[Effects of Olaparib, a PARP-1 Inhibitor, on Triple Negative Breast Cancer Cells with a BRCA1 Mutation].

In 2018, olaparib, a PARP inhibitor, was approved for the treatment of BRCA1/2 gene-mutation positive and HER2-negative inoperable and recurrent breast cancer; BRCA1/2 gene testing was also listed as a companion diagnostics. Here, we identified microRNAs(miRNAs) expressed after treatment with olaparib, which differed in the presence or absence of BRCA1 mutations in triple negative breast cancer(TNBC), and examined the changes in miRNAs after exposure to the combination of the PARP-1 inhibitor and a chemotherapeutic agent. After exposure to the PARP-1 inhibitor, the expression of miR-141, miR-155, miR-205, and miR-223 decreased in MDA-MB-231, HCC1143, and BT549 cells and increased more than 10 times in MDA-MB-436 cells. Moreover, the expression of miR-141 in MDA-MB-436 cells treated with the PARP-1 inhibitor together with gemcitabine increased more than 10 times; additionally, the expression of miR-205 increased more in the context of combination therapy versus single exposure to olaparib. The miR-200 family(including miR-141)and miR- 205 are known to function as ZEB1/2 targets and to act as epithelial-to-mesenchymal transition(EMT)-suppressors. Overall, these results suggest that it may be possible to recover the sensitivity of TNBC cells to chemotherapy via the suppressing EMT through the use of a PARP-1 inhibitor in the context of BRCA1 mutation.

Skin grafting utilizing a skin of lateral thoracic area for chest wall reconstruction in patient who underwent mastectomy for locally advanced breast cancer.

Locally advanced breast cancer sometimes results in a large chest wall defect at mastectomy. When closing the wound horizontally, the skin tension is usually severe in the middle of the wound, while the skin of the lateral area tends to make a dog-ear deformity. Triangle technique is a procedure to prevent the dog ear in which the skin and subcutaneous fat of the axilla are cut into an equilateral triangle. Herein, we present a case of breast cancer who underwent a mastectomy and closed the wound with a skin graft by utilizing the skin removed from lateral thoracic area using triangle technique. An 85-year-old female visited our institution complaining about the mass on her right breast. Preoperative images showed a 10 cm-sized mass with suspicious axillary and mediastinal lymph nodes swelling. A biopsy revealed a hormone receptor-negative, HER2-positive invasive ductal carcinoma. A mastectomy and axillary lymph node sampling were performed for a local control as the tumor did not respond to four cycles of triweekly trastuzumab combined with S-1. After a transverse elliptical incision, a skin of the lateral thoracic area was harvested using triangle technique. As the middle of the wound had excessive closing tension, the skin was grafted on the defect. After 10 day fixation by a tie-over dressing, the wound healed without complications. This procedure is a simple method for closing a large defect after mastectomy preventing both the dog-ear deformity and a new wound scarring of a donor site.

Protein expression profile and microRNA expression signature in estrogen receptor-positive and -negative breast cancers: report of two cases.

BACKGROUND: Identification of the proteins that are associated with estrogen receptor (ER) status is a first step in selecting drugs against hormone-dependent breast cancer. Recently, the proteins associated with ER status were reported using liquid chromatography and tandem mass spectrometry, and microRNA (miRNA) profiling of breast cancer subtype was demonstrated using real-time-PCR. METHODS: We present herein two cases with differential protein expression and miRNA profiling in ER-positive and -negative breast cancer. RESULTS: Proteins associated with fatty acid metabolism were uniquely detected in ER-positive breast cancer. The level of miR-181a expression in ER-positive cancer was higher than that in ER-negative cancer, while the expression of miR-27a, miR-107, and miR-195 was lower in ER-positive compared with ER-negative cancer. CONCLUSION: These cases suggest that fatty acid synthase (FAS) and FAS-related miRNAs are important in ER-positive breast cancer.

Evaluation of the dislocation and long-term sonographic detectability of a hydrogel-based breast biopsy site marker.

PURPOSE: To evaluate the usefulness of the HydroMARK, a hydrogel-based breast biopsy site marker for ultrasound localization of breast lesions, we investigated the tendency for dislocation and sonographic detectability of the marker placed in patients. MATERIALS AND METHODS: The marker was placed in lesions that were expected to become obscured after biopsy for a suspicious breast lesion or after neoadjuvant chemotherapy for breast cancer. The patients consented to return for a repeat ultrasound ± mammography examination, and the degree of displacement of the marker was measured as the marker-to-residual lesion distance. RESULTS: The marker was placed after stereotactic biopsy, ultrasound-guided biopsy, and before/during neoadjuvant chemotherapy, in 11, 22, and 7 lesions, respectively. Surgical resection was performed for 22 of the 40 lesions, while remaining 18 benign lesions were followed. The marker was sonographically detectable in 89.7% (35/39), 100% (35/35), and 100% (18/18) of the cases, respectively, at a median of 8 days, 13 weeks, and 11 months after the deployment. The degree of displacement was lower in the ultrasound-guided placement group than in the stereotactic placement group (median displacement: 0 vs. 4.3 mm; p = 0.001), it was also lower in the core-needle biopsy and neoadjuvent therapy cases than in the vacuum-assisted biopsy cases (p = 0.003). At a median interval of 2.5 months after deployment, the marker remained unchanged in location in all cases (n = 18, p = NS). CONCLUSIONS: The HydroMARK appears to be a safe and effective marker with the advantageous characteristics of a low tendency for dislocation with time and long-term sonographic detectability.

Breast carcinoma metastasis to meningioma in the thoracic spine: A case report and review of the literature.

CONTEXT: Systemic metastasis to a primary tumor of the central nervous system is uncommon. Breast carcinomas metastasizing to a possibly preexisting meningioma in the spine are reported very rarely. STUDY DESIGN: Case report. FINDINGS: A 69-year-old female was referred to us with progressive gait disturbance. She had undergone a total mastectomy for carcinoma of the right breast 11 years previously. A magnetic resonance imaging of the thoracic spine showed an intra- and extradural spinal cord tumor. The patient underwent resection of the tumor via laminectomy from T2 to T4. After the operation, the patient's neurological status improved significantly, and she was able to walk without assistance. Histological examination showed the tumor to be a fibrous-type meningioma within a metastatic breast cancer tumor. The patient underwent 40 Gy radiation treatment for local control of the tumor. However, the tumor recurred locally 7 months after the surgery. The patient died of carcinomatous pleurisy 13 months after the surgery. CONCLUSION: This case illustrates that a primary meningioma in the thoracic spine can be a recipient of breast cancer metastasis, which may alter the treatment strategy.

[A case of endocrine cell carcinoma of the ascending colon with liver metastasis treated with hepatectomy after excision of the primary lesion and systemic chemotherapy].

A 77-year-old man who complained of melena was admitted to our department. Colonoscopy revealed a type 2 tumor in the hepatic flexure of the ascending colon. Biopsy examination revealed a poorly differentiated adenocarcinoma. Abdominal computed tomography(CT)revealed 3 tumors within the posterior segment of the right hepatic lobe. Initially, a right hemicolectomy was performed. Immunohistochemically, the tumor was diagnosed as an endocrine cell carcinoma. After surgery, a capecitabine, oxaliplatin, and bevacizumab(CapeOX/BEV)regimen was administered. However, after 5 chemotherapy courses, abdominal CT revealed enlargement of the 3 tumors in the posterior segment of the right hepatic lobe. There was no metastasis besides the liver metastasis. The patient underwent a radical hepatectomy of the posterior segment. At 8 months post-surgery, the patient remains alive and well. Endocrine cell carcinoma of the colon and rectum is usually malignant and is associated with a very poor prognosis because of rapid hematogenous or lymphogenous metastasis. Effective multimodal treatment regimens, including surgery and new chemotherapies such as molecular targeted therapies, should be established to improve the prognosis of patients with endocrine cell carcinomas of the colon and rectum.

Phase II clinical trial of high-dose toremifene as primary hormone therapy in aromatase inhibitor-resistant breast cancer.

BACKGROUND: Third-generation aromatase inhibitors(AIs)are now common in adjuvant hormone therapy for breast cancer in postmenopausal women. However, a suitable treatment has yet to be established for patients who develop cancer recurrence during or after adjuvant AI therapy. PATIENTS AND METHODS: This prospective study evaluated the efficacy and safety of 120mg/day toremifene citrate(TOR-120)administered orally to 23 patients with recurrent breast cancer who were receiving or had received adjuvant AI therapy. Primary therapy for recurrence was TOR-120 monotherapy. RESULTS: The response rate was 13. 0%(partial response: three patients), the clinical benefit rate was 78. 3%(partial response: three patients; long-term stable disease: 15 patients), and median time to progression was 8. 1 months. Grade 1 adverse events such as loss of appetite, sweating, flushing and edema face were observed. CONCLUSION: TOR-120 monotherapy was effective and safe as a primary hormone therapy for recurrent breast cancer unresponsive to AIs.

[Pathological complete response in advanced gastric carcinoma by S-1/CDDP combination chemotherapy].

A59 -year-old woman was referred to our hospital for a close examination and treatment of an advanced gastric carcinoma. A physical examination and CT scan showed that the right cervical and axillar lymph nodes were swelling, and a histopathological examination of the axillar lymph node revealed metastatic growth of the gastric carcinoma (Stage IV). Then, we started S-1/CDDP combination chemotherapy. S-1 (80 mg/m2/day)was orally administered for 3 weeks followed by 2 weeks of rest, and CDDP (60 mg/m2) was administered by drip on day 8. Since the distant metastases were greatly reduced after 6 courses of combination therapy, a distal gastrectomy with lymph nodes dissection (D2) was performed. Histopathological examination of the resected tissues revealed no residual cancer cells, suggesting a pathologically complete response. The clinical course after the operation went well without any complications, and the patient is alive with no evidence of recurrence 1 year after surgery. S-1/CDDP combination chemotherapy appears to be one of the effective treatments for advanced gastric carcinoma.

[A patient with pulmonary metastasis from breast cancer after surgery who responded to S-1].

We report a 60-year-old female with pulmonary metastasis from breast cancer who responded to S-1. In November 2001, she underwent surgery. In October 2005, relapse was detected. As there was no hormone sensitivity, chemotherapy was selected, and oral administration of S-1 at 120 mg/day (2 divided doses) was initiated. After the fourth course, the tumor marker level returned to the reference value. Thoracic CT at the end of the sixth course revealed the disappearance of the metastatic focus. Adverse reactions during the administration period were mild. S-1 showed potent antitumor effects and good tolerance, and it may be useful for treating metastatic/recurrent breast cancer.

[Examination of the safety of docetaxel/cyclophosphamide combination therapy for advanced recurrent breast cancer].

In the treatment of recurrent breast cancer in patients previously treated with anthracycline drugs, taxane drugs are generally used. This time, we retrospectively studied the safety of docetaxel/cyclophosphamide combination therapy (hereinafter referred to as TC therapy). Ten patients (mean age: 52.8 years old) were included in the study. Metastatic/recurrent sites included 3 skin, 2 each of contralateral breast, lung and bone, and 1 each of liver, carcinomatous pleurisy and supraclavicular lymph node. Seven patients had a history of anthracycline treatment. The patients received TC at doses of 60 mg/m(2) and 500 mg/m(2), respectively, every 3 weeks. With regard to adverse events, non-hematotoxic events included alopecia in all the patients, generalized malaise in 5, and abnormal nail in 1. Hematotoxic events were grades 2 and 3 decreased neutrophil count in 5 patients. One patient had grade 4 pyrexia associated with oral candida. The patient was admitted and treated with fluid replacement and granulocyte colony-stimulating factor (G-CSF). There were no other patients in whom the treatment was prolonged or dosage was reduced due to adverse reactions. TC therapy is considered to be a beneficial treatment method in terms of safety since it can be instituted on an outpatient basis.

Interaction between stromal fibroblasts and colorectal cancer cells in the expression of vascular endothelial growth factor.

BACKGROUND: Vascular endothelial growth factor (VEGF), a potent angiogenic factor, has been implicated in metastasis of colorectal cancer (CRC). The present study aimed to clarify whether cancer-stromal interaction induces the production of VEGF. MATERIALS AND METHODS: Human colonic fibroblasts (CCD-18Co) and CRC (SW480, SW620) cells were analyzed in this study. The cell cycle of colonic fibroblasts during co-culture was analyzed by flow cytometry. VEGF and TGF-beta1 released into the conditioned media in co-culture models were measured. Northern blot with human specific VEGF probe was performed to identify the expression of VEGF in this model. RESULTS: Co-culture of colonic fibroblasts with CRC cells increased the viability of fibroblasts during co-culture. Cell cycle analysis revealed that most of the fibroblasts co-cultured with CRC cells were arrested at G1 phase and few cells were in sub-G1 phase that indicates apoptosis. Although VEGF protein was detected in the culture media of all of the monocultures, co-cultivation of CRC with fibroblasts resulted in synergistic increase of VEGF production compared with monocultures. However TGF-beta1 protein was not detected in any conditioned medium. VEGF mRNA was detected in both CRC and fibroblasts. Under co-culture condition, an abundance of VEGF mRNA expression was noted in fibroblasts relative to CRC cells. CONCLUSIONS: The present study suggests that CRC manipulates the host stroma to suppress apoptosis and up-regulate VEGF production.

[A case of postoperative pulmonary metastasis of breast cancer treated with docetaxel and cyclophosphamide therapy].

A 55-year-old woman underwent a partial breast resection in our hospital for breast cancer in May 2002. For adjuvant therapy, she received cyclophosphamide, pirarubicin and 5-FU infusion a total of 6 times, and anastrozole. Then, in May of 2004, an abnormal shadow was detected on her of chest X-ray. After CT scan we diagnosed multiple pulmonary metastasis of breast cancer. We used combination therapy of docetaxel 60 mg/m(2) and cyclophosphamide 500 mg/m(2). After 9 months, pulmonary metastasis disappeared on her CT scan. During chemotherapy, she showed no major side effect.

Specific enhanced expression of platelet-derived endothelial cell growth factor in submucosa of human colorectal cancer.

PURPOSE: Platelet-derived endothelial cell growth factor, identified to be an angiogenic factor, has been implicated in metastases of colorectal cancer. This study aimed to clarify the role and localization of platelet-derived endothelial cell growth factor associated with human colorectal cancer invasion. METHODS: Thirty-two patients with colorectal cancer who had undergone surgery were analyzed. Platelet-derived endothelial cell growth factor enzyme activities in the colorectal cancer specimens were measured. Cells that expressed platelet-derived endothelial cell growth factor were identified and localized by immunohistochemical analysis with anti-human platelet-derived endothelial cell growth factor antibody and by in situ hybridization with specific RNA probe. RESULTS: Platelet-derived endothelial cell growth factor enzyme activity increased significantly in cancer tissues compared with normal colonic mucosa at various distances from the cancer. Immunohistochemical analysis and in situ hybridization demonstrated platelet-derived endothelial cell growth factor expression in stromal macrophages and fibroblasts located in cancer tissues and surrounding noncancerous tissues, although the tumor cells and normal colonic mucosa were negative. The value of platelet-derived endothelial cell growth factor expression was highest at the border of the colorectal cancer (35.3 +/- 8.9 percent), followed by the cancer nest (15.2 +/- 9.2 percent) and normal mucosa (7.7 +/- 3.4 percent). In the border area, the highest value of platelet-derived endothelial cell growth factor expression was observed in the submucosa (35.3 +/- 8.9 percent), followed by the muscular propria (21.9 +/- 7.7 percent) and the subserosa (14.9 +/- 5.5 percent). CONCLUSIONS: Stromal macrophages and fibroblasts are responsible for elevated platelet-derived endothelial cell growth factor activity in colorectal cancer. The significance of enhanced expression of platelet-derived endothelial cell growth factor in the submucosa at the cancer border remains unclear. Cancer stroma may be an important factor for cancer angiogenesis and may serve as a treatment target through specific modulation of angiogenic factors.