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Background: Nipple-sparing mastectomy (NSM) is an increasingly popular surgical procedure for treatment of breast cancer. However, NSM is controversial because of its association with locoregional recurrence. We started performing NSM in 1978. Methods: We investigated the surgical safety including nipple necrosis, and nipple–areola recurrence (NAR) and skin flap recurrence (SFR) after NSM for 1071 patients with breast cancer, including 31 with stage 0, 414 with stage 1, 479 with stage 2, 141 with stage 3 and 6 with stage 4, from 1985 to 2017. Our NSM method involved creating a thick skin flap to avoid surgical complications. No patients received radiotherapy. In 1034 patients with stage 1–3 breast cancer treated with NSM who developed NAR or SFR, we evaluated cancer stage, nuclear grade, lymph node metastasis, tumor–nipple–areola distance, and histological classification as tubule forming, solid and scirrhous type. In 748 patients with early stage 1 and 2A breast cancer treated with NSM, NAR and SFR were evaluated for estrogen receptor and HER2 expression. We evaluated disease-free interval and frequency of late NAR and SFR. Results: Median follow-up after NSM was 87 (3–397) months. There was only one case of total nipple necrosis among all 1071 patients. There were 96 patients (9.0%) with local recurrence, including 44 (4.0%) with NAR and 52 (4.8%) with SFR. NAR was seen in 1 (3.1%), 14 (3.4%), 17 (5.1%), 5 (3.4%), 7 (5.0%) and 0 patients with stage 0, 1, 2A, 2B, 3 and 4 cancer, respectively. SFR was seen in 0, 15 (3.6%), 8 (2.7%), 7 (4.8%), 22 (15.6%) and 0 patients with stage 0, 1, 2A, 2B, 3 and 4 cancer, respectively. Median disease-free interval of NAR and SFR was 3.4 (0.96–22.3) and 2.5 (0.21–21.2) years, respectively. Twenty-three (53%), 12 (27.9%) and 6 (14%) patients had NAR at more than 3, 5 and 10 years after NSM, respectively. Twenty (38%), 13 (25%) and 6 (11.5%) patients had SFR at more than 3, 5 and 10 years after NSM, respectively. Therefore, late NAR and SFR were observed. Patients with stage 1–3 cancer treated with NSM who had significantly more frequent NAR, were characterized by high nuclear grade and tubule-forming type cancer. Patients with significantly more frequent SFR were characterized by stage 3 cancer, positive lymph node metastasis and age ≤40 years. Patients with early stage breast cancer treated with NSM with significantly more frequent NAR had negative estrogen receptor expression, positive HER2 expression and shorter tumor–nipple–areola distance (≤2 cm). Overall survival was significantly better in patients with NAR (97% at 5 years and 80% at 10 years) than SFR (71% at 5 years and 50% at 10 years). Regarding SFR, overall survival was significantly worse for multiple (≥2) and diffuse (clinical inflammatory syndrome) recurrence than for single-nodule recurrence. There was no significant difference in prognosis between NAR and single-nodule SFR. Conclusions: Our data showed that clinicopathological features and prognosis differed between patients with NAR and SFR. There was no significant difference in prognosis between NAR and single-nodule SFR. Late NAR and SFR were seen, and careful long-term follow-up observation is necessary after NSM. Citation Format: Sakurai T, Suzuma T, Yoshimura G, Sasaki E, Umemura T, Sakurai T. Clinicopathological features and prognosis of nipple–areola and skin flap recurrence after nipple-sparing mastectomy for breast cancer over 20 years [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P2-14-08.

Introduction: Achievement of a good cosmetic outcome is one of the most important goals of surgical treatment of breast cancer. However, most patients must undergo a mastectomy if the outcome of breast-conserving surgery is discordant. All potential techniques that maintain oncological safety should be considered to maximize the cosmetic outcome for patients who require a mastectomy. We began performing nipple-sparing mastectomy (NSM) in 1978. Recent reports have suggested that NSM is oncologically as safe as mastectomy and affords a better cosmetic outcome. Conversely, the surgical complications and recurrence associated with NSM remain controversial. Objective: In the present study, we review the safety of the NSM surgical technique, discuss nipple–areola recurrence and skin flap recurrence after NSM, and compare recurrence and prognosis between NSM and mastectomy based on our long-term follow-up data. Patients and Methods: We retrospectively analyzed 723 patients with early-stage breast cancer who underwent NSM from 1985 to 2007. The patients' median age, tumor size, and tumor–areola distance were 50 y, 2.1 cm, and 1.5 cm, respectively. We used a thick skin flap method to avoid surgical complications including nipple and skin flap necrosis. We analyzed nipple–areola recurrence and skin flap recurrence after NSM. We also analyzed 100 patients who underwent mastectomy for early-stage breast cancer during the same period as those who underwent NSM. We compared the local recurrence rate (LRR), disease-free survival (DFS) rate, and overall survival (OS) rate among all 723 patients who underwent NSM and 100 patients who underwent mastectomy. No patients in either group received radiotherapy. Results: Among all patients who underwent NSM, stage 0, 1, 2A, and 2B disease was present in 21, 320, 253, and 129 patients, respectively. Notably, no nipple necrosis occurred during the average 114-month follow-up period. Local recurrence developed in 49 patients (6.7%), including recurrence at the nipple–areola complex in 24 (3.3%) and recurrence at the skin flap in 25 (3.4%). The average disease-free interval in patients with nipple–areola recurrence was 50 months, and that in patients with skin flap recurrence was 68 months. The clinical features of nipple–areola recurrence were a low rate of ER positivity (27%), high rate of Her2/neu positivity (60%), Paget type recurrence rate of 52%, and small tumor–areola distance (0.5 cm). The clinical features of skin flap recurrence were a relatively high rate of ER positivity (55%), solitary type recurrence rate of 88%, and diffuse type recurrence rate of 12%. The prognosis of diffuse type skin flap recurrence was significantly worse than that of solitary type recurrence (p = 0.01). There were no significant differences between the NSM and mastectomy groups in the LLR (6.7% vs. 4.0%, respectively), 10-y DFS rate (88% vs. 90%, respectively), or 10-y OS rate (92% vs. 91%, respectively). Conclusion: Our long-term follow-up data show that NSM should be considered as an alternative option for mastectomy when the outcome of breast-conserving surgery is discordant in patients with early-stage breast cancer. Citation Format: Sakurai T, Suzuma T, Yoshimura G, Jinta E, Umemura T, Sakurai T. Long-term follow-up of nipple-sparing mastectomy for early-stage breast cancer without radiotherapy: A single-center study at a Japanese institution. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P2-12-09.

Introduction: Cosmetic outcome is one of the most important goals of surgical treatment for breast cancer. Therefore, to maximize the cosmetic outcome for patients who require a mastectomy, the actions that can be taken from an oncologically safe perspective must be considered. Recent reports have suggested that nipple-sparing mastectomy (NSM) is oncologically as safe as a standard mastectomy and provides a better cosmetic outcome. However, little is known about the outcome of NSM for patients with multifocal breast cancer. Aim: To determine the oncological and technical outcomes of NSM for patients with multifocal breast cancer compared with NSM for patients with unifocal breast cancer using retrospective long-term follow-up data. Patients and Methods: We retrospectively analyzed 799 patients with primary breast cancer who underwent NSM, including 45 patients with multifocal breast cancer and 754 patients with unifocal breast cancer. The indications for NSM in this study were defined as any stage, any tumor size and any tumor–areola distance. Briefly, NSM was performed when no involvement of the nipple areola complex was revealed by radiographic and clinical examinations. Our surgical notes for NSM comprised a thick skin flap method for conserving the breast volume using subcutaneous fat and avoiding surgical complications including nipple necrosis. No patients received radiotherapy. We compared the local recurrence rate (LRR), disease-free survival (DFS), breast cancer-specific survival (BCSS) and overall survival (OS) between the 45 multifocal breast cancer and 754 unifocal breast cancer cases. Results: The numbers of multifocal breast cancer cases in stages 0, 1, 2A, 2B, 3 and 4 were 1, 17, 12, 8, 7 and 0, respectively. The corresponding numbers of unifocal breast cancer cases were 18, 288, 223, 117, 102 and 6, respectively. The median follow-up periods of the multifocal and unifocal breast cancer cases were 108 and 98 months, respectively. No nipple necrosis was recorded in either group (0/45, 0/754). Regarding NSM for patients with multifocal breast cancer, there were 8 patients (17.7%) with local recurrence, including 4 (8.9%) at the nipple and 4 (8.9%) at the skin flap. In NSM for patients with unifocal breast cancer, there were 63 patients (8.3%) with local recurrence, including 26 (3.4%) at the nipple and 37 (4.9%) at the skin flap. There were significant differences between NSM for patients with multifocal and unifocal breast cancer in the LRR (17.7% vs. 8.3%, p = 0.03) and DFS (10 yr, 72.4% vs. 83.8%, p = 0.04), but no significant differences in the BCSS (10 yr, 83.6% vs. 90.9%, p = 0.18) and OS (10 yr, 83.6% vs. 89.5%, p = 0.32). Conclusions: The present results suggest that NSM for patients with multifocal breast cancer can be technically performed as safely as NSM for patients with unifocal breast cancer. Our long-term follow-up data show that survival after NSM for multifocal breast cancer is equal to that after NSM for unifocal breast cancer. However, careful local observation after NSM is required. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P2-18-08.

[Introduction] Mastectomy has been conducted in general for cases in which breast conservation is inapplicable. Since Nipple-sparing Mastectomy (NSM) conserves nipple-areola, it is not only more advantageous in an aspect that nipple-areola reconstruction isn't required in case of breast reconstruction compared with mastectomy but also significantly meaningful because the sensation of nipple-areola is preserved in about 70% cases by skin flap preparation based on thick flap method we have adopted. On the other hand, NSM is controversial relating to complication of surgery and recurrence as well. [Objective] We've made (1) review of safety in NSM surgical technique, (2) discussion over recurrence and prognosis comparing with those in mastectomy, and (3) consideration of performance in immediate reconstructions. [Result] (1) Of all cases of NSM, the number of cases in stage 0, 1, 2A, 2B, 3 and 4 was 21, 305, 239, 123, 112 and 6 respectively. During 104 months of follow-up period in average, total of seven complication cases (0.9%) were observed, including two flap necrosis cases and five postoperative bleeding cases, but no nipple necrosis case was recorded. Although nipple-areola recurrence rate (%) in stage 0, 1, 2A, 2B and 3A was 0, 2.9, 4.6, 2.4 and 5.3 respectively, prognosis of nipple-areola recurrence cases was good showing no difference between stages (OS: 60M; 93%, 100M; 84%). Skin flap recurrence rate (%) in stage 0, 1, 2A, 2B and 3 was 0, 3.2, 3.3, 4.0 and 14.2 respectively, and prognosis of skin flap recurrence cases was significantly worse in stage 2B and 3 compared with that in stage 1 and 2A (p < 0.001). (2) We analyzed local recurrence rate, recurrent free survival and overall survival between 806 of NSM cases and 200 of mastectomy cases which had been performed during the same period, and the result showed no significant difference in those rates between NSM and mastectomy cases. (3) Infectious complication was observed in one out of 18 immediate reconstruction cases using free dermal fat graft. Among 124 immediate reconstruction cases using implant, complications were observed in five postoperative bleeding. [Conclusion] NSM was excellent in cosmetic aspect showing equivalent results in local recurrence rate and prognosis compared with those in mastectomy cases. Besides, patient's satisfaction was also higher in those who had had NSM alone without reconstruction. Our long term follow-up data shows that NSM may be considered as an alternative option for mastectomy in cases in which breast-conserving surgery is inapplicable in breast cancer patients. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P2-15-03.

Recurrent breast cancer has a very poor response rate to chemotherapy. To understand the degree of acquisition of multidrug resistance in recurrent disease, 24 recurrent breast tumors and 127 primary tumors were evaluated and compared for chemosensitivity in the histoculture drug response assay (HDRA). The evaluation rate was 98.8%. The HDRA utilizes 3-dimensional culture of human tumors on collagen-gel rafts. Doxorubicin (DXR), 5-fluorouracil (5-FU) and mitomycin C (MMC) were tested as standard agents and cisplatin (CDDP) as a candidate agent on surgical specimen of breast cancer in the HDRA. In vitro drug exposure in the HDRA was for 7 days. At the end of the assay, tumor response was assessed by the reduction of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). The mean inhibition rates of primary tumors vs. recurrent tumors were 57.9% and 38.6% for DXR (p0.0005); 59.9% and 42.8% for MMC (p0.01); 49.0% and 33.4% for 5-FU (p0.01); and 34.5% and 16.0% for CDDP (p0.005), respectively. The recurrent cases were pretreated clinically with CAF (cyclophosphamide, DXR and 5-FU), CEF (cyclophosphamide, epirubicin and 5-FU) or CMF (cyclophosphamide, methotrexate and 5-FU). In the CAF and CEF group, the HDRA sensitivity to CDDP was significantly lower in recurrent disease (p0.005) than that of primary breast cancer suggesting that one agent can induce resistance to another. This is further suggested by the fact that 64.7% of the recurrent cases were resistant to all 4 agents tested as opposed to 27% of the primary cases and that only 5.9% of the recurrent cases were sensitive to three or more agents as opposed to 18% of the primary cases. The correlation of the HDRA results to clinical outcome in the study was 80.0% with 15 cases evaluated consisting of 5 true positives, 3 false positives, 7 true negatives and no false negatives. Thus, the HDRA gives useful clinical information, in particular for the specific individualized treatment design necessary to overcome the multidrug resistance problem of recurrent breast cancer.

Hypermethylation of the retinoic acid receptor (RAR) beta2 has been detected in breast cancer cell lines and is known to repress the level of RAR beta2 transcription. RAR beta2 mRNA loss has often been detected in breast cancer tumors, whether promoter region methylation of the RAR beta2 gene accounts for its loss is still unknown. We examined the methylation status of RAR beta2 in breast tumors; 21 out of 50 (42%) breast tumors showed RAR beta2 hypermethylation. RT-PCR analysis showed a complete loss of RAR beta2 mRNA expression in 15 out of 43 (35%) breast tumors. No correlation between the hypermethylation and RAR beta2 loss was found, suggesting that hypermethylation is not fully responsible for the loss of expression of the RAR beta2 gene during breast tumorigenesis.

BRCA1 is a tumor suppressor gene that is responsible for hereditary breast and ovarian carcinoma syndrome. The primary objective of the current study was to investigate the influence of BRCA1 expression on the prognoses of sporadic breast carcinomas.A cohort of 175 Japanese women with invasive breast carcinoma who had no family history in first-degree relatives was studied. Expression of BRCA1 was determined by an immunohistochemical procedure in which the MS110 monoclonal antibody was used. Kaplan--Meier and Cox proportional regression survival analyses were used to compare negative and positive BRCA1 patients.One hundred fifteen (65.7%) of the 175 specimens showed positive BRCA1 staining (10% cells were immunoreactive). During a median follow-up of 4.4 years, negative BRCA1 patients had worse disease free survival than positive BRCA1 patients (35 % vs. 7%, respectively; P0.0001). BRCA1 expression was significantly inversely correlated with histologic grade (P0.0001) but not with lymph node status or other conventional prognostic markers. In multivariate analysis using the Cox regression model, positive BRCA1 emerged as an independent prognostic indicator for disease free survival.The results of this study suggest that BRCA1 may be a valuable marker for identifying women with sporadic breast carcinoma at high risk of developing recurrence, and who may be candidates for trials investigating new therapies in combination with standard adjuvant therapy.

The cycle regulatory protein p27, an inhibitor of cyclin-dependent kinase (CDK), has been attributed a role in resistance to cancer chemotherapy. However, the predictive value of p27 for chemosensitivity of breast cancer is still unclear. We therefore analyzed the in vitro chemosensitivity to a series of anticancer agents in fresh breast cancer specimens and correlated it with the respective expression levels of p27.The expression of p27 protein was examined immunohistochemically in 119 patients with primary breast cancer. The in vitro chemosensitivity was assessed by the histoculture drug response assay (HDRA) using mitomycin C (MMC), 5-fluorouracil (5-Fu), Doxorubicin (DXR), cisplatin (CDDP) and cyclophosphamide (CPA).Fifty-six (47%) of the 119 patients demonstrated p27 overexpression. The susceptibility of DXR and MMC in tumors with high p27 expression was significantly higher than that in tumors with low p27 expression.Immunohistochemical results regarding p27 might be therapeutically useful as an indicator of response to DXR and/or MMC based adjuvant chemotherapy for breast cancer.

We examined the chemosensitivity of non-small cell lung cancer (NSCLC) tissues to CDDP, 5-FU, ADM, MMC, ETP and SN38 using histoculture drug response assay (HDRA). One-hundred and thirty surgical specimens from NSCLC patients who were not given preoperative chemotherapy were used. The inhibition indexes of CDDP, 5-FU, MMC, ADM, ETP and SN38 were 39.1 +/- 18.2%, 48.0 +/- 19.7%, 63.3 +/- 17.7%, 47.6 +/- 22.0%, 36.9 +/- 21.1%, and 37.9 +/- 25.2%, respectively. Inhibition indexes were above the cutoff level, i.e., 'judged sensitive,' in 40 cases (31.3%) for CDDP, 34 cases (27.4%) for 5-FU, 54 cases (44.3%) for MMC, 36 cases (33.0%) for ADM, 29 cases (29.8%) for ETP, and 34 cases (37.4%) for SN38, respectively. In almost one-third of patients, the inhibition indexes of all drugs were under cutoff levels. Correlations between in vitro chemosensitivity data and patient responses to chemotherapy were obtained from 16 evaluable patients, and a 44.4% true positive rate and a 100% true negative rate were observed. Our results with HDRA for NSCLC showed a high incidence of intrinsic multidrug resistance. HDRA may help doctors to avoid non-effective chemotherapy for NSCLC patients.

We investigated the chemosensitivity of anticancer agents against primary (230 patients, 268 tumors) and recurrent breast cancer (40 patients, 51 tumors) using histoculture drug response assays (HDRA) of surgical specimens. Of the 40 recurrent breast cancer patients, 26 were pretreated with anthracycline. The efficacy of the agents was assessed according to an inhibition index of optical density detected by an ELISA reader. The inhibition rate of docetaxel against recurrent tumors was similar that against primary ones, although the rates of adriamycin, 5 fluorouracil, mitomycin and cisplatin against recurrent tumors were significantly lower than those against primary ones. The clinical response of docetaxel was also evaluated in ten patients with recurrent breast cancer. Of the ten patients with recurrent breast cancer, eight were pretreated with anthracycline, and seven showed a partial response. These results indicate that docetaxel is effective against recurrent breast cancer, even anthracycline-resistant breast cancer.

Thymidine phosphorylase (TP) is critical for angiogenic activity, but little information is available on the relationship between TP expression and other Clinicopathologic variables. Furthermore, the relationship between TP and chemosensitivity is still debated.The expression of TP was examined in 116 primary breast carcinomas and in vitro chemosensitivity was assessed in 67 of them by histoculture drug response assay (HDRA) using 5-fluorouracil (5-FU).Tumor cell TP expression was significantly inversely correlated with histological grade and positively correlated with Bcl-2 expression, but no association with other tumor variables was found. Unexpectedly, TP immunoreactivity was not related to 5-FU chemosensitivity.The present results suggest that TP is important for remodeling the existing vasculature early in tumor development and intraductal extension, expressions of TP and Bcl-2 are tightly linked and TP status can not generally predict chemotherapeutic sensitivity for 5-FU as a single molecular marker.

To evaluate the efficacy of docetaxel therapy against anthracycline-resistant breast cancer, twenty patients were treated with docetaxel. Of the 20 patients pretreated with anthracycline, 17 were clinically anthracycline-resistant and the remaining three were refractory to anthracycline on histoculture drug response assay. Nine patients had loco-regional recurrence and 11 had distant +/- loco-regional recurrence. Docetaxel (49-60 mg/m2) was administered every 4 weeks, and was infused 1-13 times (median; 3 times). Of the 19 evaluable patients, eight (42%) showed partial response with the docetaxel therapy. Durations of the response ranged from 1 to 8 months (median; 4 months). Major adverse effects of the therapy were alopecia, neutropenia, and leucocytopenia. Hypersensitivity reaction was observed in one case. In addition, severe adverse effects such as grade 2 pneumonia and grade 4 diarrhea were found in one patient each. In conclusion, although the adverse effects are not negligible, docetaxel therapy is effective against anthracycline-resistant breast cancer.

From January 1986 to May 1998, 45 lung cancer patients with chest wall invasion (P3) underwent resection (40 male, 5 female), (median age 63.2 yrs (30-79)). Histological types were squamous cell carcinoma in 20, adenocarcinoma in 14, large cell carcinoma in 7, adenosquamous cell carcinoma in 2, and unknown in 2. Operative methods of lung resection were total pneumonectomy in 2, bilobectomy in 3, lobectomy in 38, and partial lung resection in 2. Resection was regarded as complete in 35 and incomplete in 10 patients. Thirty one patients had negative lymph nodes (N0), 9 had peribronchial or hilar lymph node metastases (N1), and 5 had mediastinal lymph node metastases (N2). The extent of tumor invasion to chest wall was P3a (invasion within parietal pleura) in 11, P3b-c (invasion to intercostal muscle) in 16, P3d (invasion to rib) in 18, patients. 5-year survival rate was totally 19.7%. Cisplatin based chemotherapy and concurrent thoracic radiation following surgery (CCRT) was performed in latest nine P3d cases. Partial response was observed in 5 of 9 cases (response rate 56%) and viable tumor cell in the primary site was not seen histologically in 5 of 9 cases. Three year survival rate was 46.9% for CCRT(+) 11.1% for CCRT(-). Acturial 5-year survival rate in P3a-d was 19.76%. P3d cases had poor survival, but CCRT improved prognosis of P3d cases.

Histoculture drug response assay (HDRA) was applied to a biopsy specimen of advanced thymic cancer from a 68 years-old male patient. HDRA revealed that the tumor was not sensitive to CDDP but highly sensitive to 5-FU, ADM and MMC, which were administered as induction chemotherapy. The tumor regressed to 14% of the pretreatment size and was able to be completely resected with right and left brachiocephalic veins, superior vena cava, pericardium, right phrenic nerve and a part of right lung. Histologically, only a few small cancer nests remained in the fibrous tissue. The patient is alive and disease free 32 months after surgery. This result suggests that HDRA is useful to select anticancer agents which are sensitive to a rare kind of carcinoma such as thymic cancer.

A 81-year-old male with a high serum alpha-fetoprotein (AFP) level of 2644 ng/ml underwent left pneumonectomy for squamous cell carcinoma in the lower lobe and large cell carcinoma in the upper lobe. Both tumors were classified as pathological T2N0M0 and stage I. The AFP level was normalized to be 19 ng/ml in 49th postoperative day. Immunohistochemical staining using anti-AFP antibody demonstrated AFP granules only in the large cell carcinoma. The study of lectin affinity against the serum AFP revealed that the concanavalin A (Con-A) non-reactive fraction rate was 14%, the lentil agglutinin (LCA) non-reactive and strongly reactive subfractions were 16.7 and 83%, respectively and P2, P4 and P5 subfractions of the erythroaggultinating phytohemagglutinin (E-PHA) were 58.6, 24.9 and 16.5%, respectively. According to the analysis of 21 cases reported in the Japanese literature including our case, the AFP did not demonstrate a common affinity pattern against the Con-A but the common pattern resembling hepatocellular carcinoma against LCA and E-PHA.

In this paper, surgical results of nipple-preserved mastectomy (Glt+Ax) for breast cancer were compared with those of radical mastectomy. In p-stage I breast cancer cases, survival and loco-regional disease-free rate of the nipple-preserved cases were equivalent to those of radical mastectomy group. Although nipple-preserved cases had inferiority to the radical mastectomy cases in the survival rate in p-stage II cases, loco-regional disease-free rate of nipple-preserved cases was equal to that of radical mastectomy cases. On the basis of these results, nipple-preserved mastectomy can be a standard operation of p-stage I, II breast cancer in point of the local control at least.

Fourteen patients with known primary colorectal adenocarcinoma underwent pulmonary resection for its pulmonary metasoasis. The cumurative survival rate at five years was 25.7% in all patients and 37.5% in 9 patients with a solitary metastasis. One of two patients with both pulmonary and hepatic metastases survived 33 months with no evidence of recurrence after pulmonary and hepatic resection. Although none of seven patients with tumor smaller than 3.5 cm in diameter had regional lymph node metastasis, two of three patients with tumors larger than 3.6 cm in diameter had hilar lymph node metastases. Lobectomy and mediastinal lymph node dissection may be recommended for the patient with large tumor.

We report a thoracoscopic partial resection of the lung for the peripheral lung tumor in a 66-year-old woman. Her chest roentgenogram and computed tomographic scan showed a single tumor 1.9 cm in diameter within the periphery of the right lower lobe. A solitary metastatic lung tumor of colon cancer, which was resected one year ago, was suspected. Partial resection of the lung involving this tumor was performed using the MULTIFIRE ENDO GIA 30 disposable surgical stapler under thoracoscopy. There was neither air leak nor bleeding at the resection line. Pathological examination of the tumor revealed benign localized pleural mesothelioma. Her postoperative course was uneventful and she was discharged from the hospital on the eighth postoperative day. Thoracoscopic pulmonary resection using EndoGIA is a safe technique for a peripheral lung tumor.

Bone pain caused by bone metastases is one of the most common complications in patients with breast cancer. However, the precise molecular mechanism of bone pain is unknown. We have shown that the acid released upon bone resorption by osteoclasts and the transient receptor potential vanilloid receptor (TRPV1), an acid-sensing receptor on the algetic nerves terminating at the bone, are involved in the mechanism underlying this bone pain. In this study, we investigated the relationships among TRPV1, bone-derived insulin-like growth factor-1 (IGF-1) which is released from bone due to increased bone resorption during the progression of bone metastases, and neuropeptide calcitonin gene-related peptide (CGRP) and examined whether cancer-induced bone pain can be decreased by the inhibition of IGF-1 and CGRP. To study this in vitro, we established organ cultures of mouse dorsal root ganglions (DRGs), which are the primary sensory neurons innervating bone. Culture supernatants harvested from the mouse neonatal calvariae, which had abundant growth factor in bone, showed elevated TRPV1 and CGRP mRNA expressions in mouse DRGs. These up-regulated mRNA expressions were inhibited by the administration of a TRPV1 inhibitor (I-RTX); AG1024, a specific inhibitor of IGF receptor tyrosine kinase; or zoledronate. Taken together, these results suggest that CGRP and bone-derived IGF-1 may play a role in the induction of bone pain. To approach the role of CGRP and bone-derived IGF-1 in vivo, we established a mouse model of cancer-induced bone pain by inoculating the 4T1 mouse breast cancer cells into the marrow cavity of tibiae. Tumor-inoculated tibiae showed significantly increased pain behaviors compared with the non-tumor-bearing tibiae, indicating 4T1 cells induced bone pain. RT-PCR showed elevated mRNA expression of TRPV1 and CGRP in the ipsi-lateral tumor-bearing DRGs. The administration of a CGRP inhibitor (CGRP 8-37) in a continuous manner using an ALZET osmotic pump implanted under the mouse skin; the intraperitoneal administration of AG1024; and the administration of alendronate significantly reduced pain behaviors in tumor-bearing tibiae. In addition, mRNA expression of CGRP was decreased by CGRP 8-37, and mRNA expression of TRVP1 and CGRP was also decreased by AG1024 in the ipsi-lateral DRGs. Neither of these drugs showed a direct effect on the growth of the tumor in this study. In conclusion, our results suggest that TRPV1, CGRP, and the bone-derived IGF-1 are strongly related and might play a role in breast cancer-induced bone pain. The inhibition of the CGRP and bone-derived IGF-1 could be a potential therapeutic strategy to reduce bone pain; although further investigations are required in this direction. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 1110.

Abstract #22 Introduction: Cosmetic outcome is one of the most important aspects of surgical treatment of breast cancer. Therefore, to maximize the cosmetic outcome for patients who require a mastectomy, what can be done from an oncologically safe perspective must be considered. Recent reports have suggested that nipple-areola-sparing mastectomy (NSM) is oncologically as safe as a classical mastectomy (MT) and provides a better cosmetic outcome than MT. However, little is known about the long-term outcome of NSM. Aim: To determine the oncological and technical outcomes of NSM compared with MT using long term follow-up data. Patients and Methods: We retrospectively analyzed 788 patients, median age 51 years, with primary breast cancer who underwent NSM from 1985 to 2004. The indication of NSM in this study was defined as being for any stage, any tumor size and any tumor-areola distance. Briefly, NAC was preserved when palpation and the outlook of the nipple was normal. Median tumor size and tumor-areola distance were 2.5cm (0-10.0) and 1.8cm (0-9.0), respectively. Our surgical notes for NSM were; (1) a thin flap (approximately 5 mm thick subcutaneous adipose tissue) was placed close to the tumor, and a thick flap (more than 1cm thick subcutaneous adipose tissue) was created more than 2cm away from the tumor to conserve breast volume using subcutaneous fat, and (2) tissue under the NAC was left at 5 mm in thickness, but the major ducts were removed from within its lumen. Eighty-one patients (10%) underwent immediate breast reconstruction (IBR) using implants. We also analyzed 144 patients with breast cancer who underwent MT in the same period as those who underwent NSM. No patient received radiotherapy. We compared the local recurrence rate (LRR), disease-free survival (DFS) and overall survival (OS) between 788 NSM and 144 MT cases. Results: Median follow-up of NSM and MT was 92 (10-252) and 87 (0-231) months, respectively. To our surprise, no complications of NSM including nipple and areola necrosis were recorded (0/788). For NSM, there were 70 patients (8.9%) with local recurrence, including 23 (2.9%) at the nipple, 4 (0.5%) at the areola, 4 (0.5%) at both nipple and areola, and 39 at the skin flap (4.9%). This suggested that the rate of NAC relapse was quite low. There were no significant differences in LLR between NSM and MT, (10y, 8.9% vs. 7.6%, p=0.62), DFS (10y, 83% vs. 83%, p=0.34) and OS (10y, 88% vs. 86%, p=0.34), respectively. Cosmetic outcome of NSM was better than that of MT in the majority of patients. Conclusion: These results suggested that NSM provides a good cosmetic outcome and is as safe oncologically as MT. Our long term follow-up data shows that NSM is a possible alternative to mastectomy. Citation Information: Cancer Res 2009;69(2 Suppl):Abstract nr 22.

Three operative cases with Cor triatriatum, age ranged from 30 days to 16 months, were presented. All types were IB1 of Lucas-Schmidt's classification and one patient was associated with right upper PAPVC. One patient died of low output syndrome due to preoperative shock. Communication of abnormal diaphragm in left atrium varied from small and multiple to 5 mm in diameter. Their preoperative diagnoses were established by two-dimensional echocardiogram prior to angiocardiogram and the intracardiac communications were well evaluated by color doppler echocardiogram which was superior to angiocardiogram in this evaluation. Postoperatively, no abnormal diaphragm were detected in two survivors. The diagnosis and operative procedure for this anomaly were discussed on.