Circulating Tumor Cell Clustering Shapes DNA Methylation to Enable Metastasis Seeding.

The ability of circulating tumor cells (CTCs) to form clusters has been linked to increased metastatic potential. Yet biological features and vulnerabilities of CTC clusters remain largely unknown. Here, we profile the DNA methylation landscape of single CTCs and CTC clusters from breast cancer patients and mouse models on a genome-wide scale. We find that binding sites for stemness- and proliferation-associated transcription factors are specifically hypomethylated in CTC clusters, including binding sites for OCT4, NANOG, SOX2, and SIN3A, paralleling embryonic stem cell biology. Among 2,486 FDA-approved compounds, we identify Na+/K+ ATPase inhibitors that enable the dissociation of CTC clusters into single cells, leading to DNA methylation remodeling at critical sites and metastasis suppression. Thus, our results link CTC clustering to specific changes in DNA methylation that promote stemness and metastasis and point to cluster-targeting compounds to suppress the spread of cancer.

Neutrophils escort circulating tumour cells to enable cell cycle progression.

A better understanding of the features that define the interaction between cancer cells and immune cells is important for the development of new cancer therapies1. However, focus is often given to interactions that occur within the primary tumour and its microenvironment, whereas the role of immune cells during cancer dissemination in patients remains largely uncharacterized2,3. Circulating tumour cells (CTCs) are precursors of metastasis in several types of cancer4-6, and are occasionally found within the bloodstream in association with non-malignant cells such as white blood cells (WBCs)7,8. The identity and function of these CTC-associated WBCs, as well as the molecular features that define the interaction between WBCs and CTCs, are unknown. Here we isolate and characterize individual CTC-associated WBCs, as well as corresponding cancer cells within each CTC-WBC cluster, from patients with breast cancer and from mouse models. We use single-cell RNA sequencing to show that in the majority of these cases, CTCs were associated with neutrophils. When comparing the transcriptome profiles of CTCs associated with neutrophils against those of CTCs alone, we detect a number of differentially expressed genes that outline cell cycle progression, leading to more efficient metastasis formation. Further, we identify cell-cell junction and cytokine-receptor pairs that define CTC-neutrophil clusters, representing key vulnerabilities of the metastatic process. Thus, the association between neutrophils and CTCs drives cell cycle progression within the bloodstream and expands the metastatic potential of CTCs, providing a rationale for targeting this interaction in treatment of breast cancer.

[New treatment options in system therapy for breast carcinoma and associated new side effects].

INTRODUCTION: Breast cancer today has a significantly better prognosis than two to three decades ago. Treatment options have improved significantly. However, new systemic therapy has also resulted in side effects that clinicians must first become familiar with in order to be able to treat them optimally. This article gives an overview of the most important innovations in the last 10 years in the field of systemic therapy in breast cancer and also shows the most important side effects and their management.

The Role of HbA1c as a Positive Perioperative Predictor of Surgical Site and Other Postoperative Infections: An Explorative Analysis in Patients Undergoing Minor to Major Surgery.

BACKGROUND: Patients with diabetes mellitus type 2 (DM2) inhere impaired peripheral insulin action leading to higher perioperative morbidity and mortality rates, with hospital-acquired infections being one important complication. This post hoc, observational study aimed to analyze the impact of surgical and metabolic stress as defined by the surrogate marker hemoglobin A1c (HbA1c), in relation to self-reported DM2, on perioperative infection rates in a subcohort of the Surgical Site Infection (SSI) Trial population. METHODS: All patients of the SSI study were screened for HbA1c levels measured perioperatively for elective or emergency surgery and classified according to the American Diabetes Association HbA1c cutoff values. SSI and nosocomial infections, self-reported state of DM2 and type of surgery (minor, major) were assessed. RESULTS: HbA1c levels were measured in 139 of 5175 patients (2.7%) of the complete SSI study group. Seventy patients (50.4%) self-reported DM2, while 69 (49.6%) self-reported to be non-diabetic. HbA1c levels indicating pre-diabetes were found in 48 patients (34.5%) and diabetic state in 64 patients (46%). Forty-five patients of the group self-reporting no diabetes (65.2%) were previously unaware of their metabolic derangement (35 pre-diabetic and 10 diabetic). Eighteen infections were detected. Most infections (17 of 18 events) were found in patients with HbA1c levels indicating pre-/diabetic state. The odds for an infection was 3.9-fold (95% CI 1.4 to 11.3) higher for patients undergoing major compared to minor interventions. The highest percentage of infections (38.5%) was found in the group of patients with an undiagnosed pre-/diabetic state undergoing major surgery. CONCLUSIONS: These results encourage investment in further studies evaluating a more generous and specific use of HbA1c screening in patients without self-reported diabetes undergoing major surgery. Trial registration Clinicaltrials.gov identifier: NCT01790529.

Denosumab treatment is associated with the absence of circulating tumor cells in patients with breast cancer.

BACKGROUND: The presence of circulating tumor cells (CTCs) in patients with breast cancer correlates to a bad prognosis. Yet, CTCs are detectable in only a minority of patients with progressive breast cancer, and factors that influence the abundance of CTCs remain elusive. METHODS: We conducted CTC isolation and enumeration in a selected group of 73 consecutive patients characterized by progressive invasive breast cancer, high tumor load and treatment discontinuation at the time of CTC isolation. CTCs were quantified with the Parsortix microfluidic device. Clinicopathological variables, blood counts at the time of CTC isolation and detailed treatment history prior to blood sampling were evaluated for each patient. RESULTS: Among 73 patients, we detected at least one CTC per 7.5 ml of blood in 34 (46%). Of these, 22 (65%) had single CTCs only, whereas 12 (35%) featured both single CTCs and CTC clusters. Treatment with the monoclonal antibody denosumab correlated with the absence of CTCs, both when considering all patients and when considering only those with bone metastasis. We also found that low red blood cell count was associated with the presence of CTCs, whereas high CA 15-3 tumor marker, high mean corpuscular volume, high white blood cell count and high mean platelet volume associated specifically with CTC clusters. CONCLUSIONS: In addition to blood count correlatives to single and clustered CTCs, we found that denosumab treatment associates with most patients lacking CTCs from their peripheral circulation. Prospective studies will be needed to validate the involvement of denosumab in the prevention of CTC generation.

Oncoplastic Breast Consortium consensus conference on nipple-sparing mastectomy.

PURPOSE: Indications for nipple-sparing mastectomy (NSM) have broadened to include the risk reducing setting and locally advanced tumors, which resulted in a dramatic increase in the use of NSM. The Oncoplastic Breast Consortium consensus conference on NSM and immediate reconstruction was held to address a variety of questions in clinical practice and research based on published evidence and expert panel opinion. METHODS: The panel consisted of 44 breast surgeons from 14 countries across four continents with a background in gynecology, general or reconstructive surgery and a practice dedicated to breast cancer, as well as a patient advocate. Panelists presented evidence summaries relating to each topic for debate during the in-person consensus conference. The iterative process in question development, voting, and wording of the recommendations followed the modified Delphi methodology. RESULTS: Consensus recommendations were reached in 35, majority recommendations in 24, and no recommendations in the remaining 12 questions. The panel acknowledged the need for standardization of various aspects of NSM and immediate reconstruction. It endorsed several oncological contraindications to the preservation of the skin and nipple. Furthermore, it recommended inclusion of patients in prospective registries and routine assessment of patient-reported outcomes. Considerable heterogeneity in breast reconstruction practice became obvious during the conference. CONCLUSIONS: In case of conflicting or missing evidence to guide treatment, the consensus conference revealed substantial disagreement in expert panel opinion, which, among others, supports the need for a randomized trial to evaluate the safest and most efficacious reconstruction techniques.

Adherence to bone health guidelines in patients with hormone receptor-positive early breast cancer: Status and clinical impact in a Swiss cohort experience.

AIM: In patients with postmenopausal hormone receptor-positive breast cancer (ER + eBC), aromatase inhibitors (AIs) are widely used for effective relapse prevention. However, AIs reduce bone density and increase bone-related events (BREs). Alongside calcium and vitamin D3 supplementation, bisphosphonates and denosumab are well-known options for improving outcomes in bone health and breast cancer prognosis. This study aimed to evaluate the practice patterns of bone health guideline-based management in real-world patients with ER + eBC. MATERIAL AND METHODS: In total, 68 patients with ER + eBC treated between 2009 and 2014 at the University Hospital Basel were included in this retrospective cohort study. Chart reviews were analyzed. Baseline, clinicopathological, treatment, and BRE data were extracted. Each patient was specifically reviewed for therapy adherence to the Swiss bone health guidelines (Swiss Association against Osteoporosis 2010 [SVGO]). RESULTS: The mean patient age was 66.5 (range, 56-74) years, all post-menopausal. The most frequent tumor characteristics were tumor size of pT1-pT2 (N = 53, 77.9%) and treatment with letrozole (N = 35, 51.5%), followed by tamoxifen as a switch strategy (N = 27, 40.3%). The median treatment time with AIs was 47 (range, 30-60) months. Five patients (7.8%) experienced a fracture during or after AI treatment. Moreover, 51 (75%) patients were treated according to the SVGO recommendations. CONCLUSION: The fracture rate in our retrospective cohort was comparable to that in the larger phase III randomized trials. The adherence to bone health guidelines was satisfactory but still suboptimal. Clinicians should strictly adhere to the current bone health guidelines to ensure the best possible prevention of BREs and maintain bone health and cancer prognosis in patients with ER + eBC.

Use of alternative therapies in patients with dementia and mild cognitive impairment: a prospective, controlled study.

OBJECTIVES: To study the frequency and type of alternative therapies used in patients with dementia and Mild Cognitive Impairment. METHODS: In a prospective study, 77 outpatients and 62 healthy volunteers were interviewed using a questionnaire concerning frequency, type and motivation of the use of alternative therapies. RESULTS: 47% of patients and 18% of control subjects used alternative therapies to treat or prevent disturbances of memory (p < 0.001). No correlation could be found between use of alternative medicine and professional education, severity of disease, religion or health insurance status (p > 0.05). The most commonly used substances were vitamins. Side effects remained unreported. 52% of patients were treated with conventional medications. Only 44% of the patients informed their physician about the use of alternative medicine. CONCLUSIONS: The use of alternative therapies, particularly vitamins, and herbal preparations of unknown efficacy is common among patients with dementia and MCI. Hence, the treating physician should actively inquire about their use as some preparations have pharmacological activity or could interact with other prescribed medications.

Timing of surgical antimicrobial prophylaxis: a phase 3 randomised controlled trial.

BACKGROUND: Based on observational studies, administration of surgical antimicrobial prophylaxis (SAP) for the prevention of surgical site infection (SSI) is recommended within 60 min before incision. However, the precise optimum timing is unknown. This trial compared early versus late administration of SAP before surgery. METHODS: In this phase 3 randomised controlled superiority trial, we included general surgery adult inpatients (age ≥18 years) at two Swiss hospitals in Basel and Aarau. Patients were randomised centrally and stratified by hospital according to a pre-existing computer-generated list in a 1:1 ratio to receive SAP early in the anaesthesia room or late in the operating room. Patients and the outcome assessment team were blinded to group assignment. SAP consisted of single-shot, intravenous infusion of 1·5 g of cefuroxime, a commonly used cephalosporin with a short half-life, over 2-5 min (combined with 500 mg metronidazole in colorectal surgery). The primary endpoint was the occurrence of SSI within 30 days of surgery. The main analyses were by intention to treat. The trial is registered with ClinicalTrials.gov, number NCT01790529. FINDINGS: Between Feb 21, 2013, and Aug 3, 2015, 5580 patients were randomly assigned to receive SAP early (2798 patients) or late (2782 patients). 5175 patients (2589 in the early group and 2586 in the late group) were analysed. Median administration time was 42 min before incision in the early group (IQR 30-55) and 16 min before incision in the late group (IQR 10-25). Inpatient follow-up rate was 100% (5175 of 5175 patients); outpatient 30-day follow-up rate was 88·8% (4596 of 5175), with an overall SSI rate of 5·1% (234 of 4596). Early administration of SAP did not significantly reduce the risk of SSI compared with late administration (odds ratio 0·93, 95% CI 0·72-1·21, p=0·601). INTERPRETATION: Our findings do not support any narrowing of the 60-min window for the administration of a cephalosporin with a short half-life, thereby obviating the need for increasingly challenging SAP timing recommendations. FUNDING: Swiss National Science Foundation, Hospital of Aarau, University of Basel, Gottfried und Julia Bangerter-Rhyner Foundation, Hippocrate Foundation, and Nora van Meeuwen-Häfliger Foundation.

Etiological Observations in Seven Patients with Pancreatic Neuroendocrine Tumors (PNETs).

BACKGROUND/AIM: Pancreatic neuroendocrine tumors (PNETs) are uncommon malignancies of largely unknown pathogenesis. Observations on patients and their families can provide clues on etiology. PATIENTS AND METHODS: In a medical oncology practice cohort of 2,087 patients 5 females and 2 males with PNETs have been identified. RESULTS: Observations of etiologic interest have been made in 2 patients with PNETs. One female patient belongs to a kidney cancer family with a balanced translocation t(3;11)(q13;q21). A second female patient with PNET had a de novo translocation (t3;5)(q27;q14), its braking point could contain a tumor suppressor gene. CONCLUSION: Chromosome studies in patients with PNETs point to an etiologic role of balanced translocations.

Lymph Node Surgery - Stepwise Retirement for the Breast Surgeon?

Axillary lymph node dissection (ALND) has been standard of care for all patients with breast cancer until the 1990s. The stepwise retreat of breast surgeons from the axilla began after the introduction of the sentinel lymph node procedure. The evidence based clinical trend toward the omission of ALND has advanced to include patients with affected nodes, and several ongoing randomized controlled trials are evaluating the remaining indications for ALND. Conflicting with this trend toward less axillary surgery, indication and extent of regional nodal irradiation are currently broadened, equally supported by evidence from randomized trials. The present review summarizes this conflicting evidence, presents ongoing trials, and discusses the current and future optimal regional management of patients with affected nodes.