The role and the composition of a liaison team to facilitate the transition of adolescents and young adults: an umbrella review.

Adolescents and young adults (AYAs) benefit from healthcare transition (HCT) programs. Despite the well-established literature reviewing HCT, a considerable heterogeneity exists on the involved healthcare professionals. This review aims to explore systematic reviews on the practices and recommendations on which disciplines of professionals should be involved in HCT. An umbrella review was performed using the MEDLINE, EMBASE, and Web of Science databases. To be eligible, systematic reviews had to report on the composition and/or the rationale of members of a transition team. Seventeen reviews were included in this systematic review. A healthcare professional that coordinates HCT was identified as a key caregiver in all reviews. Other reported members of a HCT team were nurses (75% of the reviews), social workers (44%), and peers/mentors (35%). The reported key responsibilities of a HCT team were to (i) manage communication, (ii) ensure continuity of care, and (iii) maintain contact with community services.  Conclusions: A team responsible for HCT should be active on the organizational, medical, and social levels. Key members of a HCT team vary little between diseases and included a coordinator, social worker, and nurse. A coordinating physician could facilitate transition in complex conditions. At all times, the condition and needs of the AYA should determine who should be involved as caregiver. What is Known: • The psychosocial needs of adolescents and young adults during healthcare transition are largely similar between chronic diseases. What is New: • Coordinators, nurses and social workers were the most involved, independent of the condition. • A liaison team should be active on organizational-, medical- and social-levels.

Effect of early and systematic integration of palliative care in patients with advanced cancer: a randomised controlled trial.

BACKGROUND: The benefit of early integration of palliative care into oncological care is suggested to be due to increased psychosocial support. In Belgium, psychosocial care is part of standard oncological care. The aim of this randomised controlled trial is to examine whether early and systematic integration of palliative care alongside standard psychosocial oncological care provides added benefit compared with usual care. METHODS: In this randomised controlled trial, eligible patients were 18 years or older, and had advanced cancer due to a solid tumour, an European Cooperative Oncology Group performance status of 0-2, an estimated life expectancy of 12 months, and were within the first 12 weeks of a new primary tumour or had a diagnosis of progression. Patients were randomly assigned (1:1), by block design using a computer-generated sequence, either to early and systematic integration of palliative care into oncological care, or standard oncological care alone in a setting where all patients are offered multidisciplinary oncology care by medical specialists, psychologists, social workers, dieticians, and specialist nurses. The primary endpoint was change in global health status/quality of life scale assessed by the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 items (EORTC QLQ C30) at 12 weeks. The McGill Quality of Life Questionnaire (MQOL), which includes the additional existential wellbeing dimension, was also used. Analysis was by intention to treat. This trial is ongoing, but closed for accrual, and is registered with ClinicalTrials.gov, number NCT01865396. FINDINGS: From April 29, 2013, to Feb 29, 2016, we screened 468 patients for eligibility, of whom 186 were enrolled and randomly assigned to the early and systematic palliative care group (92 patients) or the standard oncological care group (94). Compliance at 12 weeks was 71% (65 patients) in the intervention group versus 72% (68) in the control group. The overall quality of life score at 12 weeks, by the EORTC QLQ C30, was 54·39 (95% CI 49·23-59·56) in the standard oncological care group versus 61·98 (57·02-66·95) in the early and systematic palliative care group (difference 7·60 [95% CI 0·59-14·60]; p=0·03); and by the MQOL Single Item Scale, 5·94 (95% CI 5·50-6·39) in the standard oncological care group versus 7·05 (6·59-7·50) in the early and systematic palliative care group (difference 1·11 [95% CI 0·49-1·73]; p=0.0006). INTERPRETATION: The findings of this study show that a model of early and systematic integration of palliative care in oncological care increases the quality of life of patients with advanced cancer. Our findings also show that early and systematic integration of palliative care is more beneficial for patients with advanced cancer than palliative care consultations offered on demand, even when psychosocial support has already been offered. Through integration of care, oncologists and specialised palliative care teams should work together to enhance the quality of life of patients with advanced cancer. FUNDING: Research Foundation Flanders, Flemish Cancer Society (Kom Op Tegen Kanker).

Stable metabolic disease on FDG-PET provides information on response to endocrine therapy for breast cancer.

BACKGROUND: The aim of this study was to assess whether outcome in advanced breast cancer patients is related to metabolic response to endocrine therapy determined by fluorodeoxyglucose positron-emission tomography (FDG-PET). METHODS: We retrospectively identified 21 consecutive breast cancer patients receiving endocrine therapy for metastatic disease (mean number of previous therapies 3.6±3.5). All patients had been evaluated with at least 2 FDG-PETs. The first scan was performed by initiation of endocrine therapy. The second scan was performed after a mean of 3.8±1.14 months. Seventy-two FDG-avid lesions were identified and followed. The mean change in SUVmax (ΔSUVmax) was calculated per patient. RESULTS: ΔSUVmax dichotomized using the group median as cut-off (8.6%) was predictive of progression-free survival (PFS). The median PFS for the response-group (N.=10, median ΔSUVmax -20.9%) was 10.1 months. The median PFS for the progressive disease-group (N.=11, median ΔSUVmax 40.6%) was 6.7 months (log-rank testing P=0.033). CONCLUSIONS: Our data suggest that breast cancer patients under hormonal therapy with stable disease on FDG-PET have a longer PFS when compared to non-responders. This finding is new, supporting the value of endocrine therapy among patients with advanced breast cancer.

Resection of single metachronous liver metastases from breast cancer stage I-II yield excellent overall and disease-free survival. Single center experience and review of the literature.

PURPOSE: Improved survival after liver resection for breast cancer liver metastases (BCLM) has been proven; however, there is still controversy on predictive factors influencing outcomes. The analysis of factors related to primary and metastatic cancer eventually influencing long-term outcomes and a review of the literature are presented in this report. METHODS: Twenty-seven patients diagnosed with metachronous BCLM between 1996 and 2013 were retrospectively reviewed. Patients who had a minimum disease-free interval between primary tumor and liver metastasis of 12 months, no more than 3 liver lesions, no macroscopic extra-hepatic disease and in which systemic therapy showed a good response were included. RESULTS: Twenty-two patients (82%) were initially diagnosed with a stage I-II disease. Twelve patients presented with multiple liver metastases. The 5 years overall survival (OS) rate was 78%, while the 5 years disease-free survival (DFS) rate was 36%. Initial tumor stage III-IV at first diagnosis and number of metastases >1 was significantly associated with a shorter DFS at multivariate analysis (p = 0.03 and p = 0.04 respectively). Patients with multiple lesions had a median DFS of 15 months compared to 47 months in patients with a single lesion (p = 0.03). CONCLUSIONS: Resection of single BCLM from primary stage I-II cancer offers very good long-term survival rates and a low morbidity.

Two schedules of etirinotecan pegol (NKTR-102) in patients with previously treated metastatic breast cancer: a randomised phase 2 study.

BACKGROUND: New therapeutic options are needed for patients with heavily pretreated breast cancer. Etirinotecan pegol is a long-acting topoisomerase-I inhibitor designed to provide prolonged tumour-cell exposure to SN38, the active metabolite. We aimed to assess the efficacy and safety of two etirinotecan pegol dosing schedules in patients with previously treated metastatic breast cancer to determine an optimum dosing schedule for phase 3 trials. METHODS: In this randomised, two-stage, open-label phase 2 trial, we recruited patients aged 18 years or older who had received taxane therapy and undergone two or fewer previous chemotherapy regimens for metastatic breast cancer, with an Eastern Cooperative Oncology Group performance status of 0 or 1, from 18 sites in three countries. Eligible patients were randomly assigned (1:1) to etirinotecan pegol 145 mg/m(2) every 14 days or every 21 days. The primary endpoint was the proportion of patients with a confirmed objective response as defined by Response Evaluation Criteria in Solid Tumors version 1.0, analysed by intention to treat. Safety was assessed in all patients who received at least one dose of study drug. FINDINGS: 70 patients (35 in each group) were randomly assigned to treatment between Feb 17, 2009 and April 13, 2010. Of the 70 patients, 20 (29%; 95% CI 18·4-40·6) achieved an objective response (two [3%] had a complete response and 18 [26%] had a partial response). Ten patients on the 14-day schedule achieved an objective response (29%; 95% CI 14·6-46·3; eight partial responses, two complete responses) as did ten on the 21-day schedule (29%; 95% CI 14·6-46·3; all partial responses). The most common grade 3 or worse adverse events were delayed diarrhoea (seven [20%] of 35 patients on the 14-day schedule vs eight [23%] of 35 patients on the 21-day schedule), fatigue (five [14%] vs three [9%]), neutropenia (four [11%] vs four [11%]), and dehydration (three [9%] vs four [11%]); 14 [20%] patients discontinued treatment because of drug-related toxicity. There were two possible drug-related deaths (acute renal failure and septic shock) in the 14-day group; other drug-related serious adverse events reported by more than one patient included ten [14%] patients with diarrhoea (six [17%] patients on the 14-day schedule vs four [11%] on the 21-day schedule), six [9%] with dehydration (two [6%] vs four [11%]), two [3%] with nausea (two [6%] vs none), and two [3%] with vomiting (two [6%] vs none). INTERPRETATION: On the basis of the overall clinical data, pharmacokinetics, and tolerability profile, etirinotecan pegol 145 mg/m(2) every 21 days has been selected for a phase 3 trial against treatment of physician's choice in patients with advanced breast cancer.

Cancer risk in immune-mediated inflammatory diseases (IMID).

Inflammation and cancer have a profound yet ambiguous relationship. Inflammation - especially chronic inflammation - has protumorigenic effects, but inflammatory cells also mediate an immune response against the tumor and immunosuppression is known to increase the risk for certain tumors.This article reviews current literature on the role of inflammation in cancer and the cancer risk in immune-mediated inflammatory diseases (IMIDs). We discuss the effect on cancer risk of different drug classes used in the treatment of IMIDs treatment, including biologicals such as tumor necrosis factor (TNF) inhibitors.Overall cancer incidence and mortality risk are similar to the general population in inflammatory bowel disease (IBD), and slightly increased for rheumatoid arthritis and psoriasis, with risk profiles differing for different tumor types. Increased risk for non-melanoma skin cancer is associated with thiopurine treatment in IBD, with the combination of anti-TNF and methotrexate in rheumatoid arthritis and with PUVA, cyclosporine and anti-TNF treatment in psoriasis. Data on the safety of using biologic or immunosuppressant therapy in IMID patients with a history of cancer are scarce.This review provides clinicians with a solid background to help them in making decisions about treatment of immune-mediated diseases in patients with a tumor history.This article is related to another review article in Molecular Cancer: http://www.molecular-cancer.com/content/12/1/86.

Vacuolar H+ ATPase expression and activity is required for Rab27B-dependent invasive growth and metastasis of breast cancer.

The secretory Rab27B small GTPase promotes invasive growth and metastasis in estrogen receptor (ER) α-positive breast cancer cells by orchestrating the peripheral targeting of vesicles secreting proinvasive growth regulators. Increased Rab27B expression is associated with poor prognosis in breast cancer patients. The molecular mechanisms of peripheral Rab27B secretory vesicle distribution are poorly understood. Mass spectrometry analysis on green fluorescent protein (GFP)-Rab27B vesicles prepared from GFP-Rab27B transfected MCF-7 human breast cancer cells detected eight subunits of the vacuolar H(+)-ATPase (V-ATPase) and the presence of V0a1 and V0d1 subunits was confirmed by Western blot analysis. Reversible inhibition of V-ATPase activity by bafilomycin A1 or transient silencing of V0a1 or V0d1 subunits demonstrated that V-ATPase controls peripheral localization and size of Rab27B vesicles. V-ATPase expression and activity further controls Rab27B-induced collagen type I invasion, cell-cycle progression and invasive growth in the chorioallantoic membrane assay. In agreement, Rab27B-dependent extracellular heat shock protein90α release and matrix metalloprotease-2 activation is markedly reduced by bafilomycin A1 and transient silencing of V0a1 and V0d1 subunits. Poor prognosis ERα-positive primary breast tumors expressing high levels of Rab27B also expressed multiple V-ATPase subunits and showed a strong cytoplasmic and peripheral V-ATPase V1E expression. In conclusion, inhibiting V-ATPase activity by interfering agents and drugs might be an effective strategy for blocking Rab27B-dependent proinvasive secretory vesicle trafficking in ERα-positive breast cancer patients.

Stromal architecture and periductal decorin are potential prognostic markers for ipsilateral locoregional recurrence in ductal carcinoma in situ of the breast.

AIMS: The incidence of ductal carcinoma in situ (DCIS) has increased since the introduction of screening mammography. Recurrence prediction is still not accurate, and could be improved by identifying additional prognostic markers. Periductal stroma actively participates in early breast cancer progression. Therefore, the aim of this study was to explore the prognostic potential of stromal characteristics in DCIS. METHODS AND RESULTS: Histopathological features and hormone receptor/HER2 status were analysed in a first cohort of 65 cases of DCIS with a median follow-up of 112 months. Cox regression analysis revealed that myxoid stromal architecture was significantly associated with increased ipsilateral locoregional recurrence (P = 0.015). Next, we performed immunohistochemical screening of nine stromal proteins in a second cohort of 82 DCIS cases, and correlated their expression with stromal architecture. Because reduced stromal decorin expression correlated most strongly with myxoid stroma (P < 0.001), it was selected for further analysis in the first cohort. Patients with reduced periductal decorin expression had a higher risk of recurrence (P = 0.008). Furthermore, HER2 overexpression was significantly associated with invasive but not with in situ recurrence (P = 0.007). CONCLUSIONS: Periductal myxoid stroma and reduced periductal decorin expression seem to be prognostic for overall ipsilateral locoregional recurrence in DCIS, whereas HER2 expression might be a more specific biomarker for invasive recurrence.

Use of tamoxifen before and during pregnancy.

For premenopausal patients with receptor-positive early breast cancer, administration of tamoxifen for 5 years constitutes the main adjuvant endocrine therapy. During pregnancy, tamoxifen and its metabolites interact with rapidly growing and developing embryonic or fetal tissues. Information about tamoxifen and pregnancy was gathered by searching PubMed. In addition, we had access to the records of the pharmaceutical company AstraZeneca. Because these observations are retrospective and other therapies and diagnostic measures are possible confounders, a causal relationship was not established between tamoxifen treatment and pregnancy outcome. The records from AstraZeneca documented three live births with congenital anomalies and four live births without congenital anomalies related to tamoxifen treatment before pregnancy. Tamoxifen therapy during pregnancy resulted in 16 live births with congenital malformations and a total of 122 live births without malformations. The 122 live births without malformations included 85 patients from a prevention trial that did not record a single anomaly, whereas the AstraZeneca Safety Database alone reported 11 babies with congenital malformations of 44 live births. Additionally, there were: 12 spontaneous abortions, 17 terminations of pregnancy without known fetal defects, six terminations of pregnancy with fetal defects, one stillbirth without fetal defects, two stillbirths with fetal defects, and 57 unknown outcomes. The relatively high frequency of severe congenital abnormalities indicates that reliable birth control during tamoxifen treatment is mandatory. After tamoxifen use, a washout period of 2 months is advisable based on the known half-life of tamoxifen. In case of an inadvertent pregnancy, risks and options should be discussed.

The use of chemotherapy regimens carrying a moderate or high risk of febrile neutropenia and the corresponding management of febrile neutropenia: an expert survey in breast cancer and non-Hodgkin's lymphoma.

BACKGROUND: The use of chemotherapy regimens with moderate or high risk of febrile neutropenia (defined as having a FN incidence of 10% or more) and the respective incidence and clinical management of FN in breast cancer and NHL has not been studied in Belgium. The existence of a medical need for G-CSF primary and secondary prophylaxis with these regimens was investigated in a real-life setting. METHODS: Nine oncologists and six hematologists from different Belgian general hospitals and university centers were surveyed to collect expert opinion and real-life data (year 2007) on the use of chemotherapy regimens with moderate or high risk of febrile neutropenia and the clinical management of FN in patients aged <65 years with breast cancer or NHL. Data were retrospectively obtained, over a 6-month observation period. RESULTS: The most frequently used regimens in breast cancer patients (n = 161) were FEC (45%), FEC-T (37%) and docetaxel alone (6%). In NHL patients (n = 39), R-CHOP-21 (33%) and R-ACVBP-14 (15%) were mainly used. Without G-CSF primary prophylaxis (PP), FN occurred in 31% of breast cancer patients, and 13% had PSN. After G-CSF secondary prophylaxis (SP), 4% experienced further FN events. Only 1 breast cancer patient received PP, and did not experience a severe neutropenic event. Overall, 30% of chemotherapy cycles observed in breast cancer patients were protected by PP/SP. In 10 NHL patients receiving PP, 2 (20%) developed FN, whereas 13 (45%) of the 29 patients without PP developed FN and 3 (10%) PSN. Overall, 55% of chemotherapy cycles observed in NHL patients were protected by PP/SP. Impaired chemotherapy delivery (timing and/or dose) was reported in 40% (breast cancer) and 38% (NHL) of patients developing FN. Based on oncologist expert opinion, hospitalization rates for FN (average length of stay) without and with PP were, respectively, 48% (4.2 days) and 19% (1.5 days). Similar rates were obtained from hematologists. CONCLUSIONS: Despite the studied chemotherapy regimens being known to be associated with a moderate or high risk of FN, upfront G-CSF prophylaxis was rarely used. The observed incidence of severe neutropenic events without G-CSF prophylaxis was higher than generally reported in the literature. The impact on medical resources used is sizeable.

Use and timing of referral to specialized palliative care services for people with cancer: A mortality follow-back study among treating physicians in Belgium.

BACKGROUND: Referral to specialized palliative care services (SPCS) occurs often late in the illness trajectory but may differ across cancer types. We examined differences between cancer types in the use and timing of referral to specialized palliative care services (SPCS) and in the reasons for non-referral. METHODS: We conducted a population-based mortality follow-back survey among physicians who certified a representative sample of deaths in Flanders, Belgium. We focused only on sampled death cases of cancer (n = 2392). The questionnaire asked about the use of the existing types of SPCS and the timing of referral to these services. RESULTS: Response rate was 58% (1394/2392). Patients who died from breast, respiratory, head and neck, genitourinary or gastrointestinal cancer had higher chances of using SPCS compared to hematologic cancer patients. The most prevalent reason for non-referral was that regular care sufficiently addressed palliative and supportive care needs (51%). This differed significantly between cancer types ranging from 77,8% for breast cancer and 42.1% for hematologic cancer. A second prevalent reason for not using SPCS was that it was not meaningful (enough) (23.9%), particularly for hematologic malignancies (35,1%) and only in 5.3% for breast cancer. CONCLUSION: Differences in referral across different types of cancer were found. Referral is more often delayed or not initiated for patients with hematologic cancer, possibly due to differences in illness trajectory. An influencing reason is that physicians perceive palliative care as not meaningful or not meaningful enough for these patients which may be linked to the uncertainty in the disease trajectory of hematologic malignancies.

A pilot study to investigate the feasibility and cardiac effects of pegylated liposomal doxorubicin (PL-DOX) as adjuvant therapy in medically fit elderly breast cancer patients.

In this pilot study, we examined the feasibility and toxicity in 16 elderly women age > or =65 receiving six cycles of pegylated liposomal doxorubicin (PL-DOX) cyclophosphamide as adjuvant chemotherapy for breast cancer. An extensive cardiologic assessment was also performed including echocardiographic Doppler-based strain rate imaging (SRI), a promising new sensitive technique to assess cardiac function. All but one patient finished the six planned cycles without major dose reductions or delay, and with limited serious toxicity showing the feasibility of this regimen. Significant decreases in radial strain and strain rate were found after six cycles of treatment while left ventricle ejection fraction remained unchanged. SRI may be a useful tool in the follow-up of elderly patients treated with anthracyclines, allowing early initiation of preventive measures in order to prevent further irreversible cardiac damage.

Gastrin-releasing peptide receptor imaging in human breast carcinoma versus immunohistochemistry.

UNLABELLED: This study reports on the uptake of (99m)Tc-RP527 by human breast carcinoma and its relationship to gastrin-releasing peptide receptor (GRP-R) expression as measured by immunohistochemistry (IHC). METHODS: Nine patients referred because of a clinical diagnosis suggestive of breast carcinoma and 5 patients with tamoxifen-resistant bone-mestastasized breast carcinoma underwent (99m)Tc-RP527 scintigraphy. The findings were compared with routine staging examinations in all patients and with routine histology and IHC GRP-R staining in the first 9 patients. All 9 patients with suspected breast lesions were tumor positive. RESULTS: The uptake of (99m)Tc-RP527 was evident in the primary tumor in 8 of 9 patients and in involved lymph nodes and part of the distant metastasis limited to the bone when present. (99m)Tc-RP527 uptake was not found in any of the tamoxifen-resistant patients. CONCLUSION: Uptake by primary breast carcinoma was significantly correlated with the presence of GRP-Rs as assessed by means of IHC.

Selumetinib in Combination With Dacarbazine in Patients With Metastatic Uveal Melanoma: A Phase III, Multicenter, Randomized Trial (SUMIT).

Purpose Uveal melanoma is the most common primary intraocular malignancy in adults with no effective systemic treatment option in the metastatic setting. Selumetinib (AZD6244, ARRY-142886) is an oral, potent, and selective MEK1/2 inhibitor with a short half-life, which demonstrated single-agent activity in patients with metastatic uveal melanoma in a randomized phase II trial. Methods The Selumetinib (AZD6244: ARRY-142886) (Hyd-Sulfate) in Metastatic Uveal Melanoma (SUMIT) study was a phase III, double-blind trial ( ClinicalTrial.gov identifier: NCT01974752) in which patients with metastatic uveal melanoma and no prior systemic therapy were randomly assigned (3:1) to selumetinib (75 mg twice daily) plus dacarbazine (1,000 mg/m2 intravenously on day 1 of every 21-day cycle) or placebo plus dacarbazine. The primary end point was progression-free survival (PFS) by blinded independent central radiologic review. Secondary end points included overall survival and objective response rate. Results A total of 129 patients were randomly assigned to receive selumetinib plus dacarbazine (n = 97) or placebo plus dacarbazine (n = 32). In the selumetinib plus dacarbazine group, 82 patients (85%) experienced a PFS event, compared with 24 (75%) in the placebo plus dacarbazine group (median, 2.8 v 1.8 months); the hazard ratio for PFS was 0.78 (95% CI, 0.48 to 1.27; two-sided P = .32). The objective response rate was 3% with selumetinib plus dacarbazine and 0% with placebo plus dacarbazine (two-sided P = .36). At 37% maturity (n = 48 deaths), analysis of overall survival gave a hazard ratio of 0.75 (95% CI, 0.39 to 1.46; two-sided P = .40). The most frequently reported adverse events (selumetinib plus dacarbazine v placebo plus dacarbazine) were nausea (62% v 19%), rash (57% v 6%), fatigue (44% v 47%), diarrhea (44% v 22%), and peripheral edema (43% v 6%). Conclusion In patients with metastatic uveal melanoma, the combination of selumetinib plus dacarbazine had a tolerable safety profile but did not significantly improve PFS compared with placebo plus dacarbazine.

Phosphorylated HER-2 tyrosine kinase and Her-2/neu gene amplification as predictive factors of response to trastuzumab in patients with HER-2 overexpressing metastatic breast cancer (MBC).

AIM: Trastuzumab (T), a humanised monoclonal antibody against HER-2, is active in HER-2-positive MBC patients. However, nearly 60% of the patients do not benefit from T, stressing the need for additional predictive markers. The following markers could be implicated in response to T: (1) the magnitude of Her-2 gene amplification; (2) the co-expression of the other HER family receptors, possibly responsible for HER-2 trans-activation; (3) the activated status of HER-2; (4) the activated status of downstream effectors as mitogen-activated protein kinases (MAPKs), p38 and p27. METHODS: Medical files of patients with MBC treated with T either as a single agent or in combination with chemotherapy (CT) were reviewed. HER family members (EGFR, HER-2, HER-3, HER-4), the phosphorylated forms of EGFR (p-EGFR), HER-2 (p-HER-2) and of the downstream effectors were evaluated in the archival tumours. The correlation between clinical outcome and the expression of these markers was investigated. RESULTS: (1) Increasing values of Her-2 amplification were associated with a higher probability of achieving an objective response; (2) no statistical significant correlation between the expression of the HER family receptors was found; (3) p-HER-2 was predictive of response in patients treated with T+CT; (4) a statistically significant correlation between p-ERK 1/2, p-p38 and p-HER-2 emerged, pointing to the activated vertical pathway p-HER-2-->p-MAPKs. CONCLUSIONS: p-HER-2 and the magnitude of Her-2 amplification were predictive of response to T and their role deserves to be analysed in larger and more homogenous T-treated populations such as those from large phase III trials.

Systematic review: The oncological safety of adipose fat transfer after breast cancer surgery.

OBJECTIVES: Oncological concerns have risen around the safety of adipose fat transfer (AFT) after breast cancer surgery. In this article, we present the clinical and molecular evidences, and discuss the current contradiction between them. MATERIALS AND METHODS: Every clinical trial and experimental study on AFT and its oncological influences was screened. Between September 2014 and September 2016, 856 articles from four databases were found. 105 core articles were selected. RESULTS: A total of 18 clinical studies have been published. The loco-regional recurrence (LRR) incidence rates range between 0 and 3.90% per year. For the mastectomy and breast conservative therapy group separately, a LRR per year between 0 and 1.62% and 0-3.90 has been reported, respectively. Some studies included a matched control group and found no significant difference between cases and controls, with the exception of a subgroup of patients with intraepithelial breast carcinoma. Adipose derived mesenchymal stem cells have a potential oncogenic effect on residual cancer cells after breast cancer surgery. Numerous signalling proteins and pathways have been described that can stimulate tumour initiation and growth. CONCLUSION: There is a contradiction between experimental and clinical findings. Numerous adipokines have been discovered that could potentially promote tumour initiation and growth, but clinical studies fail to point out a significant increase in LRR in patients who receive AFT after breast cancer surgery. More prospective studies are needed with a sufficient follow-up time and analysis of some critical factors, such as adjuvant radiotherapy and hormonal therapy, the origin and volume of the injected fat, and genetic influences.

Comparison of HER2 amplification status among breast cancer subgroups offers new insights in pathways of breast cancer progression.

Although the prognostic and predictive significance of human epidermal growth factor receptor 2 (HER2) in invasive breast cancer is well established, its role in ductal carcinoma in situ (DCIS) remains unclear. Reports on combined evaluation of both HER2 protein expression and HER2 amplification status in pure DCIS and DCIS adjacent to invasive ductal carcinoma (i.e., admixed DCIS) are scarce. In this study, immunohistochemistry and fluorescence in situ hybridization (FISH) were used to assess HER2 status in 72 cases of pure DCIS, 73 cases of DCIS admixed with invasive ductal carcinoma (IDC), and 60 cases of pure IDC. HER2 copy number-based amplification was present in 49% of pure DCIS, 16% of admixed DCIS, 18% of admixed IDC, and 8% of pure IDC. Amplified pure DCIS with clusters of HER2 signals showed a significantly lower HER2 copy number than amplified admixed DCIS with clusters. Whereas pure DCIS and admixed DCIS presented significant differences, the in situ and invasive component of admixed tumors showed striking similarities regarding mean HER2 and chromosome 17 centromere (CEP17) copy number, grade, and estrogen and progesterone receptor expression. The discrepant prevalence of HER2 amplification among breast cancer subgroups indirectly suggests that HER2 may not play a crucial role in the transition of in situ to invasive breast cancer. The similarities in HER2 amplification status between the in situ and invasive component of admixed tumors hint at a common biological pathway for both components. Our data support the theory that pure DCIS, pure IDC, and admixed lesions have a common progenitor, but can progress as separate lineages.

The isolation of morphologically intact and biologically active extracellular vesicles from the secretome of cancer-associated adipose tissue.

Breast cancer cells closely interact with different cell types of the surrounding adipose tissue to favor invasive growth and metastasis. Extracellular vesicles (EVs) are nanometer-sized vesicles secreted by different cell types that shuttle proteins and nucleic acids to establish cell-cell communication. To study the role of EVs released by cancer-associated adipose tissue in breast cancer progression and metastasis a standardized EV isolation protocol that obtains pure EVs and maintains their functional characteristics is required. We implemented differential ultracentrifugation as a pre-enrichment step followed by OptiPrep density gradient centrifugation (dUC-ODG) to isolate EVs from the conditioned medium of cancer-associated adipose tissue. A combination of immune-electron microscopy, nanoparticle tracking analysis (NTA) and Western blot analysis identified EVs that are enriched in flotillin-1, CD9 and CD63, and sized between 20 and 200 nm with a density of 1.076-1.125 g/ml. The lack of protein aggregates and cell organelle proteins confirmed the purity of the EV preparations. Next, we evaluated whether dUC-ODG isolated EVs are functionally active. ZR75.1 breast cancer cells treated with cancer-associated adipose tissue-secreted EVs from breast cancer patients showed an increased phosphorylation of CREB. MCF-7 breast cancer cells treated with adipose tissue-derived EVs exhibited a stronger propensity to form cellular aggregates. In conclusion, dUC-ODG purifies EVs from conditioned medium of cancer-associated adipose tissue, and these EVs are morphologically intact and biologically active.

Secretome analysis of breast cancer-associated adipose tissue to identify paracrine regulators of breast cancer growth.

Adipose tissue secretes a plethora of adipokines as evidenced by characterization of subcutaneous and visceral adipose tissue secretomes. However, adipose tissue composition and secretion pattern is depot and disease dependent, influencing the adipose tissue secretome. We investigated the secretome of cancer-associated adipose tissue (CAAT) explants from breast cancer patients and explored its role in breast cancer proliferation. CAAT proteins were identified by LC-MS/MS and human protein antibody arrays and stimulated proliferation of three breast cancer cell lines. Kinomics and transcriptomics of MCF-7 breast cancer cells treated with the secretome of CAAT revealed activation of Akt-, ERK- and JNK-pathways and differential expression of activator protein 1 (AP-1) and cAMP responsive element-binding protein (CREB) target genes. The cyclin-dependent kinase (CDK)4/6-inhibitor palbociclib significantly abrogated CAAT-enhanced breast cancer cell proliferation. Our work characterizes the specific breast CAAT protein secretome and reveals its pro-proliferative potency in breast cancer.