The impact of PIK3CA mutations and PTEN expression on the effect of neoadjuvant therapy for postmenopausal luminal breast cancer patients.

BACKGROUND: There is pressing needs to find the biomarker in the selection of neoadjuvant therapy in postmenopausal luminal breast cancer patients. We examined the hypothesis that PIK3CA mutations and low phosphatase and tensin homolog (PTEN) expression affect the response to neoadjuvant therapy and prognosis in postmenopausal luminal breast cancer patients. METHODS: Postmenopausal patients with estrogen receptor-positive, human epidermal growth factor receptor 2-negative breast cancer, up to stage II, who underwent neoadjuvant chemotherapy (NAC; n = 60) or neoadjuvant endocrine therapy (NAE; n = 55) were selected. PIK3CA exon 9 and exon 20 mutations were screened by high resolution melting analysis and confirmed by Sanger sequence. PTEN expression was evaluated by immunohistochemistry. The relationships among PIK3CA mutations, PTEN expression, clinicopathological features, the pathological effect of neoadjuvant therapy, recurrence-free survival (RFS) and overall survival were analyzed. RESULTS: Among 115 patients, PIK3CA mutations and low PTEN expression before treatment were detected in 35 patients (30.4%) and in 28 patients (24.3%), respectively. In the NAC group, tumor with PIK3CA mutations showed significantly poorer response than tumor with PIK3CA wild-type (p = 0.03). On the other hand, in the NAE group, there was no significant difference in pathological therapeutic effect between tumor with PIK3CA mutations and tumor with PIK3CA wild-type (p = 0.54). In the NAC group, the log-rank test showed no difference in RFS between patients with PIK3CA mutations and PIK3CA wild-type (p = 0.43), but patients with low PTEN expression showed significantly worse RFS compared to patients with high PTEN expression (5 year RFS 0.64 vs. 0.87, p = 0.01). In the Cox proportional hazards model for RFS, PTEN expression, progesterone receptor, and pathological therapeutic effect were predictive factors for time to recurrence (All p < 0.05). CONCLUSIONS: PIK3CA mutations are associated with resistance to NAC but do not affect the response to NAE. Low PTEN expression does not affect response to either NAC or NAE but correlates with shorter RFS in patients who received NAC. These biomarkers will be further evaluated for clinical use to treat postmenopausal luminal breast cancer patients.

[A Case of Cholesterol Granuloma of the Breast Requiring Mastectomy].

An 85-year-old woman had been followed up by a local doctor for a cystic lesion of the right breast for 3 years. The lesion was frequently treated with fine needle drainage due to its tendency to slowly increase in size over time. Following the latest drainage of the cystic lesion, the patient became aware of intermittent bleeding from the drainage site, and thus, visited our emergency department. At the time of her hospital visit, the patient had a tense fist-sized mass centered on the C area of the right breast, and the mass was eruptively bleeding from the puncture scar. We performed fine needle drainage and obtained approximately 150 cc of bloody fluid. The bleeding lesion was compressed with a sink and chest band and the patient was hospitalized. When we released the pressure the next day, her right breast was as tense as the initial presentation and purpura were observed. Based on the patient's hematological findings, which showed worsening anemia, we suspected intermittent bleeding from an intracystic tumor. The patient underwent right mastectomy three days after admission. Pathologically, a diagnosis of cholesterol granuloma of the breast was confirmed.

Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer.

PURPOSE: Although recent advances in molecular target therapy have improved the survival of breast cancer patients, high cost and frequent hospital visits result in both societal and individual burden. To reduce these problems, it has been proposed to produce antibodies in vivo. Here, we constructed gene-transduced human ceiling culture-derived proliferative adipocytes secreting anti-HER2 antibody (HER2-ccdPAs) and evaluated their ability to secrete antibody and mediate an anti-tumor effect. METHODS: Plasmid lentivirus was used as a recipient for anti-HER2 antibody cDNA and transduced into human proliferative adipocyte. Secretory antibody expression was evaluated by ELISA and western blot. Specific binding of secretory antibody to HER2 was examined by immunofluorescence analysis. Direct and indirect anti-tumor effects of supernatants from HER2-ccdPAs were evaluated using BT474 (HER2+) and MDA-MB-231 (HER2-) breast cancer cell lines. Additionally, whether adipocyte differentiation affects antibody secretion was investigated using supernatant collected from different cell maturation states. RESULTS: Anti-HER2 antibody was identified in the supernatant from HER2-ccdPAs and its production increased with the differentiation into mature adipocyte. Antibodies in supernatants from HER2-ccdPAs bound to HER2-positive breast cancer cells similar to trastuzumab. Supernatant from HER2-ccdPAs inhibited the proliferation of BT474 but not MDA-MB-231 cells, and downregulated AKT phosphorylation in BT474 cells compared with controls. Supernatants from HER2-ccdPAs also had an indirect anti-tumor effect on BT474 cells through ADCC. Additionally, Single inoculation of HER2-ccdPAs showed an anti-tumor effect in BT474 xenograft model. CONCLUSIONS: HER2-ccdPAs might be useful for cell-based gene therapy. This system could be a platform for various antibody therapies.

Oncoplastic breast-conserving surgery using chest wall perforator flaps: Three-dimensional quantitative analysis of the percentage of breast volume excised and changes over time in flap volume.

BACKGROUND AND OBJECTIVES: We investigated the effects of oncoplastic breast-conserving surgery (BCS) using chest wall perforator flaps (CWPFs) on the subsequent expected deformity and evaluated the longevity of flap volume. METHODS: We retrospectively reviewed oncological and cosmetic outcomes of 33 women who had undergone the above procedure. We calculated the percentage of breast volume excised (PBVE) from computed tomography volumetry and compared it between a historical BCS alone and the study (flap) group. We also sequentially evaluated flap volumes by magnetic resonance imaging volumetry. RESULTS: Oncoplastic BCS using 25 lateral flaps and eight inferior flaps, depending on the site of the defect, was performed; mean PBVEs were 31.1% and 19.0%, respectively. No local and two distant recurrences occurred in a median follow-up of 61 months. PBVE was 2.6 times larger in the flap than in the BCS alone group. Over half the patients in the BCS alone group had poor cosmetic results when PBVE exceeded 15%, whereas patients in the flap group achieved good cosmetic results with PBVE >25%. In most patients, 80% of flap volume was maintained 5 years after surgery. CONCLUSIONS: CWPF improves cosmetic outcomes in patients with predicted deformity after BCS alone and maintains its volume for at least 5 years.

[Clinicopathological Examination of Differentiated Gastric Cancer].

OBJECTIVE: The common type carcinoma of gastric cancer is divided into 3 groups, papillary adenocarcinoma(pap), well differentiated tubular adenocarcinoma(tub1)and moderately tubular adenocarcinoma(tub2). In this study, we tried to individualize treatments of them by evaluating their clinicopathological features. METHODS: Examined resected specimens were collected from 2000 to 2016. We compared among pap, tub1, and tub2 as the clincopathological features retrospectively. RESULTS: Histological diagnosis was confirmed to 55 cases with pap, 639 cases with tub1 and 718 cases with tub2. Comparing the ratio of lymph node metastasis(LNM)according to the depth of invasion, tub2 and pap show higher incidence of LNM than tub1 in T1b, T2, and T4(a+b). Tub2 and pap patients have larger number of LNM and worse 5 year survival rates than tub1 patients. CONCLUSION: We demonstrated that tub2 and pap may have higher malignancy and show earlier LNM than tub1. When we consider of endoscopic treatment, individualizataing tub1, tub2 and pap is important.

[Two Cases of Hepatocellular Carcinoma Skin Metastasis].

Case 1: A7 2-year-old man, during diabetes medical treatment, was introduced at our hospital for liver cancer treatment. He had a subcutaneous mass 4 cm in size in the right precordial region, and subsequently underwent an operation. Histopathological findings indicated subcutaneous metastasis of hepatocellular carcinoma. Case 2: A6 0-year-old man presented with a subcutaneous mass noted in the right shoulder during hepatocellular carcinoma treatment. It was diagnosed as metastasis of the hepatocellular carcinoma to the dermis. Metastasis to the skin of internal organ-related tumors is relatively rare and is reported with approximately a 1.4-6.7%frequency of all dissection cases. Hepatocellular carcinoma is infrequent and it is reported that hypodermal and skin metastasis is 0.3-0.7% in autopsy cases. In addition, metastasis of hepatocellular carcinoma to the skin is a relatively terminal symptom.

[Utility of Preoperative Chemotherapy for Locally Advanced Colorectal Cancer].

Preoperative chemotherapy has been performed for locally advanced colorectal cancer, to achieve cytoreduction, local control, and prevention of distant metastasis. The regimens of mFOLFOX6/XELOX plus bevacizumab for 3 months have been adopted to succeed curative resection for borderline resectable colorectal cancer. We examined treatment results for locally advanced colorectal cancer without distant metastasis. Thirty-four patients were examined and the mean age was 62.7 years old. The cohort comprised of 23 cases of rectal cancer and 11 of sigmoid colon cancer. Thirty cases were diagnosed as cT4b and 25 cases were as cN+before chemotherapy. Stoma creations were performed in 26 patients before preoperative chemotherapy. Reduction ratio of the tumor diameter was 33.6±28.2%. The reduction in CEA was 38.5±39.4%, and the reduction in CA19-9 was 62.8±42.3%. There were 23 extended resections combined with involved organs including 8 total pelvic exenterations. Chemotherapeutic effect was diagnosed as Grade 1a or less, 20 cases; Grade 1b, 6 cases; Grade 2, 5 cases; Grade 3, 3 cases. Recurrence was found in 9 cases and 8 of them were Grade 1a or less. Overall 5-year survival rate was 74.6%. The utility of preoperative chemotherapy for locally advanced rectal cancer is suggested not only for local treatment but also systemic therapy, especially in chemotherapeutic effective cases.

[A Case of Locally Advanced Rectal Cancer Invading Posteriorly Adjacent to Sacrum Resected by Laparoscopic Low Anterior Resection].

We report a case of locally advanced rectal cancer invading toward sacrum treated by laparoscopic low anterior resection. A man in his 60's was diagnosed with rectal cancer expanding near to sacrum. The circumferential resection margin was assessed to be scarce. After preoperative chemotherapy, we performed laparoscopic low anterior resection. In order to obtain surgical margin, we had to cut into presacral venous plexus. With prepared sufficient devices, hemostasis was safely acquired. Pathological findings revealed clear surgical margin. It is important to prepare appropriate hemostasis devices in managing cases with high risks of intraoperative hemorrhage. Laparoscopic approach may contribute to these cases, making hemostasis easier than laparotomy with the magnified view, pneumoperitoneum and Trendelenburg position.

[A Case Report--A Synchronous Liver Metastasis from Gastric Cancer Treated with Chemotherapy, Surgical Resection of the Gastric Cancer, and RFA of the Liver Metastasis].

A 71-year-old man was admitted to our hospital because of abdominal pain. An upper gastrointestinal endoscopy revealed a type 3 tumor in the lesser curvature of the gastric body. A computed tomography (CT) scan showed synchronous liver metastasis in liver S6 and S8, and a large 8a lymph node that could be encased within the common hepatic artery. The patient was diagnosed with gastric cancer with liver metastasis, Stage Ⅳ, and treated with chemotherapy (S-1 plus CDDP). After 3 courses, a CT scan showed that the liver metastasis in S8 was reduced in size.The one in S6 completely disappeared. The 8a lymph node was also reduced in size and revealed to be separated from the common hepatic artery. Total gastrectomy (D2) and radiofrequency ablation (RFA) for the S8 lesion were performed. The postoperative course was favorable and the patient was treated with postoperative adjuvant chemotherapy consisting of S-1. No recurrence has been observed for 17 months after diagnosis. After chemotherapy, if R0 resection is performed, surgical resection and RFA for liver metastasis may be a useful option for gastric cancer with liver metastasis.

[Effect of tolvaptan on ascites due to malignancy].

Ascites accompanying a malignancy is often refractory to conventional treatment with saline diuretics, making it difficult to control. We administered a new diuretic, Tolvaptan, to 10 individuals with malignancy and heart failure accompanied by ascites, which was refractory to saline diuretics, and assessed its efficacy and adverse events. We observed a significant reduction in abdominal distension following 2 weeks of Tolvaptan administration. However, we also observed significant increases in serum potassium, urea nitrogen, and creatinine levels, but no serious adverse events. This suggests that Tolvaptan may also be effective as treatment for ascites.

Ex vivo dual gene therapy using human adipocytes secreting anti-HER2 antibody on HER2-positive xenograft tumor models.

BACKGROUND: Although targeted treatments against human epidermal growth factor receptor 2 (HER2) have improved survival in patients with metastatic HER2-positive breast cancer, long and repeated treatment is time-consuming and costly for patients. To reduce these burdens, we developed ex vivo gene-transduced adipocytes that secrete anti-HER2 antibodies and evaluated their anti-tumor effects. METHODS: Ceiling culture-derived proliferative adipocytes (ccdPA) secreting anti-HER2 antibody against domain IV receptors: TRA-ccdPA, and domain II receptors: PER-ccdPA, were constructed using a plasmid lentivirus. Delivery of secreted antibody and its specific binding to HER2 breast cancer were evaluated in vitro and in vivo. To optimize antibody production from ccdPA, different conditions of ccdPA implantation were examined. Anti-tumor efficacy was evaluated in HER2-positive-cancer-inoculated nude mice. RESULTS: Anti-HER2 antibody against domain II was identified in supernatants from PER-ccdPAs. The optimal method to achieve the highest concentration of antibody in mouse sera was injecting differentiated ccdPA cells into the mammary fat pad. Antibody in supernatants from PER-ccdPAs bound to the surface of HER2-positive breast cancer cells similar to pertuzumab. Antibodies in mouse sera were delivered to HER2-positive breast cancer tumors and tumor necrosis was observed microscopically. One-time administration of combined TRA-ccdPAs and PER-ccdPAs produced antibody continuously in mouse sera, and anti-tumor effects were maintained for the duration of this study in xenograft models. Furthermore, combination therapy significantly suppressed tumor growth compared with a single administration. CONCLUSION: Ex vivo gene-transduced adipocytes might be useful for cell-based gene therapy. This system may be a platform for various antibody therapies.

Histological features of skin and subcutaneous tissue in patients with breast cancer who have received neoadjuvant chemotherapy and their relationship to post-treatment edema.

BACKGROUND: Lymphedema is a major complication of treatment for breast cancer. Although chemotherapy can cause lymphedema, there have been few reports about histological changes in skin and subcutaneous tissue after chemotherapy. The aim of our study was to determine whether chemotherapy affects blood and lymphatic vessels in the skin and subcutaneous fat and to investigate the relationship between these changes and extent of post-chemotherapy edema. METHODS: We compared histological findings in skin and subcutaneous fat of mastectomy specimens from 38 patients who had received NAC (neoadjuvant chemotherapy) and 56 who had not (non-NAC) attending our institution from 2007 to 2016. Patients whose tumor may have affected the area examined were excluded. Blood and lymphatic vessels were identified by CD31 and D2-40, respectively. We assessed microvessel density (MVD), lymphatic microvessel density (MLVD), lumen cross-sectional area (LA), and amount of endothelium (AE) in blood and lymphatic vessels. To minimize surgical effects, we measured edema, defined as ≥ 15% thicker dorsal subcutaneous tissue than baseline, on the contralateral side. RESULTS: MVD, LA, and AE of blood vessels were greater and MLVD not significantly different in the skin of NAC patients than in that of non-NAC patients. MVD was greater and AE of blood vessels less in subcutaneous fat of NAC patients than in that of non-NAC patients. Patients with edema had significantly less AE of blood vessels in skin than did those without it. CONCLUSIONS: These pathological findings can help to identify patients who will develop edema and improve their treatment.