Total Breast Reconstruction With Fat Grafting After Internal Expansion and Expander Removal.

INTRODUCTION: The development of fat grafting techniques both in cosmetic and reconstructive breast surgery has highlighted the need to recreate a breast mound using similar tissues and without visible scarring. Our technique combines skin expansion by conventional expanders and breast volume replacement by serial fat grafting and final expander removal. MATERIALS AND METHODS: Fat grafting had been performed both by Coleman technique and Bodyjet system. We report a series of 12 cases enrolled between 2008 and 2013. Each case has been presented in this article, focusing on received treatment, observed complications, and results. RESULTS: Satisfactory results were observed 6 months after the last session in most of the concluded reconstructions with a low complication rate.

Obesity, proinflammatory mediators, adipose tissue progenitors, and breast cancer.

PURPOSE OF REVIEW: There is emerging evidence that obesity is associated with an increase in the incidence, severity, and mortality from different types of cancer, including postmenopausal breast cancer. Here, we discuss the role of white adipose tissue (WAT) cells and of related soluble factors in the local and metastatic growth of this neoplastic disease. Moreover, we discuss the recent increase in the use of WAT-derived progenitor cells in breast cancer patients to enhance the quality of breast reconstruction and the related risks. RECENT FINDINGS: In several murine models, WAT cells and progenitors were found to have cooperative roles in promoting local breast cancer. Moreover, they were found to contribute to adipocytes and pericytes supporting the cancer vasculature, and stimulated the metastatic progression of breast cancer. There are some clinically retrospective data showing a significant increase in the frequency of intraepithelial neoplasia in patients who received a lipofilling procedure for breast reconstruction compared with controls. SUMMARY: Preclinical models and clinical studies are urgently needed to investigate how to inhibit the tumor-promoting activity of WAT cells and progenitors. The risks associated with the use of WAT cells for breast reconstructions should be better investigated retrospectively and prospectively.

Adipose tissue cells, lipotransfer and cancer: a challenge for scientists, oncologists and surgeons.

Despite recent evidence of the cancer-promoting role of adipose tissue-derived progenitor and differentiated cells, the use of lipotransfer for tissue/organ reconstruction after surgical removal of cancer is increasing worldwide. Here we discuss in a multidisciplinary fashion the preclinical data connecting obesity, adipose cells and cancer progression, as well as the clinical data concerning safety of lipotransfer procedures in cancer patients. A roadmap towards a more rationale use of lipotransfer in oncology is urgently needed and should include preclinical studies to dissect the roles of different adipose tissue-derived cells, the evaluation of drugs currently candidate to inhibit the interaction between adipose and tumor cells, and carefully designed clinical trials to investigate the safety of lipotransfer procedures in cancer patients.

Do clinicopathological features of the cancer patient relate with nipple areolar complex necrosis in nipple-sparing mastectomy?

BACKGROUND: The selections of nipple-sparing mastectomy (NSM) are principally depending on oncologic indication and oncologic safety. The main complication of NSM is nipple areolar complex (NAC) necrosis, and it is usually related to surgical technique. However, the patients' clinicopathological factors should be also considered. METHOD: We retrospectively reviewed 934 consecutive NSM patients during 2002-2007 at the European Institute of Oncology, Milan, Italy. We identified a group of patient who had NAC excision because of NAC necrosis and compared this group with those who had successful NAC conservation. We analyzed the association between the risk of NAC necrosis and the clinicopathological features of the patients. RESULTS: Among 934 NSM, 772 were invasive cancers and 162 were in situ cancers. Of the 934, 40 NAC (4.2%) were removed during the postoperative period because of necrosis. When we considered age, BMI, menopausal status, smoking status, tumor size, axillary lymph node status, in situ or invasive cancer histology, presence of extensive situ component, grading, estrogen receptor, progesterone receptor, HER2/neu overexpression, Ki-67 proliferative index, and peritumoral vascular invasion, no association was observed between patients' clinicopathological features and NAC necrosis incidence. CONCLUSIONS: In our study, clinicopathological features have no significant impact on necrosis complication in therapeutic NSMs. Positive retroareolar margin is the risk of necrosis. Further studies are required to avoid bias due to the different cancer treatments such as different reconstruction techniques and intraoperative radiation protocols. The correlation between breast morphology and NAC necrosis should also be investigated in the future.

Conservative mastectomy: extending the idea of breast conservation.

Conservative mastectomy is a surgical technique to remove breast glandular tissue without disruption to the appearance of the breast. The main contraindication to this operation is involvement of the nipple-areola complex. Preservation of a healthy nipple does not affect long-term survival rates. Intraoperative retroareolar biopsy and accurate removal of all mammary tissue are mainstays to guarantee oncological safety of the technique. A complication, however infrequent, is nipple necrosis, which can be treated successfully by local excision. Several breast reconstructive techniques are used during conservative mastectomy and aesthetic results are good in most cases.

Paget's disease as a local recurrence after nipple-sparing mastectomy: clinical presentation, treatment, outcome, and risk factor analysis.

BACKGROUND: Paget's disease is a rare clinical and histological type of local recurrence (LR) after breast cancer treatment both in case of conservative surgery or nipple-sparing mastectomy (NSM) with or without intraoperative radiation. METHODS: We performed an analysis of 861 NSM with electron beam intraoperative radiotherapy (ELIOT) patients treated at the European Institute of Oncology from 2002 to 2008, focused on Paget's disease local recurrence. RESULTS: In 861 patients (713 invasive carcinoma and 148 intraepithelial neoplasia), there were 36 local recurrences (4.18%), and among these were 7 Paget's disease local recurrences (0.8%). Median follow-up was 50 months. Four cases presented with nipple areola complex (NAC) erosions, two crusted lesions, and one ulcerated NAC. The average latency period from the NSM to Paget's disease local recurrence is 32 months (range, 12-49). Complete NAC removal was performed in all seven recurrences. The average follow-up after NAC removal was 47.4 months (range, 20-78). We found neither locoregional relapse nor metastatic event in this group. All patients were alive without disease. CONCLUSIONS: Paget's disease local recurrence can be found in a significant proportion after NSM. Any suspicious lesion on NAC requires prompt pathological confirmation. Primary carcinoma with ductal intraepithelial neoplasia or invasive ductal carcinoma with extensive in situ component, negative hormonal receptor, high pathological grade, overexpression of HER2/neu, and "HER2 positive (nonluminal)" subtype tend to be significantly associated with more Paget's disease local recurrence and should be followed carefully.

Risk of locoregional recurrence in patients with false-negative frozen section or close margins of retroareolar specimen in nipple-sparing mastectomy.

BACKGROUND: Our purpose was to evaluate the locoregional recurrence (LRR) of patients with false-negative, frozen-section or close margins of retroareolar specimen in nipple-sparing mastectomy (NSM) procedure. METHODS: From 2002-2008, we recruited patients who had atypia or presence of cancer cells in definitive histology of retroareolar tissue despite of absence of tumor cell in intraoperative retroareolar frozen section. We also included the close margin cases defined as the presence of tumor cells at the first frozen section, but after deeper core out of retroareolar tissue were revealed free of malignancy. The incidence of LRR and NAC recurrence were reported, and the factors associated were analyzed. RESULTS: Of 948 NSM procedures, there were 88 false-negative, frozen-sections and 10 close margin cases. The 5-year cumulative incidence of LRR and NAC recurrence was 11.2 % (10/98 patients) and 2.4 % (2/98 patients), respectively. Analyzing the definitive results of retroareolar tissue, the 5-year cumulative incidence of LRR was 42.9 % (n = 4) for atypia, 10 % (n = 2) for lobular carcinoma in situ (LCIS), 10 % (n = 1) for close margins, 8.7 % (n = 3) for ductal carcinoma in situ (DCIS), and 0 % for invasive carcinoma. In situ carcinoma as a primary tumor was a significant predictor of NAC recurrence (P < 0.01). CONCLUSIONS: Despite a high reliability of frozen section, there is still a minority of false-negative results. Nevertheless, the LRR is considerably low. This fact suggests the possibility of preservation of the NAC after discussion with the patient.

Update on breast reconstruction techniques and indications.

Breast reconstruction is considered as part of the breast cancer treatment when a mastectomy is required. Implants or expanders are the most frequent techniques used for the reconstructions. Expander provides usually a better symmetry. A contralateral mastoplasty often is required to improve the symmetry. The nipple areola complex, which can be preserved in certain conditions, is usually removed and can be reconstructed in a second stage under local anesthesia. In case of radical mastectomy and/or radiotherapy, a musculocutaneous flap, such as rectus abdominis or latissimus dorsi autologous flaps, is required. When microsurgical facilities are available, free or perforator flaps respecting the muscle are preferred to decrease the donor site complications. In situ carcinomas or prophylactic mastectomy can be reconstructed immediately as well as invasive carcinoma according to the recent literature. Locally advanced breast cancer can be reconstructed after complete oncologic treatment. Radiotherapy of the thoracic wall is proposed in case of lymph node metastases, raising the discussion about the technique choice and the timing of the reconstruction. Plastic surgery procedures can improve the cosmetic results of the conservative surgery, also extending its indications and reducing both mastectomy and reexcision rates. Oncoplasty techniques are becoming more and more sophisticated, requiring the skill of trained plastic surgeons. Numerous publications confirm the psychosocial benefit resulting from the breast reconstruction.

Sarcoid-like reaction in breast cancer: a long-term follow-up series of eight patients.

PURPOSE: Finding an intrathoracic or axillary mass in a breast cancer patient should raise suspicion of a pulmonary or mediastinal nodal metastasis or axillary recurrence. Surprisingly, noncaseating epithelioid cell granuloma can be found in this type of lesion, as in sarcoidosis or a sarcoid-like reaction. METHODS: This series included eight breast cancer patients in whom a late sarcoid-like reaction developed: as an intrathoracic lesion in six, and as an ipsilateral axillary lesion in two. The latency period from oncological surgery to the diagnosis of sarcoidosis was 40 months and the average follow-up after the diagnosis of sarcoidosis was 63.38 months. RESULTS: None of the patients suffered relapse or oncological events during the period of this study. CONCLUSION: To avoid misdiagnosis and overtreatment, pathological examination should always be carried out. We do not recommend any specific treatment for sarcoidosis in a breast cancer patient, but routine oncological follow-up is appropriate. A larger series with statistical analysis is necessary to evaluate the prognosis.

γ-Aminobutyric acid type B receptor changes in the rat striatum and substantia nigra following intrastriatal quinolinic acid lesions.

Changes in the regional distribution of the metabotropic GABA type B receptors (GABA(B)) were investigated in a rat model of Huntington's disease. Animals received a unilateral intrastriatal injection of quinolinic acid (QA), and GABA(B) immunoreactivity was monitored 3, 11, and 21 days postinjection in the striatum and substantia nigra (SN). Two antibodies, recognizing either the GABA(B1) or the GABA(B2) receptor subtypes, were used. QA injection rapidly induced a protracted increase in GABA(B1) or GABA(B2) immunoreactivity in the lesioned striatum, despite the neuronal loss. In the SN, a continuous increase in GABA(B1) and GABA(B2) immunoreactivity was observed at all time points in the ipsilateral pars reticulata (SNr), whereas the pars compacta (SNc) was unaffected by this phenomenon. This increase was supported by a densitometric analysis. At day 21 postlesion induction, intensely labeled stellate cells and processes were found in the ipsilateral SNr, in addition to immunoreactive neurons. Double labeling of GABA(B1) and glial fibrillary acidic protein (GFAP) showed that the stellate cells were reactive astrocytes. Hence, part of the sustained increase in GABA(B) immunoreactivity that takes place in the SNr and possibly the striatum may be ascribed to reactive astrocytes. It is suggested that GABA(B) receptors are up-regulated in these reactive astrocytes and that agonists might influence the extent of this astroglial reaction.

Clinical study of the feasibility, complications, and cosmetic outcomes of immediate autologous fat grafting during breast-conserving surgery for early-stage breast cancer in China.

BACKGROUND: The resection of tumors in small breasts or in areas such as the upper and inner parts of the breast may have disabling cosmetic results. Tumor resection reduces the volume of the breast and may result in asymmetry or distortion of the nipple-areola complex. Autologous fat transfer/grafting has been shown to be a reliable technique for improving these poor cosmetic results. This study aimed to evaluate the feasibility, complications, and cosmetic outcomes of immediate autologous fat grafting during breast-conserving surgery (BCS) in Chinese patients with early-stage breast cancer. METHODS: This retrospective study included 58 patients with early breast cancer treated by the same surgical team from October 2016 to May 2017. The patients were divided into two groups: BCS with lipofilling (experiment group, n=30) and BCS without lipofilling (control group, n=28). All patients received the recommended breast cancer treatment with complementary radiotherapy. The follow-up period after the completion of radiotherapy ranged from 36-44 months. The resected and grafted volumes, complications, esthetic results, patient satisfaction, and recurrence rate within 3 years were compared between the groups. RESULTS: The average resected and grafted volumes in the lipofilled group were 47 and 74 mL, respectively, with only one seroma and no other complications. Regarding physician evaluation, BCS with lipofilling resulted in better cosmetic outcomes than BCS without lipofilling (33% versus 15%, respectively). Poor responses occurred in only 7% of patients with lipofilling, compared with 15% without lipofilling. Regarding patient self-evaluation, Breast-Q scores including patient satisfaction with their breasts and psychosocial well-being, were significantly higher in patients who received lipofilling compared with non-lipofilled patients. Regional recurrence occurred in one patient (case 21) (3.7%) in the lipofilling group and systemic recurrence occurred in one patient (case 12) (3.8%) in the control group. CONCLUSIONS: Immediate autologous fat grafting is a promising, effective, and convenient technique for partial breast reconstruction after BCS, with potentially higher levels of patient and physician satisfaction compared with traditional BCS. TRIAL REGISTRATION: Chinese Clinical Trial Registry ChiCTR-ONN-17010514. Registered 24 January 2017.

A novel indole-3-propanamide exerts its immunosuppressive activity by inhibiting JAK3 in T cells.

We previously identified an indole-3-propanamide derivative, 3-[1-(4-chlorobenzyl)indol-3-yl]-N-(pyridin-4-yl)propanamide (AD412), as a potential immunosuppressive agent. Here, we document that AD412 inhibited the proliferative response of CD3/CD28-stimulated human T cells without inhibiting their interleukin 2 (IL-2) production and also inhibited the proliferation of CTL-L2 cells in response to IL-2. These results prompted us to analyze the effect of our compound on the three main signaling pathways coupled to the IL-2 receptor. We provide evidence that AD412 inhibited the JAK1/3-dependent phosphorylations of Akt, STAT5a/b, and ERK1/2 in IL-2-stimulated CTL-L2 cells. In contrast, AD412 had little effect on the JAK1/2-dependent INF-gamma-induced phosphorylation of STAT1 in U266 cells. This suggested a preferential inhibition of JAK3 over JAK1 or JAK 2 activities by AD412 that was confirmed by in vitro kinase assays with purified JAK2 and JAK3 kinases. In addition, we provide evidence that the inhibition of IL-2 response by AD412 was not due to inhibition of IL-2Ralpha up-regulation because neither AD412 nor JAK3 inhibitors described previously [4-[(3-bromo-4-hydroxyphenyl)amino]-6,7-dimethoxyquinazoline (WHI-P154) and alpha-cyano-(3,4-dihydroxy)-N-benzylcinnamid (AG-490)] significantly inhibited IL-2-induced IL-2Ralpha overexpression. Finally, we further document the immunosuppressive activity of AD412 in vivo by showing that its administration per os significantly prolonged heart allograft graft survival. This molecule may thus represent an interesting lead compound to develop new immunosuppressive agents in the field of transplantation and autoimmune diseases.

Surgical closure of chest wall in noninflammatory locally advanced breast carcinoma with ulceration of the skin.

Patients with noninflammatory locally advanced breast cancer with ulceration of skin or muscle or parietal wall infiltration, better named "extended locally advanced breast cancer," may require cancer surgery and plastic reconstruction of the chest wall after multidisciplinary evaluation. The decision is made to improve quality of life, independently of prognosis, and severity of the disease. The aim of this study is to evaluate the best method for surgical closure of the chest wall and to check whether ablative surgery is an appropriate procedure in regards to the treatment of cancer. From October 1997 to June 2006, 27 patients with noninflammatory extended locally advanced breast cancer with ulceration of the skin, who were not candidate or did not respond to a neo-adjuvant treatment, underwent radical mastectomy and reconstructive surgery. Sixteen patients (59%) were affected by primary tumors of the breast, and eleven patients (41%) had local recurrence after mastectomy or conservative breast surgery. Two main techniques were used for breast reconstruction: transverse rectus-abdominis musculo cutaneous flap in 19 patients (70%), and a fasciocutaneous flap in eight patients (30%). The best procedure in each patient was chosen according to the extent of skin loss or previous radiotherapy to the chest wall. Fourteen patients (52%) died during the follow-up and the median length of survival was 16 months (range 3-79) in transverse rectus-abdominis musculo cutaneous group and 4 months (range 2-23) in fasciocutaneous flap group. The median length of follow-up after treatment for patients still alive was 32.5 months (range 0-96) in transverse rectus-abdominis musculo cutaneous flap group, and 18 months (range 8-41) in fasciocutaneous flap group. At the end of the follow-up, 10 patients were alive without evidence of disease and three patients developed metastatic lesion or local recurrence. The longest recorded disease free interval for a patient still alive and tumor free was 96 months. Only three patients (11%) had local complications: two wound infections and one partial necrosis of the transverse rectus-abdominis musculo cutaneous flap. Median hospital stay was 7 days (range 3-13) for transverse rectus-abdominis musculo cutaneous and 6 days (range 3-13) for fasciocutaneous flap. Our results confirmed that transverse rectus-abdominis musculo cutaneous group and fasciocutaneous flap flaps are good reconstructive options in patients with extended locally advanced breast cancer. Quality of life has improved in this group of patients, with acceptable survival periods and in some cases very important survival rates.

N-Pyridinyl(methyl)-indole-1- or 3-propanamides and propenamides acting as topical and systemic inflammation inhibitors.

In this study, the synthetic way to new N-pyridinyl(methyl)indolylpropanamides acting as non acidic NSAIDs has been described. Pharmacomodulation was carried out at N(1) and C(5) of the indole ring and at the level of the propanamide chain. N(3)-pyridinylmethyl-[1(4-chlorobenzyl-5-chloroindol-3-yl)propanamide represents one of the most potent compounds in the TPA-induced mouse ear swelling assay, with a level of activity higher than that of ibuprofen and comparable to that of dexamethasone.

Technical tricks to improve the cosmetic results of breast-conserving treatment.

The paper describes different manoeuvres and surgical details that may help the general surgeon to improve the aesthetic outcomes after breast-conserving treatment for cancer. Among them, the pre-operative planning, the position of the patient in the operative room, the mobilisation of the glandular tissue when the tumour has been removed. All these manoeuvres contribute to achieving better symmetry with the healthy breast and to improve the final aesthetic result, minimising the surgical conflict between large resections and defects for optimal control of local disease and the consequent breast deformities.

Synthetic N-pyridinyl(methyl)-indol-3-ylpropanamides as new potential immunosuppressive agents.

Several N-pyridinyl(methyl)-indol-3-ylpropanamides were synthesized and pharmacological evaluations of their immunosuppressive potential were performed. Among thirteen compounds tested in vitro on murine T proliferation, three showed interesting inhibiting activity. For the most active compound (propanamide 18), immunosuppressive activity was documented both in vitro on human T lymphocytes proliferation and in vivo on mice delayed-type hypersensitivity. These experimental data demonstrated that these compounds hold potential as immunosuppressive agents.

Fat Grafting after Invasive Breast Cancer: A Matched Case-Control Study.

BACKGROUND: Fat grafting has been widely indicated for postmastectomy and postlumpectomy breast reconstruction. The literature emphasizes the clinical efficacy of fat grafting, but experimental studies raise important questions about the recurrence risk because of the stimulation of remaining cancer cells by progenitor or adult adipocytes. Because breast conservative treatment provides a higher risk of residual cancer cells in the breast tissue compared with mastectomy, the authors set up a matched case-control study of fat grafting versus no fat grafting after breast conservative treatment. METHODS: The authors collected data from 322 consecutive patients operated on for a primary invasive breast cancer who subsequently underwent fat grafting for breast reshaping from 2006 to 2013. All patients were free of recurrence before fat grafting. For each patient, the authors selected one patient with similar characteristics who did not undergo fat grafting. RESULTS: After a mean follow-up of 4.6 years (range, 0.1 to 10.2 years) after fat grafting, or a corresponding time for controls, the authors observed no difference in the incidence of local events (fat grafting, n = 14; controls, n = 16; p = 0.49), axillary nodes metastasis (fat grafting, n = 3; controls, n = 6; p = 0.23), distant metastases (fat grafting, n = 14; controls, n = 15; p = 0.67), or contralateral breast cancer (fat grafting, n = 4; controls, n = 4; p = 0.51). CONCLUSION: Fat grafting seems to be a safe procedure after breast conservative treatment for breast cancer patients. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

Conservative mastectomy versus nipple-sparing mastectomy: preliminary considerations of oncological safety on 30 patients not receiving intra-operative radiotherapy.

BACKGROUND: For several years, there has been broad consensus that nipple-sparing mastectomy is a safe surgical treatment for breast cancer. However, the technique is associated with a relatively high risk of local recurrence (LR) behind the nipple-areola complex (NAC). It is for this reason that some years ago we introduced intraoperative radiotherapy with electrons (ELIOT) targeted specifically to the NAC to reduce the probability of recurrence there. However, in some cases we preferred to avoid ELIOT when the NAC appears to have a poor blood supply to ensuring the best chance of NAC survival. METHODS: From July 2003 to April 2010 at our institute, 30 patients received nipple-sparing mastectomy but neither ELIOT nor external radiotherapy, as the surgeon considered the irradiation would markedly compromise the chances of NAC survival, because of sub-optimal vascularization. RESULTS: After a median follow-up of 5 years there were no LRs with minor post-operative complications. CONCLUSIONS: This preliminary case series indicates that the presented technique can be a safe procedure in breast cancer surgery, but requires greater number of cases and a longer follow-up to confirm the oncological safety.