Development of a patient decision aid for patients with breast cancer who consider immediate breast reconstruction after mastectomy.

PURPOSE: The aim of this study was to develop a patient decision aid (pDA) that could support patients with breast cancer (BC) in making an informed decision about breast reconstruction (BR) after mastectomy. METHODS: The development included four stages: (i) Establishment of a multidisciplinary team; (ii) Needs assessment consisting of semi-structured interviews in patients and a survey among healthcare professionals (HCPs); (iii) Creation of content, design and technical system; and (iv) Acceptability and usability testing using a think-aloud approach in patients and interviews among HCPs and representatives of the Dutch Breast Cancer Patient Organization. RESULTS: From the needs assessment, three themes were identified: Challenging period to make a decision, Diverse motivations for a personal decision and Information needed to make a decision about BR. HCPs valued the development of a pDA, especially to prepare patients for consultation. The pDA that was developed contained three parts: first, a consultation sheet for oncological breast surgeons to introduce the choice; second, an online tool including an overview of reconstructive options, the pros and cons of each option, information on the consequences of each option for daily life, exercises to clarify personal values and patient stories; and third, a summary sheet with patients' values, preferences and questions to help inform and guide the discussion between the patient and her plastic surgeon. The pDA was perceived to be informative, helpful and easy to use by patients and HCPs. CONCLUSION: Consistent with information needs, a pDA was developed to support patients with BC who consider immediate BR in making an informed decision together with their plastic surgeon. PATIENT OR PUBLIC CONTRIBUTION: Patients participated in the needs assessment and in acceptability and usability testing.

Surgical Complications of Skin-Sparing Mastectomy and Immediate Implant-Based Breast Reconstruction in Women Concurrently Treated With Adjuvant Chemotherapy for Breast Cancer.

BACKGROUND AND AIM: To date, studies on adjuvant chemotherapy as a risk factor for the surgical outcome of combined mastectomy and breast reconstruction were hampered by the inclusion of mixed reconstructive cohorts of both delayed and immediate timing and of both autologous and implant-based techniques. Consequently, there is a paucity of data on the impact of adjuvant chemotherapy on surgical complication rates after combined skin-sparing mastectomy and immediate implant-based breast reconstruction. METHODOLOGY: We compared the postoperative complications that occurred within 16 weeks after this combined procedure in 131 women (139 breasts) treated with adjuvant chemotherapy with those in a control group of 491 women (517 breasts) not receiving any adjuvant therapy within 16 weeks. RESULTS: In line with the clinically indicated selection of women to undergo adjuvant chemotherapy, the interventional group differed significantly from the control group in 7 of the 12 patient- and procedure-related characteristics. The prevalence of minor complications (13.7% and 12.4%, respectively, P = 0.68) and major complications (31.7% and 29.4%, respectively, P = 0.60) did not differ significantly between the interventional group and the controls. The fraction of breasts that needed unscheduled surgery (0.29 and 0.24, respectively, P = 0.20), the fraction of total number of interventions (0.34 and 0.33, respectively, P = 0.24), and the fraction of implants lost (0.72 and 0.67, respectively, P = 0.86) did not differ significantly between both groups. The onset of chemotherapy, furthermore, seemed not to influence the occurrence or severity of complications. CONCLUSIONS: Like other women who have to undergo mastectomy, women who need to undergo adjuvant chemotherapy can potentially benefit from combined skin-sparing mastectomy and immediate implant-based breast reconstruction.

The impact of an online patient decision aid for women with breast cancer considering immediate breast reconstruction: study protocol of a multicenter randomized controlled trial.

BACKGROUND: Most breast cancer patients undergoing mastectomy are candidates for breast reconstruction. Deciding about breast reconstruction is complex and the preference-sensitive nature of this decision requires an approach of shared decision making between patient and doctor. Women considering breast reconstruction have expressed a need for decision support. We developed an online patient decision aid (pDA) to support decision making in women considering immediate breast reconstruction. The primary aim of this study is to assess the impact of the pDA in reducing decisional conflict, and more generally, on the decision-making process and the decision quality. Additionally, we will investigate the pDA's impact on health outcomes, explore predictors, and assess its cost-effectiveness. METHODS: A multicenter, two-armed randomized controlled trial (1:1) will be conducted. Women with breast cancer or ductal carcinoma in situ who will undergo a mastectomy and are eligible for immediate breast reconstruction will be invited to participate. The intervention group will receive access to the online pDA, whereas the control group will receive a widely available free information leaflet on breast reconstruction. Participants will complete online questionnaires at: baseline (T0), 1 week after consultation with a plastic surgeon (T1), and 3 (T2) and 12 months (T3) after surgery. The primary outcome is decisional conflict. Secondary outcomes include other measures reflecting the decision-making process and decision quality (e.g., decision regret), patient-reported health outcomes (e.g., satisfaction with the breasts) and costs. DISCUSSION: This study will provide evidence about the impact of an online pDA for women who will undergo mastectomy and are deciding about breast reconstruction. It will contribute to the knowledge on how to optimally support women in making this difficult decision. TRIAL REGISTRATION: This study is retrospectively registered at ClinicalTrials.gov ( NCT03791138 ).

F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries and veins.

OBJECTIVE: Vascular endothelial-cadherin- and integrin-based cell adhesions are crucial for endothelial barrier function. Formation and disassembly of these adhesions controls endothelial remodeling during vascular repair, angiogenesis, and inflammation. In vitro studies indicate that vascular cytokines control adhesion through regulation of the actin cytoskeleton, but it remains unknown whether such regulation occurs in human vessels. We aimed to investigate regulation of the actin cytoskeleton and cell adhesions within the endothelium of human arteries and veins. APPROACH AND RESULTS: We used an ex vivo protocol for immunofluorescence in human vessels, allowing detailed en face microscopy of endothelial monolayers. We compared arteries and veins of the umbilical cord and mesenteric, epigastric, and breast tissues and find that the presence of central F-actin fibers distinguishes the endothelial phenotype of adult arteries from veins. F-actin in endothelium of adult veins as well as in umbilical vasculature predominantly localizes cortically at the cell boundaries. By contrast, prominent endothelial F-actin fibers in adult arteries anchor mostly to focal adhesions containing integrin-binding proteins paxillin and focal adhesion kinase and follow the orientation of the extracellular matrix protein fibronectin. Other arterial F-actin fibers end in vascular endothelial-cadherin-based endothelial focal adherens junctions. In vitro adhesion experiments on compliant substrates demonstrate that formation of focal adhesions is strongly induced by extracellular matrix rigidity, irrespective of arterial or venous origin of endothelial cells. CONCLUSIONS: Our data show that F-actin-anchored focal adhesions distinguish endothelial phenotypes of human arteries from veins. We conclude that the biomechanical properties of the vascular extracellular matrix determine this endothelial characteristic.

Impact of combined skin sparing mastectomy and immediate subpectoral prosthetic reconstruction on the pectoralis major muscle function: a preoperative and postoperative comparative study.

BACKGROUND: We assessed the subjective and objective functional loss induced by detachment of the pectoralis major muscle and whether synergistic function of adjacent muscles compensates for such loss. METHODS: A preoperative to postoperative comparison of the Disability of the Arm, Shoulder and Hand score, 3-dimensional video-analysis of the range of motion, and dynamometric force assessment with electromyography registration were prospectively conducted in 22 women who underwent bilateral preventive breast surgery. RESULTS: Although the statistically significant postoperative increase of the Disability of the Arm, Shoulder and Hand score (P = < 0.01) was indicative of more subjective disability, this difference is irrelevant for activities of daily life. This is in line with the observed postoperative lack of restrictions of range of motion of the shoulder. The mean postoperative maximum force measured in 4 directions reflective of the pectoralis major muscle function was 7.13 N, or 3.8%, lower than the preoperative force (P = 0.079). The mean postoperative maximum force in the 2 contramovement directions was 15.5 N, or 14%, higher than the preoperative force (P = 0.04). Electromyographically, both parts of the deltoid muscle preoperatively and postoperatively showed the same peaks in the 6 directions. Contrastingly, the clavicular part of the pectoralis major muscle postoperatively showed a statistically significant increase of peak of muscle activity in 3 of 4 directions reflective of pectoralis major function and in both contramovement directions, indicating compensatory activity. CONCLUSIONS: Daily life consequences of partial detachment of the pectoralis major muscle were acceptable in our patients.

Oncological status is not a determinant of refraining from breast reconstruction among 490 candidates for mastectomy and post-mastectomy radiotherapy.

BACKGROUND: Although breast reconstruction in the setting of post-mastectomy radiotherapy (PMRT) is controversial, we offer nipple-sparing mastectomy and immediate implant-based breast reconstruction ([N]SSM/IIBR) to women needing primary mastectomy regardless of PMRT. Nevertheless, some of these women have no reconstruction. PURPOSE: To assess the uptake of breast reconstruction in women who undergo PMRT and the patient characteristics associated with such uptake. Additionally, we assessed the determinants of forgoing breast reconstruction. METHODOLOGY: Demographic, physical and oncological characteristics of women who underwent mastectomy, PMRT and breast reconstruction were compared to the characteristics of those who did not undergo breast reconstruction from 2013 through 2018. As determinants of delaying or refraining from breast reconstruction, we distinguished between an oncological reason, patient's preference, patient's co-morbidity, combined tobacco abuse and obesity and the need for PMRT. RESULTS: 490 women received PMRT. Of these, 396 women (81%) underwent combined [N]SSM/IIBR and PMRT or mastectomy and PMRT with delayed breast reconstruction. Ninety-four additional women (19%) did not undergo breast reconstruction. The latter group differed significantly from those who did in demographic and physical characteristics but not in terms of oncological diagnosis and history. Patient's preference was the single most frequent determinant of not performing either immediate or delayed breast reconstruction among these 94 women. Oncological status was not a major determinant in refraining from reconstruction. CONCLUSION: The significant difference in non-oncological characteristics between the reconstructed and non-reconstructed women confirms the importance of these characteristics in the preference for either reconstruction or non-reconstruction.

Surgical outcomes following breast reconstruction in patients with and without a history of chest radiotherapy for Hodgkin lymphoma: a multicentre, matched cohort study.

BACKGROUND: Breast cancer is the most common treatment-related second malignancy among women with previous chest radiotherapy for Hodgkin lymphoma (HL). Little is known about the effects of this kind of radiotherapy on the outcomes of postmastectomy breast reconstruction (BR). This study compared adverse outcomes of BR after HL-related chest radiotherapy to matched controls. METHODS: The authors conducted a retrospective, matched cohort study in two expert cancer centres in the Netherlands. BRs after therapeutic or prophylactic mastectomy in HL survivors who received chest radiotherapy were matched with BRs in nonirradiated patients without HL on age at mastectomy date, date of BR, and type of BR. The primary outcome was complication-related BR failure or conversion and secondary outcomes were complication-related re-operation, capsular contracture, major donor-site complications, and complication-related ICU admission. The authors analyzed all outcomes univariably using Fisher's exact tests and the authors assessed reconstruction failure, complication-related re-operation, and capsular contracture with multivariable Cox regression analysis adjusting for confounding and data clustering. RESULTS: Seventy BRs in 41 patients who received chest radiotherapy for HL were matched to 121 BRs in 110 nonirradiated patients. Reconstruction failure did not differ between HL survivors (12.9%) and controls (12.4%). The comparison groups showed no differences in number of reoperations, major donor-site complications, or capsular contractures. BR in HL survivors more often let to ICU admission due to complications compared with controls ( P =0.048). CONCLUSIONS: We observed no increased risk of adverse outcomes following BR after previous chest radiotherapy for HL. This is important information for counselling these patients and may improve shared decision-making.

Efficacy of a decision aid in breast cancer patients considering immediate reconstruction: results of a randomized controlled trial.

PURPOSE: Breast cancer patients face complex decisions about immediate breast reconstruction (BR) after mastectomy. We evaluated the efficacy of an online decision aid in improving the decision-making process, decision quality and health outcomes in breast cancer patients considering immediate BR. METHODS: In a multicenter randomized controlled trial, patients were allocated to either the intervention group receiving care-as-usual (CAU) with access to an online decision aid, or the control group receiving CAU with an information leaflet. The primary outcome was decisional conflict. Secondary outcomes assessed the process of decision making (e.g. preparation for decision making, satisfaction with information), decision quality (decision regret, knowledge) and health outcomes (e.g. satisfaction with BR outcomes, body image). Patients completed questionnaires at baseline (T0), 1 week after consultation with a plastic surgeon (T1), 3 months (T2), and 12 months post-surgery (T3). RESULTS: We included 250 patients. Decisional conflict decreased over time in both groups, with no between group differences. Intervention participants felt better prepared for decision making than controls (P = .002). At T2, 87% of intervention participants were (very) satisfied with the information about BR, compared to 73% of control participants (P = .011). No significant between group differences were observed in any other outcome. CONCLUSION: Our online decision aid was as effective in reducing decisional conflict as an information leaflet about immediate BR after mastectomy. However, the decision aid substantially improved the decision-making process by better preparing breast cancer patients for decisions about immediate BR.

Combined skin-sparing mastectomy and immediate implant-based breast reconstruction: Outcome following mantle field irradiation versus outcome following whole-breast irradiation.

BACKGROUND: Mastectomy may be needed in the context of previous radiotherapy in cases of breast carcinoma following mantle field radiotherapy for Hodgkin lymphoma or in cases of local relapse or second primary tumours after breast conserving therapy including whole-breast irradiation (BCT). The outcome of combined skin-sparing mastectomy and immediate implant-based breast reconstruction (SSM-IIBR) has been reported to be unfavourable in these cases. PURPOSE: To compare the outcome of SSM-IIBR after mantle field radiotherapy to that after BCT and to compare both to the outcome observed in non-irradiated breasts. METHODOLOGY: The prevalences of short-term events, device loss, long-term corrections and secondary reconstructions, and reversion to autologous tissue techniques of 42 SSM-IIBRs performed after mantle field irradiation were compared to those of 47 salvage SSM-IIBRs following BCT. Both outcomes were compared to the outcome in the contralateral, non-irradiated breast of the subgroup of 23 women in the BCT group. RESULTS: The groups were comparable in terms of patient- and procedure-related risk factors, except for time lapse after previous therapy, intraoperative device weight, and the fraction of immediate use of a definitive implant. The outcome of SSM-IIBR after mantle field irradiation significantly differs favourably from that after BCT. It matches the outcome observed in non-irradiated breasts. CONCLUSION: Skin-sparing mastectomy combined with immediate implant-based breast reconstruction is a fully justifiable option for women who previously underwent mantle field irradiation for Hodgkin lymphoma. We feel that the unfavourable outcome observed in women who previously underwent BCT necessitates an alternative reconstructive modality.

Short-Term Surgical Complications of Skin-Sparing Mastectomy and Direct-to-Implant Immediate Breast Reconstruction in Women Concurrently Treated with Adjuvant Radiotherapy for Breast Cancer.

Background Postmastectomy radiotherapy (PMRT) is allegedly associated with a higher risk of complications of combined nipple-sparing or skin-sparing mastectomy and subpectoral direct-to-implant immediate breast reconstruction ([N]SSM/SDTI-IBR). For this reason, this combination is usually advised against or, even, refused in women who need to undergo PMRT. Because this advice has never been justified, we assessed the short-term complications that may potentially be associated with PMRT after [N]SSM/SDTI-IBR. Methods We compared the complications requiring reintervention and implant loss occurring after 273 [N]SSM/SDTI-IBR that were exposed to PMRT within the first 16 postoperative weeks (interventional group) to those occurring in 739 similarly operated breasts that were not (control group). Additionally, we compared the fraction of complications requiring reintervention occurring after the onset of radiotherapy in the interventional group to that occurring after a comparable postoperative period in the control group. Results The fraction of breasts requiring unscheduled surgical reinterventions for complications and the loss of implants did not differ significantly between both groups but significantly more reinterventions were needed among the controls ( p = 0.00). The fraction of events after the onset of radiotherapy in the interventional group was higher than the fraction of events after 6.2 weeks in the control group, but not significantly so. Conclusion We found no prove for the alleged increase of short-term complications of adjuvant radiotherapy. Therefore, we advise that these should not be considered valid arguments to advice against [N]SSM/SDTI-IBR.

Decisional conflict in breast cancer patients considering immediate breast reconstruction.

BACKGROUND: Breast cancer (BC) patients who are treated with mastectomy are frequently offered immediate breast reconstruction. This study aimed to assess decisional conflict in patients considering immediate breast reconstruction, and to identify factors associated with clinically significant decisional conflict (CSDC). METHODS: Baseline data of a multicenter randomized controlled trial evaluating the impact of an online decision aid for BC patients considering immediate breast reconstruction after mastectomy were analyzed. Participants completed questionnaires assessing sociodemographic and clinical characteristics, decisional conflict and other patient-reported outcomes related to decision-making such as breast reconstruction preference, knowledge, information resources used, preferred involvement in decision-making, information coping style, and anxiety. Multivariable logistic regression analysis was performed to identify factors associated with CSDC (score > 37.5 on decisional conflict). RESULTS: Of the 250 participants, 68% experienced CSDC. Patients with a slight preference for breast reconstruction (odds ratio (OR) = 6.19, p < .01), with no preference for or against breast reconstruction (OR = 11.84, p < .01), and with a strong preference for no breast reconstruction (OR = 5.20, p < .05) were more likely to experience CSDC than patients with a strong preference for breast reconstruction. Furthermore, patients with more anxiety were more likely to experience CSDC (OR = 1.03, p = .01). CONCLUSION: A majority of BC patients who consider immediate breast reconstruction after mastectomy experience clinically significant decisional conflict. The findings emphasize the need for decision support, especially for patients who do not have a strong preference for breast reconstruction.

The design of the lateral thoracodorsal flap.

Although some of the aspects of the preoperative markings of the lateral thoracodorsal flap have been mentioned by its originators and subsequent authors, we get ongoing inquiries regarding the details of the design of the flap. These markings are made respecting the level of the contralateral nipple, with the convex inferior border of the flap extending up to the anterior axillary line, and with the straight superior border extending more medially over this line. We have used 200 lateral thoracodorsal flaps in 180 patients with no cases of more than marginal flap loss provided that the length of the flap was limited to a maximum of 17 cm. We found that this flap fills a therapeutic gap and provides a sound alternative to more extensive surgery.

Blood and lymphatic microvessel damage in irradiated human skin: The role of TGF-ß, endoglin and macrophages.

BACKGROUND AND PURPOSE: Microvascular damage is an important component of late radiation-induced morbidity. In our pre-clinical models, we demonstrated that repair of vessel injury is dependent on proper endoglin-mediated transforming growth factor-beta (TGF-ß) signalling and that it can be affected by infiltrating macrophages. We now wanted to extend these findings in irradiated patients, using skin as a model system, and assess whether bisphosphonates could modulate the response. MATERIALS AND METHODS: Paired skin biopsies from irradiated and non-irradiated sites were obtained from 48 breast cancer patients. In 8 patients, biopsies were repeated after 4months of bisphosphonate treatment. Immunohistochemistry was used to assess vascular alterations and leucocyte infiltration. Western Blot and qPCR were used to assess expression of growth factors and their receptors. RESULTS: Decreased blood vessel numbers at early time points were followed by increased endoglin expression and restoration of vessel number. Loss of small lymphatic vessels was associated with increased TGF-ß levels, whereas dilation of lymphatic vessels correlated with increased macrophage infiltration. Bisphosphonate treatment reduced leucocyte infiltration, but also prevented restoration of blood vessel numbers after irradiation. CONCLUSION: Radiation injury of the microvasculature is mediated through TGF-ß, whereas repair is modulated by the co-receptor endoglin and promoted by macrophages.

Verifying surgical results and risk factors of the lateral thoracodorsal flap.

In 1986, the combined use of the lateral thoracodorsal flap and an implant was introduced as an alternative method of delayed reconstruction of small to medium-size breasts for postmastectomy patients who are reluctant or unable to consider reconstruction by tissue expansion or by more extensive autologous tissue transplantation. So far, the technique has only been proven reproducible in Sweden. Postmastectomy radiotherapy has been proven to increase the risk of wound-healing complications after lateral thoracodorsal transplantation, and additional risk factors such as advanced age, obesity, smoking, and some general health characteristics have been indicated. The authors initiated a prospective study to assess the reproducibility of this technique outside Sweden and to confirm the proven risk factor, prove or refute the alleged ones, and possibly identify additional factors. Additionally, they applied the technique for immediate breast reconstruction and tried to expand the indications and applications of the lateral thoracodorsal flap even further. The authors report on their initial experience with 60 lateral thoracodorsal flaps and conclude that the use of this flap is a well-reproducible technique for breast reconstruction, with few complications leading to failure. Using the lateral thoracodorsal flap in combination with tissue expanders allows for reconstruction of breasts of larger than medium size. Moreover, the authors successfully applied fully deepithelialized lateral thoracodorsal flaps for additional indications. The statistical significance of postmastectomy radiotherapy as a risk factor could not be confirmed, but some general health characteristics were found to be significant patient-related risk factors. Out of five procedure-related characteristics, only increased flap length was proven to negatively influence the outcome of the procedure.

Breast-conserving therapy in patients with a relatively large (T2 or T3) breast cancer: long-term local control and cosmetic outcome of a feasibility study.

Breast-conserving therapy is widely accepted as an appropriate method of primary treatment of T1 and T2 breast cancers that measure up to 5 cm. For safe and cosmetically acceptable breast-conserving therapy in patients with larger breast cancers, the tumor volume has to be reduced preoperatively, and lost tissue volume should be replaced after wide local excision. In 1993, the authors' group reported encouraging short-term results of a combination of preoperative radiotherapy, breast-conserving surgery, and immediate tissue replacement by myocutaneous (myosubcutaneous) latissimus dorsi flap transplantation in patients with relatively large T2 and T3 breast cancers. To evaluate the long-term oncologic local control and cosmetic outcome of this treatment modality, the authors studied the results obtained in 20 patients after a minimum follow-up of 5 years. The local control rate was 0.95, as locoregional recurrence was observed in one patient who refused adjuvant chemotherapy. Both the observed 5-year survival (0.75) and the actuarial 10-year survival (0.60) in the authors' series equaled that of more radical surgical therapy. The cosmetic outcome compared with that obtained by conventional breast-conserving therapy modalities for small breast cancers. In general, patient assessment of cosmetic outcome (2.8 of 3) was higher than the assessment of a professional panel (6.3 of 10). Of six criteria providing a detailed description of the cosmesis of the reconstructed breast and donor area, the symmetry and shape of the reconstructed breast were felt to be most important by the patients and professionals alike. The authors conclude that breast-conserving therapy combining preoperative irradiation and immediate myocutaneous (myosubcutaneous) latissimus dorsi flap reconstruction is an oncologically safe and cosmetically rewarding but logistically straining modality of treatment of relatively large T2 and T3 breast cancers.

[Local recurrence after skin-sparing mastectomy]. / Lokaal recidief na huidsparende ablatio mammae.

On average, 250 skin-sparing mastectomies with immediate prosthetic reconstruction are performed in the Dutch Antoni van Leeuwenhoek Hospital each year. We report on two breast cancer patients (46 and 53 years old) who each developed a local recurrence at the entry site of the core needle biopsy after skin-sparing mastectomy with immediate prosthetic reconstruction. In hindsight, the most likely cause for these recurrences was the fact that one of the entry sites for the core needle biopsies was not marked preoperatively, and thus not excised during surgery. These examples emphasise the need for accurate documentation of the locations of these entry sites, followed by their excision, in patients undergoing skin-sparing mastectomy for invasive breast cancer.

Temporary banking of the nipple-areola complex in 97 skin-sparing mastectomies.

BACKGROUND: Despite the improved appearance associated with skin-sparing mastectomy, removal of the nipple-areola complex has a negative impact on the patient. Still, nipple-areola complex-sparing mastectomy results in preservation of a substantial amount of mammary tissue at risk. This may be prevented by preservation of the nipple-areola complex as a graft that is temporarily banked (e.g., in the groin region). METHODS: Ninety-seven nipple-areola complexes were banked as part of preventive (n = 62) or therapeutic (n = 35) skin-sparing mastectomies in 61 women with a median age of 41 years (range, 27 to 59 years) and a minimum follow-up of 2 years. The areola was harvested as a full-thickness skin graft with the nipple attached as a composite graft. In oncologic cases, the nipple-areola complexes were banked only after frozen section clearance. RESULTS: Seventy-five nipple-areola complexes were replanted onto the reconstructed mammary mound after 10 months (range, 3 to 26 months). Repeated graft take was moderate to good in 73 of these 75 nipple-areola complexes. The projection of the nipple and pigmentation of the areola were moderate to good in 45 and 74 of the 75 repeatedly transplanted grafts, respectively. CONCLUSIONS: In skin-sparing mastectomy, maximum oncologically safe conservation of autologous mammary structures can be realized by means of temporary banking of the nipple-areola complex. Even though such banking may not be successful in all women, it proved to be satisfactory in most.

Optimization of intradermal vaccination by DNA tattooing in human skin.

The intradermal administration of DNA vaccines by tattooing is a promising delivery technique for genetic immunization, with proven high immunogenicity in mice and in nonhuman primates. However, the parameters that result in optimal expression of DNA vaccines that are applied by this strategy to human skin are currently unknown. To address this issue we set up an ex vivo human skin model in which DNA vaccine-induced expression of reporter proteins could be monitored longitudinally. Using this model we demonstrate the following: First, the vast majority of cells that express DNA vaccine-encoded antigen in human skin are formed by epidermal keratinocytes, with only a small fraction (about 1%) of antigen-positive epidermal Langerhans cells. Second, using full randomization of DNA tattoo variables we show that an increase in DNA concentration,needle depth, and tattoo time all significantly increase antigen expression ( p < 0.001), with DNA concentration forming the most critical variable influencing the level of antigen expression. Finally, in spite of the marked immunogenicity of this vaccination method in animal models, transfection efficiency of the technique is shown to be extremely low, estimated at approximately 2 to 2000 out of 1 x 10(10) copies of plasmid applied. This finding, coupled with the observed dependency of antigen expression on DNA concentration, suggests that the development of strategies that can enhance in vivo transfection efficacy would be highly valuable. Collectively, this study shows that an ex vivo human skin model can be used to determine the factors that control vaccine-induced antigen expression and define the optimal parameters for the evaluation of DNA tattoo or other dermal delivery techniques in phase 1 clinical trials.

Novel insights into pathological changes in muscular arteries of radiotherapy patients.

BACKGROUND AND PURPOSE: Vascular disease is increased after radiotherapy and is an important determinant of late treatment-induced morbidity and excess mortality. This study evaluates the nature of underlying pathologic changes occurring in medium-sized muscular arteries following irradiation. MATERIALS AND METHODS: Biopsies of irradiated medium-sized arteries and unirradiated control arteries were taken from 147 patients undergoing reconstructive surgery with a vascularised free flap following treatment for head and neck (H&N) or breast cancer (BC). Relative intimal thickening was derived from the ratio of the thickness of the intima to the thickness of the media (IMR) on histological sections. Proteoglycan, collagen and inflammatory cell content were also scored. RESULTS: Intimal thickness was significantly increased in irradiated vessels: in the H&N group the IMR was 1.5-fold greater without correction for the control artery (p=0.018); in the BC group the IMR increased 1.4-fold after correction for the control artery (p=0.056) at a mean of 4 years following irradiation. There was an increase in the proteoglycan content of the intima of the irradiated IMA vessels, from 65% to 73% (p=0.024). Inflammatory cell content was increased in the intima of the irradiated H&N vessels (p=0.014). CONCLUSIONS: Radiation-induced vascular pathology differs quantitatively and qualitatively from age-related atherosclerosis.