[Successful Treatment of Estrogen Receptor Positive, HER2 Negative Breast Cancer with Life-Threatening Multiple Bone Metastases Using the Combination of Fulvestrant and Palbociclib-A Case Report].

Palbociclib, a CDK4/6 inhibitor, is found to be an effective therapeutic drug in the treatment of estrogen receptor positive (ER+)metastatic breast cancer. In this report, we describe a case of rapid progression of life-threatening multiple bone metastases of breast cancer treated with a combination of fulvestrant and palbociclib. The patient, a 58-year-old postmenopausal woman, was diagnosed with left breast cancer at the age of 43 years and underwent breast-conserving surgery. After the completion of postoperative adjuvant endocrine therapy and radiotherapy, the patient was placed on regular follow-up. Eleven years after the surgery, multiple bone metastases and multiple lymph node metastases occurred, and the patient was treated with letrozole as first-line therapy for recurrent breast cancer. Although she continued to receive this treatment for 2 years and 10 months, her general condition worsened due to the occurrence of new liver metastases and the rapid progression of existing metastatic lesions. Thus, she was sent to an emergency room. Marked hypercalcemia and a severe decrease in erythrocyte and platelet counts were observed, which could be the cause of her worsening general condition. Her performance status(PS)was 4, and palliative treatment was also considered. However, she received treatment for hypercalcemia and red blood cell transfusion; as a result, she recovered to the PS 2 where she could begin chemotherapy. Then, she began a treatment consisting of a combination of fulvestrant and palbociclib as a second-line treatment for the recurrence. The patient responded well to the treatment, and her general condition improved to PS 1. She has since maintained a good quality of life for 2 years and 11 months without serious adverse events. In conclusion, the combination of fulvestrant and palbociclib has a low risk of serious adverse events and is a worthwhile treatment for rapidly progressing, life-threatening multiple bone metastases of breast cancer.

[A Case of Breast Mucinous Carcinoma with Bladder Metastasis Effectively Treated with Endocrine Therapy and Chemotherapy].

A 57-year-old Japanese woman underwent partial mastectomy of the right breast and sentinel lymph node biopsy in July 2005. The diagnosis was mucinous carcinoma with negative margins and no lymph node metastases(pT1cN0M0, pStage Ⅰ A). Postoperative adjuvant therapy included radiation therapy and oral administration of anastrozole for 5 years. In December 2015, we observed enlargement of left supraclavicular lymph nodes; a needle biopsy revealed lymph node metastases from breast cancer. We administered toremifene and the swelling disappeared. The patient was subsequently referred to the hospital for urinary frequency in November 2016. Imaging demonstrated a bladder tumor. Transurethral biopsy of bladder revealed adenocarcinoma with mucin production consistent with breast primary. After systemic chemotherapy(UFT, eribulin), endocrine therapy(fulvestrant), and molecular targeted therapy(palbociclib), her urologic symptoms were relieved. However, 2 years and 8 months after diagnosis of bladder metastasis, the patient showed disease progression and decided to discontinue all chemotherapy and pursue palliative care. We also present a review and discussion of the relevant literature.

Vascular endothelial growth factor receptor 1 (VEGFR1) tyrosine kinase signaling facilitates granulation tissue formation with recruitment of VEGFR1+ cells from bone marrow.

Vascular endothelial growth factor (VEGF)-A facilitates wound healing. VEGF-A binds to VEGF receptor 1 (VEGFR1) and VEGFR2 and induces wound healing through the receptor's tyrosine kinase (TK) domain. During blood flow recovery and lung regeneration, expression of VEGFR1 is elevated. However, the precise mechanism of wound healing, especially granulation formation on VEGFR1, is not well understood. We hypothesized that VEGFR1-TK signaling induces wound healing by promoting granulation tissue formation. A surgical sponge implantation model was made by implanting a sponge disk into dorsal subcutaneous tissue of mice. Granulation formation was estimated from the weight of the sponge and the granulation area from the immunohistochemical analysis of collagen I. The expression of fibroblast markers was estimated from the expression of transforming growth factor-beta (TGF-ß) and cellular fibroblast growth factor-2 (FGF-2) using real-time PCR (polymerase chain reaction) and from the immunohistochemical analysis of S100A4. VEGFR1 TK knockout (TK-/-) mice exhibited suppressed granulation tissue formation compared to that in wild-type (WT) mice. Expression of FGF-2, TGF-ß, and VEGF-A was significantly suppressed in VEGFR1 TK-/- mice, and the accumulation of VEGFR1+ cells in granulation tissue was reduced in VEGFR1 TK-/- mice compared to that in WT mice. The numbers of VEGFR1+ cells and S100A4+ cells derived from bone marrow (BM) were higher in WT mice transplanted with green fluorescent protein (GFP) transgenic WT BM than in VEGFR1 TK-/- mice transplanted with GFP transgenic VEGFR1 TK-/- BM. These results indicated that VEGFR1-TK signaling induced the accumulation of BM-derived VEGFR1+ cells expressing F4/80 and S100A4 and contributed to granulation formation around the surgically implanted sponge area in a mouse model.

Vascular endothelial growth factor receptor-1 (VEGFR-1) signaling enhances angiogenesis in a surgical sponge model.

BACKGROUND: Vascular endothelial growth factor (VEGF)-A binds to both VEGF receptor (VEGFR)-1 and VEGFR-2, thereby promoting angiogenesis. It is widely accepted that VEGF-A, especially VEGFR-2, is a central player in angiogenesis, however the role of VEGFR-1 in angiogenesis remains unclear. The present study was conducted to examine the role of VEGFR-1 signaling in angiogenesis, using a quantitative in vivo angiogenesis model. METHODS: Polyurethane sponge disks were implanted into dorsal subcutaneous tissue of mice. Angiogenesis was estimated by determining the number of CD31(+) vessels by immunohistochemical analysis. The expression of pro-angiogenic factors was quantified by reverse transcription quantitative polymerase chain reaction. RESULTS: Compared to control IgG-treated mice, the number of CD31(+) vessels in the sponge implant was significantly suppressed in anti-VEGF-A neutralizing antibody-treated mice. CD31(+) vessel counts were suppressed in VEGFR-1 tyrosine kinase knockout (TKKO) mice, at the same level as in VEGFR-2 tyrosine kinase inhibitor (ZD6474)-treated mice compared to wild-type (WT) mice. The accumulation of VEGFR-1(+) cells in granulation tissue was significantly suppressed in VEGFR-1 TKKO mice compared to WT mice. In addition, expression of the pro-angiogenic growth factors, VEGF-A, matrix metalloproteinase-2, interleukin-6, and basic fibroblast growth factor in granulation tissue was suppressed in VEGFR-1 TKKO mice. A bone marrow (BM) transplantation experiment showed that the number of VEGFR-1(+) BM-derived cells and angiogenesis were significantly suppressed in VEGFR-1 TKKO mice transplanted with green fluorescent protein (GFP)(+) VEGFR-1 TKKO BM compared to WT mice transplanted with GFP(+) WT BM. CONCLUSIONS: These results suggest that the VEGFR-1 tyrosine kinase signaling has an effect on angiogenesis. A selective VEGFR-1 agonist/antagonist could be a candidate therapeutic agent to control angiogenesis with recruitment of BM cells.

Single-stage reconstruction of a full-thickness alar defect using a folded nasolabial flap combined with a redundant skin turnover flap.

BACKGROUND: The reconstructive strategy for full-thickness nasal skin defects should include recreation of a cutaneous cover, support, and internal nasal lining. The most challenging aspect of this procedure is provision of the nasal lining. These reconstructions typically require a 2-step process. Satisfactory nasal skin reconstruction in a single operation is ideal. OBJECTIVE: We used a folded nasolabial flap combined with a turnover flap for reconstruction of full-thickness alar defects. METHODS: The donor material of the lining flap was a combination of the distal portion of the nasolabial flap and redundant skin resected during its transposition. The redundant skin flap was turned upside down, with the skin surface inside the nasal cavity. The remaining portion of the defect was covered with a folded nasolabial flap. RESULTS: This procedure was successful in all 5 patients. All flaps survived completely without evidence of necrosis or narrowing of airways. Aesthetic concerns, including effacement of the nasofacial sulcus, were minor. CONCLUSION: This method has the advantage of providing well-vascularized tissue of appropriate color, texture, and thickness for external coverage, as well as a satisfactory internal lining in a single-stage procedure.