Stem cells from adipose tissue and breast cancer: hype, risks and hope.

Several recent papers have generated new hope about the use of white adipose tissue (WAT)-derived progenitor cells for soft tissue reconstruction in a variety of diseases including breast cancer (BC), a procedure that is increasingly used worldwide. We revised the available literature about WAT cells and BC. In the BC field, we believe that the hype for the exciting results in terms of WAT progenitor cell engraftment and tissue augmentation should be tempered when considering the recent and abundant preclinical studies, indicating that WAT progenitors may promote BC growth and metastasis. White adipose tissue progenitors can contribute to tumour vessels, pericytes and adipocytes, and were found to stimulate local and metastatic BC progression in several murine models. Moreover, there are clinical retrospective data showing a significant increase in the local recurrence frequency in patients with intraepithelial neoplasia who received a lipofilling procedure for breast reconstruction compared with controls. Retrospective and prospective clinical trials are warranted to investigate in depth the safety of this procedure in BC. Preclinical models should be used to find mechanisms able to inhibit the tumour-promoting activity of WAT progenitors while sparing their tissue reconstruction potential.

Evaluation of fat grafting safety in patients with intraepithelial neoplasia: a matched-cohort study.

BACKGROUND: Fat grafting is widely carried out in breast cancer patients to improve quality in breast reconstruction. Recently, in vitro and animal studies have questioned the role of adipose tissues in cancer development. DESIGNS: Matched-cohort study. We analysed: (i) 59 intraepithelial neoplasia patients who had undergone lipofilling, with no recurrence between primary surgery and lipofilling. (ii) A control group of 118 matched patients (two controls per lipofilling patient) with the corresponding recurrence-free intervals. Both groups were also matched for main cancer criteria. A local event (LE) was the primary end point, with follow-up starting from the baseline. RESULTS: Median follow-up was 63 and 66 months from surgery, and 38 and 42 from baseline, for the lipofilling and control groups, respectively; the 5-year cumulative incidence of LE was 18% and 3% (P = 0.02). Ki-67 was the significant factor in univariate survival analysis. A subgroup analysis showed that lipofilling increased the risk of LE in women <50 years, with high grade neoplasia, Ki-67 ≥ 14 or who had undergone quadrantectomy. CONCLUSION: Higher risk of LE was observed in intraepithelial neoplasia patients following lipofilling. Although further studies are required to validate our conclusions, patients belonging to this subgroup should be informed of these results and the potential risks.

Risk factors associated with recurrence after nipple-sparing mastectomy for invasive and intraepithelial neoplasia.

BACKGROUND: To identify risk factors of recurrence in a large series of patients with breast cancer who underwent a nipple-sparing mastectomy (NSM). PATIENTS AND METHODS: Breast-related recurrences and local recurrences (LR) in the breast and the nipple areola complex (NAC) were studied. Cumulative incidences of events were estimated through competing risk analysis. Multivariate Cox regression models were also applied. RESULTS: We identified 934 consecutive NSM patients during 2002-2007. Median follow-up was 50 months. In 772 invasive carcinoma patients, the rate of LR in the breast and in the NAC was 3.6% and 0.8%, respectively. In the 162 patients with intraepithelial neoplasia, the rate of LR in the breast and in the NAC was 4.9% and 2.9%, respectively. The significant risk factors of LR in the breast for the group A were grade, overexpression/amplification of HER2/neu and breast cancer molecular subtype Luminal B. In group B, the risk factors of LR in the breast and in the NAC were age (<45 years), absence of estrogen receptors, grade, HER2/neu overexpression and high Ki-67. CONCLUSIONS: The LR rate after NSM in our series was low. Biological features of disease and young age should be taken into account when considering NSM in breast cancer patients.

Locoregional recurrence risk after lipofilling in breast cancer patients.

BACKGROUND: Lipofilling has been indicated for postmastectomy and postlumpectomy breast reconstruction. The clinical literatures underline its technical efficacy but experimental studies raise important questions about the potential detrimental effect of adipocytes on the stimulation of cancer growth and reappearance. DESIGN: We collected 321 consecutive patients operated for a primary breast cancer between 1997 and 2008 who subsequently underwent lipofilling for reconstructive purpose. For each patient, we selected two matched patients with similar characteristics who did not undergo a lipofilling. RESULTS: Eighty-nine percent of the tumors were invasive. Median follow-up was 56 months from the primary surgery and 26 months from the lipofilling. Eight and 19 patients had a local event in the lipofilling and control group, respectively, leading to comparable cumulative incidence curves [P = 0.792; Hazard Ratio(Lipo vs No lipo) = 1.11 (95% confidence interval 0.47-2.64)]. These results were confirmed when patients undergoing quadrantectomy and mastectomy were analyzed separately and when the analysis was limited to invasive tumors. Based on 37 cases, the lipofilling group resulted at higher risk of local events when the analysis was limited to intraepithelial neoplasia. CONCLUSIONS: Lipofilling seems to be a safe procedure in breast cancer patients. Longer follow-up and further experiences from oncological series are urgently required to confirm these findings.

Why do women accept to undergo a nipple sparing mastectomy or to reconstruct the nipple areola complex when nipple sparing mastectomy is not possible?

In a retrospective study, we investigated the reasons why women accepted to undergo a nipple sparing mastectomy (NSM) and why women who could not keep their nipple areola complex (NAC) decided to reconstruct it. We intended to investigate whether keeping the NAC plays a psychological role, to state possible advantages of NSM. Between 2004 and 2006, 310 women with NAC sparing and 143 patients with successive NAC reconstruction were mailed a single open-ended question at follow-up 12 months after final breast reconstruction surgery or final NAC reconstruction with tattoo. The purpose was to explore personal motivations that drove women to accept NSM or to perform a NAC tattoo reconstruction. Responses were classified into 11 categories by five reviewers. We performed an analysis of the relative frequency of emerging issues. Socio-demographic and clinical data were collected. Among the patients who responded to the open-ended question, 190 patients preserved their NAC, and 100 patients received postponed NAC reconstruction. Women in the NSM group were significantly younger (P = 0.02), more highly educated (P < 0.0001), and more frequently lived in Northern Italy (P = 0.03). The reasons for accepting NSM were more frequently related to body image satisfaction and integrity of the body (P = 0.002), reduction of psychological distress (P = 0.003), and surgeon's influence (P < 0.0001). Esthetic reasons were highly associated to the control group. These results help us to better understand the psychological impact of NAC sparing versus NAC reconstruction. NSM was accepted because it was perceived as a technique that preserved the integrity of the body, reduced the feeling of mutilation, improved the breast cosmetic results, and reduced psychological distress regarding the loss of the breast.

Does nipple preservation in mastectomy improve satisfaction with cosmetic results, psychological adjustment, body image and sexuality?

We investigated the influence of nipple areolar complex (NAC) sparing in mastectomy, on patient satisfaction with cosmetic results, body-image, sexuality and psychological well-being. We developed a specific questionnaire and compared two groups of women who underwent radical mastectomy with immediate breast reconstruction (IBR). Between 2004 and 2006, 310 women with NAC preservation and 143 patients with successive NAC reconstruction were mailed the questionnaire at follow-up 1 year after definitive complete breast reconstruction surgery. 256 questionnaires was available. Our results showed significant differences in favour of the NAC sparing group regarding body image (difficulty in looking at themselves naked and being seen naked by their partners after surgery, P = 0.001 and P = 0.003, respectively); regarding satisfaction with the appearance of the nipple (P < .0001) and with the sensitivity of the nipple (P = 0.001); regarding the feeling of mutilation (P = 0.003). NAC sparing in mastectomy has a positive impact on patient satisfaction, body image and psychological adjustment.

Nipple-sparing mastectomy: risk of nipple-areolar recurrences in a series of 579 cases.

BACKGROUND: When the conservative treatment is not recommended, Nipple Sparing Mastectomy (NSM) is proposed more and more frequently for the surgical treatment of breast cancer. The risk of local recurrence behind the nipple areolar complex (NAC) is the main limiting factor of the NSM procedure. To minimize such risk, we proposed in 2002 a intraoperative radiotherapy of the preserved NAC. PATIENTS AND METHODS: From March 2002 to November 2006, 579 cases (in 570 patients) of NSM were performed for carcinoma. The median follow up time was 19 months (Range: 1-60). The subcutaneous mastectomy was performed through an incision removing a portion of the skin overlying the tumour. An extemporaneous histological examination was performed on the retroareolar glandular tissue. If the histology was positive the patient was not considered eligible. Then an intraoperative radiotherapy with electrons (ELIOT) of 16 Gy in one shot was delivered on the NAC area. An immediate breast reconstruction was done using implants in most cases and in several cases a musculocutaneous flaps, usually in large breast. The number of local recurrences was recorded and the correlation between their occurrence and the clinical and histological criteria were analysed using the Gray test statistical method in a competing framework. RESULTS: In 516 cases the negative retroareolar frozen section biopsy was confirmed by the final histology, while in 63 cases, the final histology showed foci of carcinoma. Seven out of these 63 cases underwent a secondary NAC removal. In the 56 cases which preserved areolas we did not observe any local recurrence after 19 months follow up. The probability of retro areola positive histology increases with the tumour size. and was not related to the nodal status. The rate of local relapses was 0.9% per year. We didn't find any significant difference in the local relapse rate according to different patient's and tumour's features. Most relapses were located close to the tumour bed but never in the NAC area. CONCLUSION: Our study confirms that the local recurrence rate in the NSM completed with local radiotherapy on the NAC is not higher than the usual rate observed in the literature and the preservation of the NAC does not increase the risk. The absence of local recurrence in the region where a portion of glandular tissue has been purposely preserved is a good argument in favour of ELIOT.

Nipple sparing mastectomy with nipple areola intraoperative radiotherapy: one thousand and one cases of a five years experience at the European institute of oncology of Milan (EIO).

In order to reduce mutilation, nipple-areola complex (NAC) conservation can be proposed for the treatment of breast cancer when mastectomy is indicated. To reduce the risk of retro areolar recurrence, a novel radiosurgical treatment combining subcutaneous mastectomy with intraoperative radiotherapy (ELIOT) is proposed. One thousand and one nipple sparing mastectomies (NSM) were performed from March 2002 to November 2007 at the European institute of oncology (EIO), for invasive carcinoma in 82% of the patients and in situ carcinoma in 18%. Clinical complications, aesthetic results, oncological and psychological results were recorded. A comparison was performed between the 800 patients who received ELIOT and the 201 who underwent delayed one-shot radiotherapy on the days following the operation. The median follow up time was 20 months (range 1-69) for a follow up performed in 83% of the patients. The NAC necrosed totally in 35 cases (3.5%) and partially in 55 (5.5%) and was removed in 50 (5%). Twenty infections (2%) were observed and 43 (4.3%) prostheses removed. The median rate of the patients for global cosmetic result on a scale ranging from 0 (worst) to 10 (excellent) was 8. Evaluation by the surgeon in charge of the follow-up gave a similar result. Only 15% of the patients reported a partial sensitivity of the NAC. Of the fourteen (1.4%) local recurrences, ten occurred close to the tumour site, all far from the NAC corresponding to the field of radiation. No recurrences were observed in the NAC. In a group of patients characterized by a very close free margin under the areola, no local recurrence was observed. Overall, 36 cases of metastases and 4 deaths were observed. No significant outcome difference was observed between the 800 patients receiving intraoperative radiotherapy (ELIOT) and the 201 patients receiving delayed irradiation.

Oncological results of immediate breast reconstruction: long term follow-up of a large series at a single institution.

BACKGROUND: Reconstruction of the breast after mastectomy is an integral part of the complete management of breast cancer. However, a delay in the reconstruction is usually proposed after the mastectomy in case of invasive cancer, while there is a general agreement for immediate breast reconstruction in case of in situ tumors. PATIENTS AND METHODS: Among a total of 677 patients having undergone a mastectomy between 1997 and 2001, 518 (76.5%) underwent an immediate breast reconstruction (IBR). All the patients had a Patey mastectomy for invasive cancer (T1-T3). An adjuvant medical treatment was given according to the biological characteristics of the tumor and lymph node status. No patient received any kind of radiotherapy. The median follow up was 70 months (range 13-114). RESULTS: The local recurrence rate was 5.2% for the group of IBR and 9.4% for the mastectomy group without IBR (NoIBR). The regional metastases rate was 1.4 vs. 1.3%. The rate of distant metastases was 13.9 vs. 16.4%. Contra-lateral breast tumor was observed in 1.5 vs. 1.3%. Death rate was 10.4 vs. 16.4%. No statistical difference was observed between the two groups in terme of overall survival (OS) and disease free survival (DFS) (HR(IBR vs. NoIBR): 1.03 and 0.99 for OS and DFS, respectively). CONCLUSION: At our institution we have compared a large series that have undergone IBR (518) with a control group (159) and followed over a prolonged period of time (70 months). This study provides the best available results to suggest that IBR is a safe and reliable treatment option for the managing invasive breast cancer.

Long-term oncological results of breast conservative treatment with oncoplastic surgery.

Oncoplastic surgery combining breast conservative treatment (BCT) and plastic surgery techniques may allow more extensive breast resections and improve aesthetic outcomes, but no long-term oncological results have been published. Long-term oncologic results of 148 consecutive BCT with concomitant bilateral plastic surgery have been analysed and were compared to historical data of BCT trials. Median follow-up was 74 months. Complete excision was obtained in 135 patients (91%); focally involved margins in 8 (5%); and close (<2 mm) margins in 5 (3%). Five patients developed ipsilateral recurrence (3%), 19 (13%) developed distant metastasis and 11 patients died (7.53%). Patients with tumours larger than 2 cm were at greater risk of local recurrences and distant metastasis. Long-term oncologic results of BCT with oncoplastic surgery are comparable with the results of BCT randomized trials.

Shoulder function after breast reconstruction with the latissimus dorsi flap: A prospective cohort study - Combining DASH score and objective evaluation.

OBJECTIVES: The latissimus dorsi (LD) flap is well-known in breast reconstruction especially in previously-irradiated patients, in order to have a low capsular contraction rate whenever an implant is associated. The aim of this study is to closely evaluate the effect of LD flap harvesting on shoulder function as well as specific movements related to the LD, both objectively and subjectively. MATERIALS AND METHODS: We retrospectively collected data on 86 patients who underwent pedicled LD muscle flap for breast reconstruction at the European Institute of Oncology between September 1995 until March 2011. RESULTS: The majority of patients showed a joint recovery superior to 80% in all joint movements examined. Disabilities of the Arm, Shoulder and Hand questionnaire revealed minimal disability similar to normal range and furthermore it appears to decrease in all sports and in particular in those who practice with LD involvement. CONCLUSION: Focusing this data, a growing, "disability-free" percentage changes depending on whether or not the patients have practiced sport could be appreciate.

When mastectomy becomes inevitable: the nipple-sparing approach.

The preservation of the nipple areola complex (NAC) could improve the quality of life in cases of mastectomy. A novel radiosurgical treatment combining subcutaneous mastectomy with intraoperative radiotherapy is proposed. Three hundred nipple-sparing mastectomies (NSM) were performed. Invasive (58%) and in situ (42%) carcinomas were included. Clinical complications, aesthetic results, oncological and psychological results were recorded. The NAC necrosed totally in 10 cases and partially in 29 and it was removed in 12. Nine infections (3%) were observed and 10 prostheses removed. Good results were rated by 82.3% of the patients and by 84.8% of the surgeons. In 7.5% a radiodystrophy was observed. The sensitivity of the NAC recovered partially in 48%. Two local recurrences occurred outside the radiated field. Overall, we observed three metastases and no deaths. Sixty-eight of the patients were satisfied with their reconstructed breast and 85.5% were satisfied having preserved the NAC.

Evaluation of skin perfusion after nipple-sparing mastectomy by indocyanine green dye. Preliminary results.

The aim of the study was to investigate the blood supply of the normal nipple areola complex (NAC) and the spared areola complex after a nipple-sparing mastectomy using the analysis of the fluorescence from the indocianine green dye (ICG) injection. Between December 2002 and July 2003 we performed the ICG analysis in 10 cases of healthy breasts and in 9 patients after a nipple-sparing mastectomy and one patient after subcutaneous mastectomy. In all cases, the resulting fluorescence was measured in three different zones: nipple, areola, surrounding mammary skin. Three parameters of the fluorescence curve (slope, maximum intensity, time to achieve a maximum level) were recorded. On the healthy breast, the nipple showed a very high perfusion as compared to the other zones. On the contrary, after the mastectomy the fluorescent pattern was completely altered, being the perfusion of the nipple very low. In conclusion, these preliminary results confirm the applicability and the importance of the ICG technique for evaluating the perfusion of the healthy and spared areola after surgery. Because of the small number of patients further studies are needed.

Efficacy of a 2% climbazole shampoo for reducing Malassezia population sizes on the skin of naturally infected dogs.

OBJECTIVE OF THE STUDY: Shampoo therapy is often recommended for the control of Malassezia overgrowth in dogs. The aim of this study was to evaluate the in vivo activity of a 2% climbazole shampoo against Malassezia pachydermatis yeasts in naturally infected dogs. ANIMALS: Eleven research colony Beagles were used. MATERIALS AND METHODS: The dogs were distributed randomly into two groups: group A (n=6) and group B (n=5). Group A dogs were washed with a 2% climbazole shampoo, while group B dogs were treated with a physiological shampoo base. The shampoos were applied once weekly for two weeks. The population size of Malassezia yeasts on skin was determined by fungal culture through modified Dixon's medium contact plates pressed on left concave pinna, axillae, groins, perianal area before and after shampoo application. Samples collected were compared by Wilcoxon rank sum test. RESULTS: Samples collected after 2% climbazole shampoo application showed a significant and rapid reduction of Malassezia population sizes. One hour after the first climbazole shampoo application, Malassezia reduction was already statistically significant and 15 days after the second climbazole shampoo, Malassezia population sizes were still significantly decreased. No significant reduction of Malassezia population sizes was observed in group B dogs. CONCLUSION: The application of a 2% climbazole shampoo significantly reduced Malassezia population sizes on the skin of naturally infected dogs. Application of 2% climbazole shampoo may be useful for the control of Malassezia overgrowth and it may be also proposed as prevention when recurrences are frequent.

Management of the axilla in conservatively treated breast cancer: 592 patients treated at Institut Gustave-Roussy.

Between June 1970 and April 1982, 592 patients with unilateral T1 and small T2 breast cancers were managed conservatively at the Institut Gustave-Roussy. The treatment policy for the axilla was to perform a lower axillary dissection and to proceed to axillary clearance ( +/- radiotherapy) in patients with axillary invasion by tumor (N+). Some N+ patients had only lower axillary dissection and radiotherapy. Five hundred fifty-eight patients underwent axillary surgery which was a lower axillary dissection in 374 patients (67%) and axillary clearance in 184 patients (33%). There was axillary invasion in 198 cases (36%). Only five patients relapsed in the axilla and the probability of axillary relapse at 5 years was 1.2%. There were no axillary relapses in N+ patients who had had an axillary clearance whether irradiated or not. The incidence of upper limb complications was significantly greater in patients undergoing axillary surgery and radiotherapy compared with axillary surgery alone (p less than 0.0001). It is concluded that a lower axillary dissection accurately identifies N-patients and an axillary clearance in N+ patients ensures good local control and avoids the morbidity associated with axillary irradiation.

Synthesis and central dopaminergic effects of N-(4,6-dimethyl-2-pyridinyl)benzamides.

N-(4,6-Dimethyl-2-pyridinyl)benzamides 1-24 and the corresponding tertiary derivatives 29-33 were synthesized and studied for possible dopamine-inhibitory properties by testing their effect on motility of naive and reserpinized mice. Unlike the orthopramides, they failed to show any antidopaminergic properties, but some of the secondary derivatives showed instead effects of postsynaptic dopaminergic agonism. The latter compounds were subsequently studied for their effects on apomorphine reversal of reserpine-induced akinesia and on cerebral HVA levels in rats. Contraversive circling induced by compound 11 in 6-hydroxydopamine-lesioned mice suggests that a direct mechanism was involved.

Cosmetic results following lumpectomy, axillary dissection and radiotherapy for small breast cancers.

Between 1970 and April 1982, 592 women with T(1), small T2, N0, N1, M0 breast cancer were managed by lumpectomy, axillary dissection and radiotherapy at the Institut Gustave-Roussy (IGR). The overall cosmetic result and the degree of asymmetry, fibrosis and telangiectasia of the treated breast were assessed by the radiation oncologist at each follow-up visit. The changes in these cosmetic parameters with time are shown. At 5 years the overall cosmetic result was excellent in 59%, good in 38% and fair or poor in 8%. A multivariate analysis was performed of the factors associated with a cosmetic defect. The most significant factors were tumour size, the presence of defect after surgery and the daily applied dose per fraction to the breast. Surgical and radiotherapy technique (especially alternate day fractionation) can significantly affect the cosmetic result obtained.

Antiinflammatory mechanism of cordiachromene A action.

The mechanism of antiinflammatory action of cordiachromene A, isolated from the chloromethylenic extract of the ascidian Aplidium antillense or chemically synthesized, was studied using different in vivo and in vitro inhibition tests on enzymes of the cyclooxygenase cascade. Cordiachromene A inhibits prostacyclin synthesis and arachidonic acid metabolism but not phospholipase A2 and peroxidase. The mechanism of action, already known to be stereospecific, operates by cyclooxygenase inhibition.

Marine bioactive compounds: stereospecific anti-inflammatory activity of natural and synthetic cordiachromene A.

A new synthesis is proposed for cordiachromene A (CCA), a bioactive component of the ascidian Aplidium antillense Gravier, using a method producing a racemic mixture. The anti-inflammatory activities of a natural extract and a chemically synthetic form of CCA were assessed in vivo by carrageenan-induced rat-paw edema. The activity of synthetic CCA was confirmed by a test on kaolin-induced granuloma in the rat. Strong activities were measured for both CCA, but comparison of results of the first test suggests that only the natural optically active isomer has an anti-inflammatory effect. CCA is similar to indomethacin in its effect on carrageenan-induced rat-paw edema and ten times as active as phenylbutazone.

Effects of tumour necrosis factor-alpha synthesis inhibitors on rat trinitrobenzene sulphonic acid-induced chronic colitis.

The fact that tumour necrosis factor-alpha (TNF-alpha) is clearly involved in the pathogenesis of intestinal bowel disease, especially Crohn's disease, suggests that TNF-alpha synthesis inhibitors could be beneficial for treatment. The present study assessed the effect of chronic oral gavage of two in vitro TNF-alpha synthesis inhibitors, JM 34 maleate or [N-(4,6-dimethylpyridin-2-yl)-furane-2-carboxamide)] maleate and XC 21 or (N-betapicolyl-tetrafluorophtalimide), on colonic inflammation in trinitrobenzene sulphonic acid-induced colitis in rats. Rats received JM 34 maleate (100 mg/kg) and XC 21 (50 mg/kg) 1 h before colitis induction and then daily for 8 days by oral gavage. The colon was removed on day 8 and processed for clinical score, myeloperoxidase activity, and soluble TNF-alpha release. Treatment with XC 21, as well as dexamethasone and sulphasalazine, reduced colonic damage and decreased (except with dexamethasone) the incidence of diarrhoea. JM 34 maleate failed to improve the clinical signs of chronic colitis. After trinitrobenzene sulphonic acid-induced colitis, myeloperoxidase activity and TNF-alpha colonic mucosal production were substantially increased compared to the control (saline instillation). Both of these inflammatory indicators were then significantly decreased (P< or =0.05) after the four chronic treatments (JM 34 maleate, XC 21, sulphasalazine, and dexamethasone). XC 21 appeared to be as efficient as sulphasalazine in improving colonic inflammation.