC) patients. This study attempted to investigate the association of lncRNA HOTTIP expression with progression and prognosis in CRC patients. LncRNA HOTTIP expression was measured in 156 CRC tissues and 21 adjacent non-malignant tissues using qRT-PCR. In present study, our results indicated that lncRNA HOTTIP was highly expressed in CRC compared with adjacent non-malignant tissues (P<0.001), and positively correlated with T stage (T1-2 vs. T3-4, P = 0.001), clinical stage (I-II stages vs. III-IV stages, P = 0.003), and distant metastasis (absent vs. present, P = 0.014) in CRC patients. Furthermore, we also observed that increased lncRNA HOTTIP expression was an unfavorable prognostic factor in CRC patients (P = 0.001), regardless of T stage, distant metastasis and clinical stage. Finally, overexpression of lncRNA HOTTIP was supposed to be an independent poor prognostic factor for CRC patients through multivariate analysis (P = 0.017). In conclusion, lncRNA HOTTIP overexpression maybe serves as an unfavorable prognosis predictor for CRC patients. However, a further larger sample size investigation is needed to support our results.

Phosphorylated insulin-like growth factor-1 receptor expression predicts poor prognosis of Chinese patients with gastric cancer.

Previous studies have established the role of phosphorylated form of insulin-like growth factor type 1 receptor (p-IGF1R) as a good candidate for tumor biomarker. The aims of this study were to investigate p-IGF1R expression status in gastric cancer (GC) specimens and to clarify its clinical significance. A total of 78 GC patients treated with radical resection were enrolled in this study. Immunohistochemistry was used to detect p-IGF1R and phosphatase and tensin homolog deleted on chromosome ten (PTEN) protein expression in paired tumor and adjacent normal tissues. Results showed a higher level of p-IGF1R protein expression in tumor tissues than that in normal tissues, and the rate of p-IGF1R protein high/moderate expression in GC and normal tissues was 52.6% (41/78) and 6.4% (5/78), respectively (p < 0.001). In contrast, PTEN protein expression was downregulated in GC, as compared with normal tissues (negative/low expression 49/78 vs. 8/78, p < 0.001). Moreover, PTEN protein downregulation was consistent with p-IGF1R upregulation. Overexpression of p-IGF1R protein was associated with lymph metastasis, clinical stage, and adverse 3-year progression-free survival (PFS). Survival analysis and Cox proportional hazards model revealed that p-IGF1R overexpression was an independent factor in predicting PFS for GC patients, apart from lymph metastasis. In conclusion, p-IGF1R is highly expressed in GC, which may be a novel biomarker to predict the clinical outcome of GC patients.

[Expression and clinical significance of metastasis-related tumor markers in colorectal cancer].

BACKGROUND AND OBJECTIVE: Besides current clinicopathologic staging system extensively used in clinic, more information of molecular staging is need for more accurate staging of colorectal cancer (CRC). This study was to evaluate the prognostic value of metastasis-related tumor markers in CRC. METHODS: The expression of CD44v6, matrix matalloproteinase-2 (MMP-2), cyclooxygenase-2 (COX-2), epidermal growth factor (EGF), epidermal growth factor receptor (EGFR) and vascular epidermal growth factor (VEGF) in a tissue microarray containing 95 specimens of CRC were detected by immunohistochemistry (IHC). The correlations of these tumor markers to the prognosis of CRC patients were analyzed. RESULTS: In patients with Dukes' A/B disease, the 5-year recurrence rates were significantly higher in CD44v6-, EGF-and EGFR-positive groups than in negative groups (30.9% vs. 8.3%,P=0.045; 38.1% vs. 8.8%, P=0.022; 27.5% vs. 11.8%, P=0.047, respectively). In patients with Dukes' C disease, the 5-year recurrence rates were significantly higher in MMP-2-, COX-2-and VEGF-positive group than in negative groups (73.3% vs. 37.5%, P=0.045; 69.2% vs. 25.0%, P=0.017; 62.5% vs. 25.0%, P=0.03, respectively). In patients with Dukes' A/B disease, there were a significantly higher 5-year recurrence rate and a lower 5-year survival rate in those with more than three positive markers than in those with 1-3 positive markers (P=0.019, P=0.03). However, there was no significant difference in patients with Dukes' C disease in such condition. CONCLUSIONS: Over-expression of CD44v6, EGF and EGFR are related to poor prognosis of Dukes' A/B CRC, while over-expression of MMP-2, COX-2 and VEGF are related to poor prognosis of Dukes' C CRC. For patients with Dukes' A/B CRC, the more positive markers, the higher 5-year recurrence rate and the poorer 5-year survival.

[Meta-analysis of postoperative adjuvant chemotherapy for Dukes' B colorectal carcinoma].

BACKGROUND & OBJECTIVE: The necessity of adjuvant chemotherapy after radical surgery for patients with Dukes' B (stage II) colorectal carcinoma remains controversial. This study was to evaluate effect of postoperative adjuvant chemotherapy on survival of Dukes' B patients with meta-analysis. METHODS: The results of literatures on postoperative adjuvant chemotherapy for Dukes' B patients from 1985 to 2003 were analyzed synthetically.The 5-year survival rates of postoperative adjuvant chemotherapy group and surgery alone group were compared. RESULTS: Eight published randomized controlled trails were eligible, and had 6 518 patients totally. The 5-year mortality was lower in postoperative adjuvant chemotherapy group than in surgery alone group with odds ratio (OR) of 0.79, and 95% confidence interval (CI) of 0.7-0.9, (P<0.05). CONCLUSION: Postoperative adjuvant chemotherapy could improve 5-year survival rate of Dukes' B patients.

[Long-term result of low anterior resection with stapling devices for rectal cancer].

BACKGROUND & OBJECTIVE: Currently, to preserve the anal function and improve the patients' quality of life, low anterior resection has become the preferred option in curative rectal cancer surgery. As the use of stapling instruments provides more reliable anastomoses in low anterior resection for rectal cancer, it enlarges the indication of this procedure. The aim of this study was to review the operation results and their outcomes of 449 rectal cancer patients who recieved of curative low anterior resections with stapling devices, and intent to find some measures that can reduce complications and improve long-term effects of this procedure. METHODS: The study included 449 patients who had a potentially curative anterior resection with stapled anastomosis in rectal cancer between Jan.1990 and Sept. 2002 at Sun Yat-sen University Cancer Center. All patients had complete follow-up data. All data were analyzed by SPSS8.0 software, risk factors for anastomotic leakage and recurrence were analyzed by Logistic regression, survival was analyzed by life table, and prognostic factors were screened by multivariate COX model. RESULTS: There were 11 cases of anastomotic leakage and 23 cases of anastomotic recurrence after operation. The 5-year survival rate was 78.4%. Age of >/= 65 years, and tumor involvement of more than half circumference were risk factors for anastomotic leakage, blood transfusion during operation was the risk factor for anastomotic recurrence. The independent factors for poor survival were stage of disease and tumor differentiation. CONCLUSIONS: Stapling devices can improve the anal reservation rate in low rectal cancer surgery, and stapled anastomoses is safe and feasible. Adequate preparation of bowel ends, a tension-free anastomosis with excellent blood supply and skilled stapled anastomoses were key measures to reduce anastomotic leakage, While TME, multidisciplinary therapy and the principle of avoiding medical spread, were key measures to improve treatment effect of rectal cancer.