Chunyan Lan

Expression of M2-polarized macrophages is associated with poor prognosis for advanced epithelial ovarian cancer

Macrophages are polarized into two functionally distinct forms, M1 and M2, in response to different microenvironment. Tumor-associated macrophages (TAMs) generally have M2 phenotype and promote tumor progression. Few studies to date have described the infiltration of M2-polarized macrophages in ovarian cancer. We used two macrophages markers, CD68 and CD163, to analyze the expression of TAMs and to clarify the relationship between the M2 form and survival in advanced ovarian cancer. Clinical data of 110 patients with stages III-IV epithelial ovarian cancer at Sun Yat-sen University Cancer Center between 1999 and 2007 were retrospectively reviewed. Immunohistochemical staining of CD68 and CD163 was performed. Correlations between macrophage density and patient survival were analyzed. Our data showed that no significant difference was observed in survival between patients in the high- and the low-CD68 expression groups. In contrast, the progression-free survival (PFS) rates (p = 0.003) and overall survival (OS) rates (p = 0.004) were significantly higher in the low-CD163 expression group than in the high-CD163 expression group, respectively. Similarly, we also observed significantly improved 3-year PFS (49.8% vs. 11.0%, p < 0.001) and OS (77.4% vs. 45.0%, p < 0.001) rates in patients in the low-CD163/CD68 ratio group when compared with the high-CD163/CD68 ratio group. Multivariate analysis identified the density of CD163-positive cells as well as the ratio of CD163/CD68 as negative predictors for PFS and OS, respectively. Our results show that the infiltration of CD163-positive M2 macrophages as well as activation of macrophages towards the M2 phenotype may contribute to poor survival in advanced ovarian cancer.

High density of IL-17-producing cells is associated with improved prognosis for advanced epithelial ovarian cancer

Interleukin (IL)-17 is the signature cytokine of T helper 17 cells. The role of IL-17 in the tumor microenvironment is still controversial. Few studies describing IL-17 expression in ovarian cancer have been reported. We have therefore analyzed the in situ tumor expression of IL-17 in advanced ovarian cancer and the possible correlation of IL-17 expression with tumor-associated macrophages (TAMs) and with survival in advanced ovarian cancer. Clinical data of 104 patients with stage III–IV epithelial ovarian cancer at the Sun Yat-sen University Cancer Center between 2000 and 2008 were retrospectively reviewed. Immunohistochemical staining of IL-17 and CD163 (marker for TAMs) was performed. Our data showed that levels of IL-17 were significantly increased in ovarian cancer compared with normal ovarian tissues (P<0.001). The high IL-17 expression group included more patients with grade 1 tumors than the low IL-17 expression group (P=0.042). High IL-17 expression correlated with improved progression-free survival (PFS) in advanced ovarian cancer (P<0.001). However, no significant difference was observed in overall survival between the high and low IL-17 expression groups. Multivariate analysis revealed that the density of IL-17-producing cells was a positive prognostic factor for PFS (P=0.001). Moreover, a positive correlation between the density of IL-17-producing cells and TAMs was identified (r=0.354, P<0.001). Our results indicate that the infiltration of IL-17-producing cells might contribute to improved PFS in advanced ovarian cancer. Our findings provide a new insight into the complex role of IL-17 in the tumor microenvironment of ovarian cancer.

Quantitative histology analysis of the ovarian tumour microenvironment

Concerted efforts in genomic studies examining RNA transcription and DNA methylation patterns have revealed profound insights in prognostic ovarian cancer subtypes. On the other hand, abundant histology slides have been generated to date, yet their uses remain very limited and largely qualitative. Our goal is to develop automated histology analysis as an alternative subtyping technology for ovarian cancer that is cost-efficient and does not rely on DNA quality. We developed an automated system for scoring primary tumour sections of 91 late-stage ovarian cancer to identify single cells. We demonstrated high accuracy of our system based on expert pathologists’ scores (cancer = 97.1%, stromal = 89.1%) as well as compared to immunohistochemistry scoring (correlation = 0.87). The percentage of stromal cells in all cells is significantly associated with poor overall survival after controlling for clinical parameters including debulking status and age (multivariate analysis p = 0.0021, HR = 2.54, CI = 1.40–4.60) and progression-free survival (multivariate analysis p = 0.022, HR = 1.75, CI = 1.09–2.82). We demonstrate how automated image analysis enables objective quantification of microenvironmental composition of ovarian tumours. Our analysis reveals a strong effect of the tumour microenvironment on ovarian cancer progression and highlights the potential of therapeutic interventions that target the stromal compartment or cancer-stroma signalling in the stroma-high, late-stage ovarian cancer subset.

Endometrial Stromal Sarcoma Arising from Endometriosis: A Clinicopathological Study and Literature Review

Objectives: We aimed to investigate the nature of endometrial stromal sarcoma (ESS) arising from endometriosis. Methods: The clinical data of 5 patients with ESS arising from endometriosis were reviewed retrospectively. The expression of CD117, HER2/neu, EGFR, VEGF, and PDGFR was analyzed by immunohistochemical staining. Results: The median age of the 5 patients was 45 years. The primary tumor sites were the ovary in 2, the pelvis in 2, and the cervical canal in 1 patient. Three patients had disseminated disease at diagnosis. Four patients underwent complete tumor resection. All of the 5 cases received adjuvant chemotherapy and 2 received progesterone therapy, while none were treated with radiotherapy. No recurrence occurred in the 4 cases who had complete tumor resection, and the only patient who progressed was the patient in whom the tumor was unresectable. Tumor cells in all cases exhibited positive staining for PDGFR and were negative for CD117 and HER2/neu. The expression of EGFR and VEGF was observed in 2 and 4 cases, respectively. Conclusion: ESS arising from endometriosis is rare. Complete tumor resection in ESS arising from endometriosis may reduce the recurrence rate.

Clinical significance of ascites in epithelial ovarian cancer.

The prognostic significance of ascites in the dissemination of metastases in epithelial ovarian cancer (EOC) is unclear. Our study aimed to investigate the association between clinicopathological factors and the development of ascites, as well as its prognostic significance. Three hundred and thirty three patients with primary EOC were suitable for inclusion. We analyzed the correlation between clinicopathological factors, including the extent of metastases, and ascitic volume. The prognostic significance of ascites was assessed using the Kaplan-Meier method and multivariate Coxs regression analysis. The average ascitic volume was 1,800 ml. Significantly, more patients with advanced FIGO stage disease presented with ascites. The volume of ascites increased significantly when metastatic disease was present in more than three regions (p<0.05), and this was the sole factor identified as associated with ascitic volume by multiple linear regression analysis. Median survival was significantly different between those with an ascitic volume less than 1,800 ml (median survival = 58 months), and those with a volume greater than 1,800 ml (median survival = 28.6 months) (p<0.05). Subgroup analysis of stage III and IV patients also revealed a poor prognosis in the presence of massive ascites (p = 0.03). Multivariate analyses found that massive ascites and poor differentiation were independent poor prognostic factors for stage III and IV EOC patients by Cox regression, using a backward elimination procedure. The volume of ascites increased significantly with the extent of metastastic disease. Massive ascites and poor tumor differentiation were associated with a worse prognosis in patients with advanced stage ovarian cancer.

Adjuvant docetaxel and carboplatin chemotherapy administered alone or with radiotherapy in a “sandwich” protocol in patients with advanced endometrial cancer: a single-institution experience

Objective: To evaluate the outcomes of adjuvant chemotherapy administered alone or with radiotherapy in a “sandwich” protocol in patients with advanced endometrial cancer. Methods: The authors retrospectively reviewed the clinical records of patients with staged III – IV disease who received adjuvant chemotherapy (docetaxel plus carboplatin) administered alone or interposed with radiotherapy between January 2004 and August 2010. Results: Of the 35 study patients, 10 (28.6%) had stage IIIA disease, 15 (42.9%) had IIIC1 disease, 7 (20.0%) had IIIC2 disease and 3 (8.6%) had IVB disease. Nine (90.0%) of the 10 patients with stage IIIA disease received four to six cycles of adjuvant docetaxel and carboplatin chemotherapy alone. All 25 patients with stage IIIC – IVB disease and 1 patient with stage IIIA disease received radiotherapy sandwiched between chemotherapy cycles (total, three to six cycles). The 3-year progression-free survival (PFS) and overall survival (OS) rates were 73.0 and 87.0%, respectively, for all patients. For patients with stage IIIC – IVB disease, the 3-year PFS and OS rates were 62.4 and 81.8%, respectively. Conclusion: Combination chemotherapy with docetaxel and carboplatin interposed with radiotherapy is efficacious and well tolerated for stage IIIC – IVB endometrial cancer. Adjuvant chemotherapy alone with docetaxel and carboplatin might be sufficient for stage IIIA disease.

Neoadjuvant docetaxel combined with cisplatin and followed by radical surgery for the treatment of locally advanced (stage IB2 – IIB) cervical cancer: preliminary results of a single-institution experience

Objectives: We aimed to determine the efficacy and toxicity of treating locally advanced cervical cancer (LACC) with a neoadjuvant chemotherapy (NAC) regimen combining docetaxel and cisplatin followed by radical surgery. Methods: We retrospectively reviewed the clinical records of patients with stage IB2 – IIB (tumor diameter ≥ 4 cm) disease admitted between January 2007 and July 2009 who, before radical hysterectomy and pelvic lymph node dissection, received two to three courses of an NAC regimen comprising docetaxel (75 mg/m2) and cisplatin (70 – 75 mg/m2). Results: Fifty-two patients with LACC received 109 cycles of NAC. The objective response rate was 86.5% (26.9% CR and 17.3% pathological CR). Stage IB2 disease had a more favorable response to NAC (95.7%, p = 0.019). Deep stromal invasion and lymph-vascular space metastasis rates were significantly lower in NAC responders (p = 0.033) than in nonresponders (p = 0.012). Most side effects of NAC were mild or moderate. Log-rank test showed the 2-year overall survival and progression-free survival rates were 100 and 90.3% for NAC responders, compared with only 57.1% (p = 0.000) and 68.6% for nonresponders (p = 0.012), respectively. Conclusion: Neoadjuvant docetaxel combined with cisplatin yielded a high response rate with well tolerable toxicity for LACC and could decrease pathological risk factors in NAC responders.

The outcome and efficacy of adjuvant chemotherapy alone in patients with stage IIIA endometrial carcinoma with solitary adnexal involvement: A retrospective single-institution study

OBJECTIVES The appropriate adjuvant therapy for patients with endometrial carcinoma with solitary adnexal involvement is unclear. We conducted a retrospective single-institution study to evaluate the outcome and efficacy of adjuvant chemotherapy alone in this population. METHODS All patients with endometrial carcinoma who received primary surgical treatment between January 1999 and May 2010 were reviewed. The patients who were diagnosed with stage IIIA disease based only on isolated adnexal involvement and treated with surgical procedures followed by adjuvant chemotherapy alone were included. Demographic, clinicopathologic, treatment and outcome data were collected. Recurrence and survival were analyzed. RESULTS Among 1453 reviewed patients, 67 patients were identified. The median age was 48 years. All patients were treated with platinum-based adjuvant chemotherapy, with the majority (36/67, 53.7%) receiving paclitaxel plus carboplatin. The total number of cycles of chemotherapy administered was 305 (median four cycles/person). Most of the chemotherapy related toxicities were mild or moderate. The median follow-up time was 76 months. Eight patients experienced recurrence. The majority of initial relapses were distant (7/8, 87.5%), characterized by liver metastases (3/8, 37.5%). The 5-year disease-free survival (DFS) and overall survival (OS) rates were 89.6% and 91.9%, respectively. Multivariate analysis confirmed that grade 3 tumor was an independent predictor of worse DFS and OS (HR=5.19, P=0.048; HR=6.55, P=0.037, respectively). CONCLUSION Patients with stage IIIA endometrial carcinoma with solitary adnexal involvement have favorable outcomes. Adjuvant chemotherapy alone may be effective and feasible for these patients.

Apatinib combined with oral etoposide in patients with platinum-resistant or platinum-refractory ovarian cancer (AEROC): a phase 2, single-arm, prospective study

BACKGROUND Anti-angiogenic therapy combined with chemotherapy could improve the outcomes of patients with platinum-resistant ovarian cancer. Apatinib is an oral tyrosine kinase inhibitor that selectively inhibits VEGF receptor 2. We assessed the efficacy and safety of the combination therapy of apatinib and oral etoposide, considering the potential advantage of home administration without hospital admission, in patients with platinum-resistant or platinum-refractory ovarian cancer. METHODS In this phase 2, single-arm, prospective study, we recruited patients aged 18-70 years with platinum-resistant or platinum-refractory ovarian cancer at the Sun Yat-sen University Cancer Center (China). The treatment consisted of apatinib at an initial dose of 500 mg once daily on a continuous basis, and oral etoposide at a dose of 50 mg once daily on days 1-14 of a 21-day cycle. Oral etoposide was administered for a maximum of six cycles. Treatment was continued until disease progression, patient withdrawal, or unacceptable toxic effects. The primary endpoint was the proportion of patients achieving an objective response according to Response Evaluation Criteria in Solid Tumors, version 1.1. We used Simons two-stage design, and analysed efficacy in the intention-to-treat and per-protocol populations. Safety analyses included enrolled patients who had received at least one dose of study medication, but excluded those without any safety data. This study is registered with ClinicalTrials.gov, number NCT02867956. FINDINGS Between Aug 10, 2016, and Nov 9, 2017, we screened 38 and enrolled 35 patients. At the data cutoff date (Dec 31, 2017), 20 (57%) patients had discontinued the study, and 15 (43%) patients remained on treatment. Objective responses were achieved in 19 (54%; 95% CI 36·6-71·2) of 35 patients in the intention-to-treat population and in 19 (61%; 42·2-78·2) of 31 patients in the per-protocol population. The most common grade 3 or 4 adverse events were neutropenia (17 [50%]), fatigue (11 [32%]), anaemia (ten [29%]), and mucositis (eight [24%]). Serious adverse events were reported in two patients who were admitted to hospital (one patient had anaemia and anorexia; the other patient had increased ascites due to disease progression). No treatment-related deaths were recorded. INTERPRETATION The combination of apatinib with oral etoposide shows promising efficacy and manageable toxicities in patients with platinum-resistant or platinum-refractory ovarian cancer, and further study in phase 3 trials is warranted. FUNDING None.

Should the Optimal Adjuvant Treatment for Patients With Early-Stage Endometrial Cancer With High-Intermediate Risk Factors Depend on Tumor Grade?

Objectives To explore whether the optimal adjuvant treatments for patients with early-stage endometrial cancer with high-intermediate risk (HIR) factors should depend on tumor grade. Methods A retrospective analysis of patients with HIR endometrial cancer from 1999 to 2012 was conducted. The adjuvant treatments and survival were evaluated. Results A total of 129 patients with HIR were identified, of which 71 had grade 1–2 tumor and 58 had grade 3 tumor. The adjuvant treatment chosen differed significantly between patients with grade 1–2 and grade 3 tumors (P < 0.001). Most of the patients (76.1%) with grade 1–2 tumors received no adjuvant treatment; however, chemotherapy alone was the most frequent (75.9%) adjuvant treatment for patients with grade 3 tumors. In the grade 1–2 group, no significant differences in the 5-year progression-free survival (94.1% vs 96.3%; P = 0.857) and overall survival (OS) rates (94.1% vs 98.1%; P = 0.401), respectively, were observed between patients who received adjuvant treatment (radiation and chemotherapy with or without radiation) and those who did not. For grade 3 disease, patients undergoing adjuvant chemotherapy alone had a favorable outcome with the 5-year progression-free survival rate of 84.4% and the OS rate of 95.5%. Conclusion It is logical to speculate that surgery followed by observation might be sufficient for patients with HIR with grade 1–2 tumor. Further prospective trials are required to confirm the issue owing to the limited number of this population. More studies are warranted to clarify the feasibility and efficacy of adjuvant chemotherapy alone in patients with HIR with grade 3 tumor.