Poor Treatment Outcomes with Second-Line Chemotherapy in Advanced Synovial Sarcoma.

INTRODUCTION: Synovial sarcoma (SS) predominantly affects adolescents and young adults. Doxorubicin with or without ifosfamide therapy is the standard first-line treatment for unresectable or metastatic SS. However, there is no standard second-line chemotherapy regimen. The purpose of the current study was to evaluate the outcomes of second-line chemotherapy for patients with SS. METHODS: We retrospectively evaluated the outcomes of 61 patients with unresectable or metastatic SS who had received first-line chemotherapy at our institution between 1997 and 2017. Patients who received second-line chemotherapy were included in the analysis. Outcomes of the chemotherapy were evaluated. RESULTS: Among the 61 patients treated with first-line chemotherapy, we identified 32 patients who received second-line chemotherapy. Most patients (62.5%) were under 40 years of age. Regarding second-line chemotherapy regimens, 6 (18.8%) patients were treated with doxorubicin with/without ifosfamide, 6 (18.8%) with ifosfamide and etoposide, 4 (12.5%) with docetaxel and gemcitabine, 5 (15.6%) with pazopanib, 2 (6.2%) with trabectedin, and 1 (3.1%) with eribulin. The overall response rate according to the Response Evaluation Criteria in Solid Tumors for all patients was 9.4%. Eleven patients (34.3%) achieved disease-control for >6 months. The median follow-up duration was 15.2 months. The 1-year progression-free and overall survival rates were 33.1% and 67.1%, respectively. CONCLUSION: Our exploratory study revealed that the response rate of second-line chemotherapy regimens for patients with SS was 9.4%. Therefore, there is an urgent need to develop more active therapeutic regimens for SSs.

[Ifosfamide and Paclitaxel for Recurrent or Metastatic Uterine Carcinosarcoma].

AIM: This study aimed to retrospectively evaluate the efficacy and safety of ifosfamide plus paclitaxel(IT)in Japanese patients with recurrent or metastatic uterine carcinosarcoma. METHODS: This study included 15 patients who received IT(ifosfamide [1.6 g/m / 2 on days 1-3]and paclitaxel[135mg/m2 on day 1]every 3 weeks)for recurrent or metastatic uterine carcinosarcoma. RESULTS: The overall response rate was 38.4%, and the disease control rate was 92.3%. The median progression- free survival was 7.0 months, and the median overall survival was 9.0 months after initiation of IT therapy. The most common hematological adverse event was Grade 1-2 neutropenia. Peripheral neuropathy of Grade 1 or 2 was observed in 33.3% of cases. There was no treatment-related death. CONCLUSION: IT therapy showed good efficacy and tolerability in Japanese patients with recurrent or metastatic uterine carcinosarcoma.

HER3 protein expression as a risk factor for post-operative recurrence in patients with early-stage adenocarcinoma and adenosquamous carcinoma of the cervix.

Patients with cervical adenocarcinoma (AC) and adenosquamous carcinoma (ASC) have a poorer prognosis than those with squamous cell carcinoma (SCC). Erb-b2 receptor tyrosine kinase 3 (HER3) is a member of the epidermal growth factor receptor family and its expression is associated with unfavorable prognosis in several cancer types, including SCC of the cervix. As there is limited information on the prognostic value of HER3 for AC and ASC of the cervix, the present study aimed to evaluate the expression of HER3 and its impact on post-operative recurrence in patients with AC and ASC of the cervix. This retrospective study included 39 patients with early-stage AC and ASC who underwent primary surgery between January 1997 and December 2017. Immunohistochemical staining for HER3 was performed on formalin-fixed paraffin-embedded surgical specimens. The possible influence of HER3 expression on disease-free survival (DFS) was studied by using multivariate Cox regression with adjustment for established risk factors of post-operative recurrence. High expression of HER3 (HER3-high) was detected in 85.1% of cases of AC (23/27) and in 58.3% of cases of ASC (7/12). The median follow-up duration was 63.1 months and Kaplan-Meier analysis indicated that the 5-year DFS rates of patients with AC and ASC of the cervix were 56.7% in patients with HER3-high and 77.8% in patients with HER3-low (log rank, P=0.20). On multivariate analysis, HER3-high [hazard ratio (HR)=6.32, 95% CI: 1.10-36.26, P=0.039), pelvic lymph node metastasis (HR=7.61, 95% CI: 2.07-28.00, P=0.002) and vascular invasion (HR=4.28, 95% CI: 1.12-16.31, P=0.033) were indicated to be independent predictors of DFS. To date, the present study is the most comprehensive analysis to evaluate the expression of HER3 in patients with early-stage AC and ASC of the cervix. The results suggested that HER3 overexpression may be an independent risk factor for post-operative recurrence. However, these results and the prognostic value of HER3 should be confirmed in a larger sample.

Neoadjuvant chemotherapy promotes the expression of HER3 in patients with ovarian cancer.

HER3 (erbB3) signaling serves an important role in the development and chemoresistance of ovarian cancer, and is activated by chemotherapy. To evaluate the influence of neoadjuvant chemotherapy and other clinical factors on the expression of HER3, as well as to examine its role as a prognostic marker, the present study evaluated archived tissues from patients who underwent surgery for ovarian cancer between 2011 and 2018 at our hospital. Immunohistochemical staining for HER3 was performed using formalin-fixed paraffin-embedded surgical specimens and biopsy samples. In total, data from 111 patients with sufficient surgically resected tumor samples were extracted. A total of 28 patients with histology type high-grade serous carcinoma (HGSC) had specimens available from both pre-chemotherapy biopsies and post-chemotherapy surgery. High HER3 expression (HER3-high) was observed in 64 patients (58%), whereas low HER3 expression (HER3-low) was observed in 47 patients (42%). Multivariate logistic regression analysis identified neoadjuvant chemotherapy [odds ratio (OR), 7.49; 95% confidence interval (CI), 2.48-22.64; P<0.001) and non-HGSC histology (OR, 5.42; 95% CI, 1.99-14.78; P<0.001) as significant predictive factors for HER3-high. In pre-chemotherapy biopsy specimens, 15 patients were HER3-high and 13 were HER3-low. After chemotherapy, eight of 13 patients with HER3-low exhibited a change in status to HER3-high, with a trend toward poorer progression-free survival compared to that of patients whose status remained HER3-low. In conclusion, HER3 overexpression was revealed to be common among patients with ovarian cancer, especially in those with non-HGSC histology. In addition, HER3 expression may be promoted by chemotherapy. These findings suggested that patients with ovarian cancer are good candidates for emerging HER3-targeting therapies.

Stroma-derived matrix metalloproteinase (MMP)-2 promotes membrane type 1-MMP-dependent tumor growth in mice.

Matrix metalloproteinase-2 (MMP-2) is a stroma-derived MMP belonging to the type IV collagenase family. It is believed to mediate tumor cell behavior by degrading deposits of type IV collagen, a major component of the basement membrane. The membrane type 1-MMP (MT1-MMP) is a highly potent activator of MMP-2 and is expressed in many tumor and stromal cells. However, the roles played by stromal MMP-2 in tumor progression in vivo remain poorly understood. We established a colon epithelial cell line from an Mt1-mmp(-/-) mouse strain and transfected these cells with an inducible expression system for MT1-MMP (MT1rev cells). Following s.c. implantation into Mmp-2(+/+) mice and induction of MT1-MMP expression, MT1rev cells grew rapidly, whereas they grew very slowly in Mmp-2(-/-) mice, even in the presence of MT1-MMP. This MT1-MMP-dependent tumor growth of MT1rev cells was enhanced in Mmp-2(-/-) mice as long as MMP-2 was supplied via transfection or coimplantation of MMP-2-positive fibroblasts. MT1rev cells cultured in vitro in a three-dimensional collagen gel matrix also required the MT1-MMP/MMP-2 axis for rapid proliferation. MT1rev cells deposit type IV collagen primarily at the cell-collagen interface, and these deposits seem scarce at sites of invasion and proliferation. These data suggest that cooperation between stroma-derived MMP-2 and tumor-derived MT1-MMP may play a role in tumor invasion and proliferation via remodeling of the tumor-associated basement membrane. To our knowledge, this is the first study demonstrating that MT1-MMP-dependent tumor growth in vivo requires stromal-derived MMP-2. It also suggests that MMP-2 represents a potential target for tumor therapeutics.

Multifunctional roles of MT1-MMP in myofiber formation and morphostatic maintenance of skeletal muscle.

Sequential activation of muscle-specific transcription factors is the critical basis for myogenic differentiation. However, the complexity of this process does not exclude the possibility that other molecules and systems are regulatory as well. We observed that myogenic differentiation proceeded through three distinct stages of proliferation, elongation and fusion, which are distinguishable by their cellular morphologies and gene expression patterns of proliferation- and differentiation-specific markers. Treatment of the differentiating myoblasts with inhibitors of matrix metalloproteinases (MMPs) revealed that MMP activity at the elongation stage is a critical prerequisite to complete the successive myoblast cell fusion. The MMP regulated the myogenic differentiation independently from the genetic program that governs expression of the myogenic genes. Membrane-type 1 matrix metalloproteinase (MT1-MMP) was identified as a major contributor to this checkpoint for morphological differentiation and degraded fibronectin, a possible inhibitory factor for myogenic cell fusion. A MT1-MMP deficiency caused similar myogenic impediments forming smaller myofibers in situ. Additionally, the mutant mice demonstrated some central nucleation of the myofibers typically found in muscular dystrophy and MT1-MMP was found to cleave laminin-2/4 in the basement membrane. Thus, MT1-MMP is a new multilateral regulator for muscle differentiation and maintenance through processing of stage-specific distinct ECM substrates.