• Bench to bedside gap
• Clinical tumor dormancy
• Complex system dynamics
• Dormancy-based model
• Tissue level cancerogenesis

• Humans
• Breast Neoplasms/pathology
• Breast Neoplasms/genetics
• Female
• Neoplasm Recurrence, Local
• Mastectomy
• Mutation

• Histological grade
• Mucoepidermoid carcinoma
• Pleural dissemination
• Recurrence
• Thymic cancer

• Acceleration
• Breast cancer
• Metastasis
• Surgery

• Cell Movement
• Embryonic Development
• Epithelial-Mesenchymal Transition
• Humans
• Neoplasm Metastasis/pathology
• Neoplasms/pathology
• Pericytes

Current cancer therapies aim at eradicating cancer cells from the body. However, killing cells generates cell “debris” which can promote tumor progression. Thus, therapy can be a double-edged sword. Specifically, injury and debris generated by cancer therapies, including chemotherapy, radiation, and surgery, may offset their benefit by promoting the secretion of pro-tumorigenic factors (e.g., eicosanoid-driven cytokines) that stimulate regrowth and metastasis of surviving cells. The debris produced by cytotoxic cancer therapy can also contribute to a tumor microenvironment that promotes tumor progression and recurrence. Although not well understood, several molecular mechanisms have been implicated in debris-stimulated tumor growth that we review here, such as the involvement of extracellular vesicles, exosomal miR-194-5p, Bax, Bak, Smac, HMGB1, cytokines, and caspase-3. We discuss the cases of pancreatic and other cancer types where debris promotes postoperative tumor recurrence and metastasis, thus offering a new opportunity to prevent cancer progression intrinsically linked to treatment by stimulating resolution of tumor-promoting debris.

• Bak
• Bax
• Caspase-3
• Chemotherapy
• Debris
• Exosomal miR-194-5p
• Extracellular vesicles
• HMGB1
• Inflammation
• Metastasis
• Platelet activating factor
• Radiation
• Recurrence
• Resolution of inflammation
• Smac
• Specialized pro-resolving mediators
• Surgery
• Tumor progression

• Antineoplastic Agents
• Cell Line, Tumor
• Cytokines
• Eicosanoids
• Humans
• MicroRNAs
• Neoplasms/therapy
• Tumor Microenvironment

The paradigm of the Somatic Mutation Theory (SMT) is failing, and a new paradigm is underway but not yet established. What is being challenged is a conceptual approach that involves the entire human biology and the development of chronic diseases. The behavior of breast and other solid cancers is compatible with the concept that the primary tumor is able to control its microscopic metastases, in the same way that an organ (e.g., the liver) is able to control its physiological size. This finding suggested that cancer and its metastases may behave as an organoid. The new paradigm under construction considers the origin of tumors as a disturbance in the communication network between tissue cell populations and between cells and extracellular matrix, and supports a systemic approach to the study of both healthy and pathologic tissues. The commentary provides a rationale for the role of physical exercise in the control of tumor dormancy according to a human evolutionary perspective.

• cancer dormancy
• healthy aging
• low-grade chronic inflammation
• physical exercise

The initial treatment of early breast cancer has achieved important clinical results over time. However, late recurrences after many years of disease-free survival remain an open question, which has recently attracted the attention of a few researchers. The authors of this commentary suggest that the approach emerging from scientific meetings regarding this subject is marred by the lack of attention to recent clinical and laboratory data. The role of tumor dormancy and the dynamics of disease recurrence are presented here and a more general reflection on therapeutic approaches to cancer is proposed.

The problem of late recurrence in breast cancer has recently gained attention and was also addressed in an international workshop held in Toronto (ON, Canada), in which several aspects of the question were examined. This Commentary offers a few considerations, which may be useful for the ongoing investigations. A few premises are discussed: (a) clinical recurrences, especially the late ones, imply periods of tumor dormancy; (b) a structured pattern of distant metastases appearance is detectable in both early and late follow-up times; (c) the current general paradigm underlying neoplastic treatments, i.e., that killing all cancer cells is the only way to control the disease, which is strictly sprouting from the somatic mutation theory, should be re-considered. Finally, a few research approaches are suggested.

• cancer paradigms
• recurrence dynamics
• tumor dormancy

Partial hepatectomy (PHx) is the gold standard for the treatment of colorectal cancer liver metastases. However, after removing a substantial amount of hepatic tissue, growth factors are released to induce liver regeneration, which may promote the proliferation of liver micrometastases or circulating tumour cells still present in the patient. The aim of this study is to assess the effect of PHx on the growth of liver metastases induced by intrasplenic cell inoculation as well as on in vitro proliferation of the same cancer cell line. Liver tumours were induced in 18 WAG/RijHsd male rats, by seeding 250,000 syngeneic colorectal cancer cells (CC531) into the spleen. The left lateral lobe of the liver was mobilized and in half of the animals it was removed to achieve a 40% hepatectomy. Twenty-eight days after tumour induction, the animals were sacrificed and the liver was removed and sliced to assess the relative tumour surface area (RTSA%). CC531 cells were cultured in presence of foetal calf serum, non-hepatectomised (NRS) or hepatectomized rat serum (HRS), and their proliferation rate at 24, 48, and 72 h was measured. RTSA% was significantly higher in animals which had undergone PHx than in the controls (non-hepatectomised) (46.98 ± 8.76% vs. 18.73 ± 5.65%; p < 0.05). Analysing each lobe separately, this difference in favour of hepatectomized animals was relevant and statistically significant in the paramedian and caudate lobes. But in the right lobe the difference was scarce and not significant. In vitro, 2.5% HRS achieved stronger proliferative rates than the control cultures (10% FCS) or their equivalent of NRS. In this experimental model, a parallelism has been shown between the effect of PHx on the growth of colorectal cancer cells in the liver and the effect of the serum on those cells in vitro.

Cellular heterogeneity poses an immense therapeutic challenge in cancer due to a constant change in tumor cell characteristics, endowing cancer cells with the ability to dynamically shift between states. Intra-tumor heterogeneity is largely driven by cancer cell plasticity, demonstrated by the ability of malignant cells to acquire stemness and epithelial-to-mesenchymal transition (EMT) properties, to develop therapy resistance and to escape dormancy. These different aspects of cancer cell remodeling are driven by intrinsic as well as by extrinsic signals, the latter being dominated by factors of the tumor microenvironment. As part of the tumor milieu, chronic inflammation is generally regarded as a most influential player that supports tumor development and progression. In this review article, we put together recent findings on the roles of inflammatory elements in driving forward key processes of tumor cell plasticity. Using breast cancer as a representative research system, we demonstrate the critical roles played by inflammation-associated myeloid cells (mainly macrophages), pro-inflammatory cytokines [such as tumor necrosis factor α (TNFα) and interleukin 6 (IL-6)] and inflammatory chemokines [primarily CXCL8 (interleukin 8, IL-8) and CXCL1 (GROα)] in promoting tumor cell remodeling. These inflammatory components form a common thread that is involved in regulation of the three plasticity levels: stemness/EMT, therapy resistance, and dormancy. In view of the fact that inflammatory elements are a common denominator shared by different aspects of tumor cell plasticity, it is possible that their targeting may have a critical clinical benefit for cancer patients.

• cytokines/chemokines
• dormancy
• epithelial-to-mesenchymal transition
• inflammation
• macrophages
• stemness
• therapy resistance
• tumor cell plasticity

• Angiogenesis
• Cellular Mechanisms
• Lidocaine
• Metastasis

• Biopsy
• Breast cancer
• Lobular carcinoma
• Metastasis
• Polyps

• Aged
• Breast Neoplasms/pathology
• Carcinoma, Lobular/secondary
• Colorectal Neoplasms/secondary
• Female
• Humans
• Stomach Neoplasms/secondary

• breast cancer
• hazard function
• microscopic metastasis acceleration
• recurrence dynamics
• tumor dormancy
• tumor homeostasis

Dormant avascular micrometastases and single, or small groups of, non-proliferating cells are currently assumed to explain the multipeak dynamics of distant metastases (DM) following primary breast cancer surgical removal.

The hazard rate pattern for DM was analysed in 1518 premenopausal node-positive patients, enrolled in a series of randomized clinical trials on early breast cancer, which were carried out in Italy and Belgium. Patients underwent surgery alone (n = 397) or surgery plus adjuvant chemotherapy (n = 1121) and the minimal follow up was 15 years.

The DM hazard rate for patients undergoing surgery alone displayed two early sharp peaks at 9 and 33 months, a wide intermediate one spanning from about 50 to 90 months and a late peak at 115–120 months. Adjuvant chemotherapy was associated with a prominent reduction of the two early peaks leaving a residual one at about 18 months and a reduction of the intermediate peak leaving two small peaks at about 50 and 80 months. The late peak remained unchanged.

Present results reveal the ability of adjuvant chemotherapy to reduce not only the rate of early relapses, but also the rate of intermediate relapses at about the sixth year of follow up. Adjuvant chemotherapy is not impacting on the development of metastases underlying the late peak detected at the tenth year. These findings suggest the existence of a previously unknown dormancy state that, at the primary tumour surgical removal, results in evolving chemo-sensitive metastatic processes, and, moreover, of a later chemo-refractory dormancy state.

•

Breast cancer removal wakes dormant micro foci causing peaks in recurrence dynamics.

• Adjuvant chemotherapy effects
• Breast cancer
• Distant metastasis dynamics
• Dormancy states
• Surgery effects

• Belgium/epidemiology
• Breast Neoplasms/pathology
• Breast Neoplasms/surgery
• Chemotherapy, Adjuvant
• Female
• Humans
• Italy/epidemiology
• Lymphatic Metastasis/drug therapy
• Lymphatic Metastasis/physiopathology
• Neoplasm Micrometastasis/drug therapy
• Neoplasm Micrometastasis/physiopathology
• Premenopause
• Proportional Hazards Models
• Randomized Controlled Trials as Topic
• Secondary Prevention/statistics & numerical data

• Acanthamoeba
• Apoptosis.
• Cancer
• Cancer stem cells
• Cell differentiation
• Dedifferentiation
• Encystation
• Phenotypic switching
• Protozoa
• Signalling

• CSCs
• chemotherapy
• combination therapy
• gene therapy
• nanoparticle
• photothermal therapy.

• Cancer
• Eicosanoids
• Inflammation
• Oncology
• Surgery

• Breast cancer
• HER2
• Heterogeneity
• Late recurrence

• Breast cancer
• Late recurrences
• Recurrence dynamics
• Tumor dormancy
• Tumor homeostasis

The number of patients requesting autologous breast reconstruction (ABR) after mastectomy for breast cancer has increased over the past decades. However, concern has been expressed about the oncological safety of ABR. The aim of our study was to assess the effect of ABR on distant relapse.

In this retrospective cohort study, data was analysed from patients who underwent mastectomy for invasive breast cancer in University Hospitals Leuven between 2000 and 2011. In total, 2326 consecutive patients were included, 485 who underwent mastectomy with ABR and 1841 who underwent mastectomy alone. The risk of relapse in both groups was calculated using a Cox proportional hazards analysis, adjusted for established prognostic factors. ABR was considered as a time-dependent variable. Additionally, the evolution of the risk over follow-up time was calculated.

With a median follow-up of 68 months, 8% of patients in the reconstruction group developed distant metastases compared to 15% in the mastectomy alone group (univariate HR 0.70, 95% CI 0.50–0.97, p = 0.0323). However, after adjustment for potential confounding factors in a Cox multivariable analysis, the risk of distant relapse was no longer significantly different between groups (multivariate HR 0.82, 95% CI 0.55–1.22, p = 0.3301). Moreover, the risk of metastasis after reconstruction was not time-dependent.

These findings suggest that there is no effect of ABR on distant relapse rate and thus that ABR is an oncological safe procedure. The rate of local recurrence was too low to make any significant conclusions.

• Autologous breast reconstruction
• Invasive breast cancer
• Metastases
• Surgical stress
• Tumour dormancy

• ERCP
• Ovarian cancer
• ampullary metastasis
• obstructive jaundice

Little is known about the occurrence, timing and prognostic factors for first and also subsequent local (LR), regional (RR) or distant (DM) breast cancer recurrence. As current follow-up is still consensus-based, more information on the patterns and predictors of subsequent recurrences can inform more personalized follow-up decisions.

Women diagnosed with stage I-III invasive breast cancer who were treated with curative intent were selected from the Netherlands Cancer Registry (N = 9342). Extended Cox regression was used to model the hazard of recurrence over ten years of follow-up for not only site-specific first, but also subsequent recurrences after LR or RR.

In total, 362 patients had LR, 148 RR and 1343 DM as first recurrence. The risk of first recurrence was highest during the second year post-diagnosis (3.9%; 95% CI 3.5–4.3) with similar patterns for LR, RR and DM. Young age (<40), tumour size >2 cm, tumour grade II/III, positive lymph nodes, multifocality and no chemotherapy were prognostic factors for first recurrence. The risk of developing a second recurrence after LR or RR (N = 176) was significantly higher after RR than after LR (50 vs 29%; p < 0.001). After a second LR or RR, more than half of the women were diagnosed with a third recurrence.

Although the risk of subsequent recurrence is high, absolute incidence remains low. Also, almost half the second recurrences are detected in the first year after previous recurrence and more than 80% are DM. This suggests that more intensive follow-up for early detection subsequent recurrence is not likely to be (cost-)effective.

The online version of this article (doi:10.1007/s10549-017-4340-3) contains supplementary material, which is available to authorized users.

• Breast cancer
• Follow-up
• Prognostic factors
• Recurrence patterns
• Recurrence risk

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms/epidemiology
• Breast Neoplasms/mortality
• Breast Neoplasms/pathology
• Breast Neoplasms/therapy
• Combined Modality Therapy
• Female
• Humans
• Middle Aged
• Neoplasm Grading
• Neoplasm Metastasis
• Neoplasm Recurrence, Local
• Neoplasm Staging
• Netherlands/epidemiology
• Patient Outcome Assessment
• Prognosis
• Registries
• Tumor Burden

• Breast cancer
• Breast reconstruction
• Multivariate regression
• Recurrence dynamics
• Surgery
• Tumor dormancy

• Adult
• Aged
• Aged, 80 and over
• Breast Neoplasms/epidemiology
• Breast Neoplasms/surgery
• Carcinoma, Intraductal, Noninfiltrating/epidemiology
• Carcinoma, Intraductal, Noninfiltrating/surgery
• Disease Progression
• Female
• Humans
• Mammaplasty
• Margins of Excision
• Mastectomy/methods
• Middle Aged
• Neoplasm Micrometastasis
• Neoplasm Recurrence, Local/epidemiology
• Neoplasm Recurrence, Local/surgery
• Netherlands/epidemiology
• Time-to-Treatment
• Young Adult

• The Norwegian Cancer Association
• Reasearch council of Norway
• Helse Vest
• Associazione Italiana per la Ricerca sul Cancro (IT)

• Cell-signaling
• Peri-operative biology
• Surgery

Clinical dormancy is frequently observed in breast cancer. In the present study, we aimed to characterize circulating tumor cells (CTCs) in dormancy candidates (DC) with early breast cancer in terms of proliferation and apoptosis.

Cytospins of peripheral blood mononuclear cells (PBMCs) were obtained from DC (n = 122) who were disease-free for at least 5 years and from metastatic patients (n = 40) who relapsed more than 5 years after surgery. Sequential samples from eight DC (n = 36) who maintained a prolonged disease-free status and from eight DC (n = 27) presenting late relapse during follow-up, were also analyzed. PBMCs were triple stained with a pancytokeratin, antibody along with anti-Ki67 and anti-M30 antibodies as proliferation and apoptosis markers, respectively.

CTCs were identified in 40 (33%) of 122 DC and in 15 (37.5%) of 40 metastatic patients. In total, twenty-five (62.5%) DC had exclusively dormant (Ki67(-)/M30(-)), seven (17.5%) had proliferative Ki67(+)/M30(-), four (10%) had apoptotic Ki67(-)/M30(+) and four (10%) had both phenotypes of proliferative and apoptotic CTCs. In comparison, 53.4% of CTC-positive metastatic patients had exclusively dormant and 46.6% had proliferative CTCs; none had apoptotic CTCs (P = 0.039). Among all CTCs detected in DC patients, 82.4% were dormant, whereas in the nondormant population, 32.5% were proliferative and 67.5% apoptotic. The respective percentages in metastatic patients were 59.1%, 100% and 0% (P <0.0001). Moreover, apoptotic CTCs prevailed among nondormant CTCs detected in sequential samples from DC who remained in a prolonged disease-free status compared to those presenting late relapse during follow-up (70.6% versus 43.5% (P = 0.0002)).

The apoptotic index of CTCs is increased during clinical dormancy, whereas the proliferation index is increased on relapse. In addition, apoptotic CTCs are more frequently encountered during follow-up in DC patients who remain disease-free compared to those with subsequent late relapse, suggesting that monitoring proliferation and apoptosis in CTCs during clinical dormancy merits further investigation as a tool for predicting late disease recurrence.

The online version of this article (doi:10.1186/s13058-014-0485-8) contains supplementary material, which is available to authorized users.

The study estimates mortality dynamics (event-specific hazard rates over a follow-up time interval) for uveal melanoma.

Three thousands six hundred seventy two patients undergoing radical or conservative treatment for unilateral uveal melanoma, whose yearly follow-up data were reported in three published datasets, were analysed. Mortality dynamics was studied by estimating with the life-table method the discrete hazard rate for death. Smoothed curves were obtained by a Kernel-like smoothing procedure and a piecewise exponential regression model. The ratio deaths/patients at risk per year was the main outcome measure.

The three explored hazard rate curves display a common bimodal pattern, with a sudden increase peaking at about three years, followed by reduction until the sixth-seventh year and a second surge peaking at about nine years after treatment.

The bimodal pattern of mortality indicates that uveal melanoma metastatic development cannot be explained by a continuous growth model. Similar metastasis dynamics have been reported for other tumours, including early breast cancer, for which it supported a paradigm shift to an interrupted growth model, the implications of which are episodes of ‘tumour dormancy’. We propose that the concepts of tumour homeostasis, tumour dormancy and enhancement of metastasis growth related to primary tumour removal, convincingly explaining the clinical behaviour of breast cancer, may be used for uveal melanoma as well. To confirm this proposition, a careful analysis of uveal melanoma metastasis dynamics is strongly warranted.

• Breast cancer
• Isolated locoregional recurrence
• Local breast treatment
• Long-term clinical outcome
• Prognostic variables

• NSAIDs
• anaesthesia
• cancer
• metastases
• opioids
• recurrence
• regional

• Cancer
• Choroidal
• Metastasis
• Uveal melanoma

• Antineoplastic Agents/therapeutic use
• Breast Neoplasms/drug therapy
• Breast Neoplasms/pathology
• Drug Design
• Female
• Humans
• Models, Theoretical

The common goal within the overwhelming interests in stem cell research is to safely translate the science to patients. Although there are various methods by which this goal can be reached, this editorial emphasizes the safety of mesenchymal stem cell (MSC) transplant and possible confounds by the growing information on cancer stem cells (CSCs). There are several ongoing clinical trials with MSCs and their interactions with CSCs need to be examined. The rapid knowledge on MSCs and CSCs has now collided with regards to the safe treatment of MSCs. The information discussed on MSCs can be extrapolated to other stem cells with similar phenotype and functions such as placenta stem cells. MSCs are attractive for cell therapy, mainly due to reduced ethical concerns, ease in expansion and reduced ability to be transformed. Also, MSCs can exert both immune suppressor and tissue regeneration simultaneously. It is expected that any clinical trial with MSCs will take precaution to ensure that the cells are not transformed. However, going forward, the different centers should be aware that MSCs might undergo oncogenic events, especially as undifferentiated cells or early differentiated cells. Another major concern for MSC therapy is their ability to promote tumor growth and perhaps, to protect CSCs by altered immune responses. These issues are discussed in light of a large number of undiagnosed cancers.

• Mesenchymal stem cells
• Cancer stem cells
• Cytokines
• Regulatory T-cells
• Breast cancer
• Major histocompatibility antigen

• Breast Neoplasms/genetics
• Breast Neoplasms/surgery
• Female
• Gene Regulatory Networks
• Humans
• Neoplasm Recurrence, Local/genetics
• Research Design
• Systems Biology

The surgical treatment of early breast cancer has evolved from the removal of the entire breast and surrounding tissues (mastectomy) to the removal of the tumour together with a margin of healthy tissue (lumpectomy). Adjuvant radiotherapy, however, is still mainly given to the whole breast. Furthermore, external beam radiotherapy is often given several months after initial surgery and requires the patient to attend the radiotherapy centre daily for several weeks. A single fraction of radiotherapy given during surgery directly to the tumour bed (intraoperative radiotherapy) avoids these problems. The rationale and level-1 evidence for the safety and efficacy of the technique are reviewed.

• Animals
• Dose-Response Relationship, Radiation
• Energy Transfer
• Environmental Exposure
• Humans
• Models, Theoretical
• No-Observed-Adverse-Effect Level
• Radiation, Ionizing
• Risk Assessment