Cathepsin C promotes colorectal cancer metastasis by regulating immune escape through upregulating CSF1.

Since metastasis remains the primary reason for colorectal cancer (CRC) associated death, a better understanding of the molecular mechanism underlying CRC metastasis is urgently needed. Here, we elucidated the role of Cathepsin C (CTSC) in promoting CRC metastasis. The expression of CTSC was detected by real-time PCR and immunohistochemistry in the human CRC cohort. The metastatic capacities of CTSC-mediated metastasis were analyzed by in vivo metastasis model. Elevated CSTC expression was positively associated with tumor differentiation, tumor invasion, lymph node metastasis, and AJCC stage and indicated poor prognosis in human CRC. CTSC overexpression in CRC cells promoted myeloid-derived suppressor cells (MDSCs) and tumor-associated macrophages (TAMs) recruitment by the CSF1/CSF1R axis. In contrast, the knockdown of CSF1 reduced CTSC-mediated MDSCs and TAMs infiltration and CRC metastasis. Depletion of either MDSCs or TAMs decreased CTSC-mediated CRC metastasis. In human CRC tissues, CTSC expression was positively associated with intratumoral MDSCs and TAMs infiltration. Furthermore, the combination of CTSC inhibitor AZD7986 and anti-PD-L1 antibody blocked CTSC-induced CRC metastasis. CTSC overexpression promoted MDSCs and TAMs infiltration by CSF1/CSF1R axis. Interruption of this oncogenic loop may provide a promising treatment strategy for inhibiting CTSC-driven CRC metastasis.

The Prognosis and Risk Stratification Based on Pelvic Lymph Node Characteristics in Patients With Locally Advanced Cervical Squamous Cell Carcinoma Treated With Concurrent Chemoradiotherapy.

BACKGROUND: The purpose of this study is to determine the prognostic significance of pelvic lymph node (PLN) characteristics and perform risk stratification in patients undergoing concurrent chemoradiotherapy for locally advanced cervical squamous cell carcinoma. METHODS: We retrospectively reviewed the records of 609 patients with Federation Internationale de Gynecologie et d'Obstetrique (FIGO) stage II to IVa who underwent concurrent chemoradiotherapy, compared overall survival (OS), distant metastasis-free survival (DMFS), and pelvic recurrence-free survival between patients with or without PLN involvement. We further analyzed prognostic factors for OS and DMFS including FIGO stage, tumor volume, and lymph node (LN) characteristics in 300 patients with PLN involvement. RESULTS: The 3-year OS rate was 81.7% versus 92.8% (P = 0.002) and the 3-year DMFS rate was 79.3% versus 92.7% (P = 0.006) in patients with or without PLN involvement, respectively. With univariable analysis, FIGO stage, LN-volume, LN-number, LN-diameter, and matted/necrotic LN affected both OS and DMFS. Based on multivariable analysis, we created a risk stratification model. For OS, the independent risk factors were FIGO stage III or IVa, LN-volume of 3 cm or more, LN-diameter of 1.5 cm or more, and matted/necrotic LN. The low-risk group (no risk factors), mid-risk group (1 or 2 risk factors), and high-risk group (3 or 4 risk factors) had a 3-year OS of 96.6%, 84.9%, and 64.7%, respectively (P = 0.005). For DMFS, LN-diameter of 1.5 cm or more, LN-number of 3 or more, and matted/necrotic LN were the independent risk factors. The subgroups for DMFS were the low-risk group (no risk factors), the mid-risk group (1 risk factor), and the high-risk group (2 or 3 risk factors), and the 3-year DMFS was 92.4%, 76.2%, and 64.6%, respectively (P = 0.001). CONCLUSIONS: The prognosis was significantly poorer for patients with high-risk lymph node characteristics. Using this risk stratification, we should select the most appropriate and individualized treatment modality to improve outcomes in those patients with a poorer prognosis.

Efficacy and Toxicity of IMRT-Based Simultaneous Integrated Boost for the Definitive Management of Positive Lymph Nodes in Patients with Cervical Cancer.

Background: The optimal radiotherapy regimen for treating metastatic lymphadenopathy in patients with locally advanced cervical cancer remains controversial. This study aimed to investigate the clinical outcomes, as well as associated toxicities, of intensity-modulated radiotherapy (IMRT) with a simultaneous integrated boost (SIB) for pelvic and para-aortic lymph nodes (LNs). Methods: Between 2011 and 2015, 74 patients with 2014 International Federation of Gynecology and Obstetrics stage IIB-IVB cervical cancer exhibiting pelvic or para-aortic LN involvement were examined. The pelvic field planning dose was 45-50 Gy in 25 fractions, and an SIB of 62.5 Gy in 25 fractions was delivered to positive LNs. Next, CT-guided brachytherapy was performed 24 Gy in 3 fractions to 42 Gy in 6 fractions once or twice weekly. Results: The median follow-up duration was 36 (range: 3-62) months. The 3-year local control, distant metastasis-free survival, and overall survival rates were 91.7%, 75.7%, and 71.4%, respectively. No residual or recurrent LNs were detected. Six patients developed grade 3 acute gastrointestinal (GI) toxicity. Twenty-nine (39.2%) and 3 (4.1%) patients developed grade 3 and 4 hematological toxicities, respectively. Twenty patients (28.5%) developed grade ≥2 chronic GI toxicity. Only 1 patient (1.4%) experienced a grade 4 rectovaginal fistula, and 3 patients (4.2%) developed grade 2 genitourinary toxicities. SIB to the LNs did not influence acute or chronic toxicity rates. Conclusions: Our findings demonstrate that a dose of 62.5 Gy to positive LNs using the IMRT with SIB method can achieve excellent clinical outcomes with acceptable toxicity.

The Efficacy and Late Toxicities of Computed Tomography-based Brachytherapy with Intracavitary and Interstitial Technique in Advanced Cervical Cancer.

Purpose: To report the efficacy and late side effects(LSEs) of CT-based image-guided brachytherapy for the treatment of cervical cancer. Materials: Between 2008 and 2014, 100 patients with FIGO stage IIB-IVA cervical carcinoma were analyzed. The patients received pelvic irradiation (45-50 Gy in 25 fractions) with concurrent chemotherapy, whereas the mean prescribed EBRT dose, including initial and boost doses to positive lymph nodes, ranged from 54 to 64 Gy. Afterwards, intracavitary(IC) or combined intracavitary/interstitial(IC/IS) brachytherapy was performed using a CT-based procedure with prescribed doses of 6 or 8 Gy in 3-7 fractions. Results: The median follow-up time was 46 months. The 5-year local control, distant metastasis-free survival, and overall survival rates were 88.9%, 81.8%, 77.9%, respectively. IC/IS brachytherapy improved the HR-CTV D90 compared with IC (p<0.01). Seven patients (7.0%) had grade 2 bladder LSEs and none had grade 3/4 bladder LSEs. There was no significant relationship between bladder LSEs and the dose-volume histogram (p>0.05 for all). Thirty-seven patients (37%) had grade 2 rectal LSEs, 3(3%) had grade 3 rectal LSE. The rectum D1cc, D2cc, and D5cc values were significantly higher in patients with grades 2/3 rectal toxicity than in those with grades 0/1 (p<0.05 for all). There was no grade 2 and above small bowel LSEs. Conclusions: CT-based brachytherapy planning can achieve excellent local control with acceptable morbidity. HR-CTV D90 can increase in the IC/IS group compared with the IC group. The D1cc, D2cc, and D5cc all showed excellent predictive values for rectal LSEs.

Individualized pelvic lymphadenectomy should follow neoadjuvant concurrent chemoradiotherapy for locally advanced cervical cancer.

To study the outcomes following concurrent chemoradiotherapy (CCRT) and subsequent radical surgery for locally advanced cervical cancer (LACC), analyze the relationship between imaging-diagnosed and postoperative-diagnosed lymph node (LN) involvement, and identify patients who would benefit from individualized pelvic lymphadenectomy.We retrospectively reviewed records of 410 patients who underwent CCRT followed by radical surgery for International Federation of Gynecology and Obstetrics Stage Ib2-IIIb disease. Correlations of LN size on imaging before CCRT with pathological responses after CCRT, overall survival (OS), distant metastasis-free survival (DMFS), and complications were analyzed.During a median follow-up of 51.3 months, the respective 5-year OS and DMFS were 86.7% and 88.6%, respectively. Pathological primary tumor type, LN size on imaging before CCRT, and pathologic response after CCRT were independent prognostic factors for OS. Patients with a LN ≥0.8 cm had a significantly higher residual carcinoma rate versus those with LN <0.8 cm (33% vs 22.6%, P = .032). Postoperative pathological positive LN frequencies differed significantly by LN size on imaging (LN <0.8 cm vs LN ≥0.8 cm, 3% vs 19.3%, P < .0001). Grade 1-3 lower extremity edema occurred in 23.9% of cases; no grade 3-4 gastrointestinal and genitourinary toxicities were observed.CCRT followed by radical surgery for LACC yielded encouraging outcomes without unacceptable complications. Additionally, patients with a LN <0.8 cm on imaging before CCRT had a very low risk of postoperative pathological positive LN identification. Individualized pelvic lymphadenectomy (e.g., omitting or limiting the extent of LN dissection) might be an alternative option for some patients with a low risk of LN metastasis.

High VEGFR1/2 expression levels are predictors of poor survival in patients with cervical cancer.

The aim of the study to evaluate the prognostic significance of vascular endothelial growth factor receptor 1 and 2 (VEGFR1/2) expression levels and to correlate these levels with clinicopathological parameters in patients with cervical cancer.Forty-two patients with International Federation of Gynecology and Obstetrics Stage IIB-IVB cervical cancer were analyzed between January 2011 and December 2012. RNA expression levels of VEGFR1/2 were assessed by branched DNA-liquidchip technology and immunohistochemistry. Associations between RNA expression levels, important clinicopathological parameters, and patient survival were statistically evaluated.Higher VEGFR1/2 expression levels were predictive of poor overall survival (P = 0.009 and P = 0.024, respectively). Patients with higher VEGFR1 expression levels were associated with poorer progression-free survival than those with lower VEGFR1 expression levels (P = 0.043). In addition, patients with higher VEGFR1 expression levels were more likely to develop distant metastases than those with lower VEGFR1 expression levels (P = 0.049). Higher VEGFR2 expression levels were associated with larger tumor size (P = 0.037).VEGFR1/2 expression levels were prognostic factors for patients with cervical cancer. Higher VEGFR1/2 expression levels were also predictive of poor overall survival.

[Efficacy observation on imatinib adjuvant therapy with longer duration in patients with gastrointestinal stromal at intermediate or high risk of recurrence].

OBJECTIVE: To evaluate the recurrence-free survival (RFS) and safety of imatinib adjuvant therapy with longer treatment duration in patients undergoing complete resection of localized primary gastrointestinal stromal tumor (GIST). METHODS: Clinical and follow-up data of 101 GIST patients between March 2004 and May 2009 with intermediate or high recurrence risk receiving imatinib adjuvant treatment and more than 3 years follow-up time in Peking University Cancer Hospital were retrospectively analyzed. Imatinib adjuvant treatment: 3 patients discontinued less than 1 year imatinib treatment because of adverse events; 24, 21 and 18 patients discontinued imatinib after 1 year, 2 years, and 3 years treatment; 8 patients received 3 years adjuvant treatment and were ongoing; 27 patients received more than 4 years imatinib adjuvant treatment. RESULTS: The median follow-up time was 60 months (95%CI:57.9-62.1). Nineteen patients had GIST recurrence, of whom recurrence happened during imatinib adjuvant therapy in 5 patients and after imatinib treatment in 14 patients. The median period from imatinib stopping to recurrence was 12.0 months (95%CI:9.6-14.4). Patients with recurrent GIST achieved tumor control after imatinib resumption. RFS of patients (n=53) with ≥3 years imatinib treatment duration was higher than that of patients (n=48) with <3 years imatinib duration (93.9% vs. 68.0%, P<0.01). In addition, prolonged adjuvant imatinib duration did not significantly increase the adverse events related to treatment (P>0.05). CONCLUSIONS: Prolonged adjuvant imatinib duration may further improve RFS rate further in patients with intermediate or high risk of recurrence after complete tumor resection without increased adverse events.

[Correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer].

OBJECTIVE: To investigate the correlation of MDR1 and ABCG2 genetic polymorphisms with the efficacy and adverse events of irinotecan chemotherapy in patients with colorectal cancer (CRC). METHODS: Clinical data of CRC patients treated with irinotecan-based chemotherapy in the Peking University Cancer Hospital between January 1996 and December 2011 were collected, and their blood samples were collected accordingly. Genomic DNA was extracted from blood samples. The following SNP detection of MDR1 and ABCG2 genes was conducted by direct sequencing method. The correlation of genetic SNPs with efficacy and toxicity of irinotecan treatment was further analyzed. RESULTS: Allele frequencies of MDR1 2677 G>T/A, ABCG2 421 C>A, 34 G>A, 376 C>T were comparable with previous studies. Genetic SNPs results from peripheral blood samples and tumor tissues were highly consistent. Patients carrying MDR1 2677 wild type had higher clinical benefit than those carrying mutant genotype, while the differences were not significant. The progression-free survival (PFS) was longer in wild-type patients as compared to mutant-type patients in second-line chemotherapy (P=0.012). There were no significant correlations between ABCG2 421 C>A, 34 G>A, 376 C>T and chemotherapy efficacy. No significant correlations were observed between MDR1 2677 G>T/A, ABCG2 421 C>A, ABCG2 34 G>A, ABCG2 376 C>T and irinotecan-related grade 3 and 4 neutropenia or diarrhea. CONCLUSION: MDR1 2677 G>T/A may be served as a biomarker in predicting the efficacy of irinotecan chemotherapy in patients with colorectal cancer.