BACKGROUND AND OBJECTIVES: Hypertherm intraperitoneal chemotherapy (HIPEC) is increasingly used in the treatment of ovarian, tubal, and primary peritoneal cancer (OC). The aim was to evaluate short-term morbidity of cytoreductive surgery (CRS) and carboplatin HIPEC.
METHODS: Prospective feasibility study performed from January 2016 to December 2017. Twenty-five patients with primary OC (FIGO III-IV) received upfront or interval CRS combined with carboplatin HIPEC at dose 800 mg/m
RESULTS: No deaths (grade 5) or grade 4 adverse events were observed. Eleven patients (44.0%) experienced at least one grade 3 adverse event, the most common being an infection (28.0%) and neutropenia (12.0%). The reoperation rate was 8.0%. The median hospital stay was 14 days (range 9-25 days), and five patients (25.0%) were readmitted within 30 days after surgery. Median time from surgery to the administration of the first dose of systemic chemotherapy was 41 days (range 24-81 days).
CONCLUSION: Our small-scale prospective study supports that CRS and carboplatin HIPEC used for primary advanced-stage OC is feasible with acceptable morbidity.

Blocking programmed death 1 (PD-1) may enhance the durability of anti-tumor responses that are induced by the combined inhibition of BRAF and MEK

Surgical resection of pancreatic cancer offers a chance of cure, but currently only 15-20% of patients are diagnosed with resectable disease, while 30-40% are diagnosed with non-metastatic, unresectable locally advanced pancreatic cancer (LAPC). Treatment for LAPC usually involves systemic chemotherapy, with the aim of controlling disease progression, reducing symptoms and maintaining quality of life. In a small proportion of patients with LAPC, primary chemotherapy may successfully convert unresectable tumours to resectable tumours. In this setting, primary chemotherapy is termed 'induction therapy' rather than 'neoadjuvant'. There is currently a lack of data from randomized studies to thoroughly evaluate the benefits of induction chemotherapy in LAPC, but Phase II and retrospective data have shown improved survival and high R0 resection rates. New chemotherapy regimens such as nab-paclitaxel + gemcitabine and FOLFIRINOX have demonstrated improvement in overall survival for metastatic disease and shown promise as neoadjuvant treatment in patients with resectable and borderline resectable disease. Prospective trials are underway to evaluate these regimens further as induction therapy in LAPC and preliminary data indicate a beneficial effect of FOLFIRINOX in this setting. Further research into optimal induction schedules is needed, as well as guidance on the patients who are most suitable for induction therapy. In this expert opinion article, a panel of surgeons, medical oncologists and gastrointestinal oncologists review the available evidence on management strategies for LAPC and provide their recommendations for patient care, with a particular focus on the use of induction chemotherapy.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population.
METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival.
RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 10
CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

The human epidermal growth factor receptor 2 (HER2) is an oncogene targeted by several kinase inhibitors and therapeutic antibodies. While the endosomal trafficking of many other receptor tyrosine kinases is known to regulate their oncogenic signalling, the prevailing view on HER2 is that this receptor is predominantly retained on the cell surface. Here, we find that sortilin-related receptor 1 (SORLA; SORL1) co-precipitates with HER2 in cancer cells and regulates HER2 subcellular distribution by promoting recycling of the endosomal receptor back to the plasma membrane. SORLA protein levels in cancer cell lines and bladder cancers correlates with HER2 levels. Depletion of SORLA triggers HER2 targeting to late endosomal/lysosomal compartments and impairs HER2-driven signalling and in vivo tumour growth. SORLA silencing also disrupts normal lysosome function and sensitizes anti-HER2 therapy sensitive and resistant cancer cells to lysosome-targeting cationic amphiphilic drugs. These findings reveal potentially important SORLA-dependent endosomal trafficking-linked vulnerabilities in HER2-driven cancers.

Episodic and ongoing hypoxaemia are well-described after surgery, but, to date, no studies have investigated the occurrence of episodic hypoxaemia following minimally-invasive colorectal surgery performed in an enhanced recovery setting. We aimed to describe the occurrence of postoperative hypoxaemia after minimally-invasive surgery in an enhanced recovery setting, and the association with morphine use, incision site, fluid intake and troponin increase. We performed a prospective observational study of 85 patients undergoing minimally-invasive surgery for colorectal cancer between 25 August 2016 and 17 August 2017. We applied a pulse oximeter with a measurement rate of 1 Hz immediately after surgery either until discharge or until two days after surgery, and recorded the oxygen saturation. We measured troponin I during the first four days after surgery, or until discharge. The median (IQR [range]) length of stay was 3 (2-4 [1-38]) days. Thirty-six percent of patients spent more than 1 h below an oxygen saturation of 90% (4.2% of the day), and with a median (IQR [range]) proportion of 1.3 (0.2-11.1 [0.0-21.4])% of the day spent with an oxygen saturation below 88%. We found no associations between time spent below an oxygen saturation of 88% and morphine use (p = 0.215), fluid intake (p = 0.446), complications (p = 0.808) or extraction site (p = 0.623). Postoperative increases in troponin I were associated both with time spent below an oxygen saturation of 88% (p = 0.026) and hypopnoea episodes (p = 0.003). Even with minimally-invasive surgery and enhanced recovery after surgery, episodic hypoxaemia and hypopnoea episodes are common, but are not associated with morphine use, fluid intake or incision site. Further studies should investigate the relationship between hypoxaemia and troponin increase.

BACKGROUND/AIM: Ovarian cancer (OC) is the 5th most common cancer among European women. Approximately 70-80% of OC is diagnosed at advanced stage resulting in an elevated mortality rate. The aim of this study was to examine whether Annexin A2 and S100A10 expression can be used as prognostic markers for epithelial ovarian cancer (EOC).
MATERIALS AND METHODS: Expression of Annexin A2 and S100A10 was evaluated in EOC tissue samples (n=303) by immunohistochemistry. The staining of the membrane, cytoplasmic and stroma was assessed according to intensity.
RESULTS: The expression of both markers correlated to histological subtype, histological grading, International Federation of Gynecology and Obstetrics (FIGO) stage, and macro-radical surgery. Univariate Cox regression analysis showed that Annexin A2 and S100A10 in stromal tissue correlated with shorter overall survival (OS). Multivariate Cox regression analysis demonstrated no independent prognostic significance of stromal Annexin A2 expression.
CONCLUSION: High expression of Annexin A2 and S100A10 in stromal tissue from EOC patients was associated with reduced OS; however, no independent prognostic value was found for any of the markers.

In recent years, following the improved prognosis of patients with cancer, interest and attention has grown around fertility issues in these patients. International guidelines on fertility preservation in patients with cancer recommend that physicians discuss with all patients of reproductive age (or their parents/guardians, if children) the risk of infertility arising from their cancer or its treatment. Oncofertility counselling is recommended at the earliest opportunity and prior to cancer treatment, to help patients make informed decisions on pursuing fertility preservation. Currently, however, such discussions are not being routinely held. In June 2017, an esteemed group of European oncofertility experts met to discuss current unfulfilled needs in oncofertility for female cancer patients. This expert group has produced here a number of key recommendations in order to guide oncologists, haematologists, and other involved professionals with oncofertility discussions and appropriate referrals for further fertility preservation counselling and follow-up.

BACKGROUND: Risk factors for local recurrence after mastectomy in ductal carcinoma in situ (DCIS) emerged as a grey area during the second "Assisi Think Tank Meeting" (ATTM) on Breast Cancer.
AIM: To review practice patterns of post-mastectomy radiation therapy (PMRT) in DCIS, identify risk factors for recurrence and select suitable candidates for PMRT.
METHODS: A questionnaire concerning DCIS management, focusing on PMRT, was distributed online via SurveyMonkey.
RESULTS: 142 responses were received from 15 countries. The majority worked in academic institutions, had 5-20 years work-experience and irradiated <5 DCIS patients/year. PMRT was more given if: surgical margins <1 mm, high-grade, multicentricity, young age, tumour size >5 cm, skin- or nipple- sparing mastectomy. Moderate hypofractionation was the most common schedule, except after immediate breast reconstruction (57% conventional fractionation).
CONCLUSIONS: The present survey highlighted risk factors for PMRT administration, which should be further evaluated.

BACKGROUND: A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma.
METHODS: In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821.
FINDINGS: Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation.
INTERPRETATION: Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma.
FUNDING: F Hoffmann-La Roche Ltd and Genentech Inc.

OBJECTIVE: As the development and progression of colorectal cancer (CRC) are known to be affected by the immune system, cell subsets such as T cells, natural killer (NK) cells, and natural killer T (NKT) cells are considered interesting targets for immunotherapy and clinical biomarker research. Until now, the role of systemic immune profiles in tumor progression remains unclear. In this study, we aimed to characterize the immunophenotype of circulating T cells, NK cells, and NKT-like cells in patients with CRC, and to subsequently correlate these immunophenotypes to clinical follow-up data.
METHODS: Using multiparameter flow cytometry, the subset distribution and immunophenotype of T cells (CD3
RESULTS: CRC patients showed profound differences in immune cell subset distribution and their immunophenotype compared to healthy donors, as characterized by increased percentage of regulatory T cells, and reduced expression level of the natural cytotoxicity receptors NKp44 and NKp46 on both CD56
CONCLUSION: The altered phenotype of circulating immune cell subsets in CRC and its association with clinical outcome highlight the potential use of PBMC subsets as prognostic biomarkers in CRC, thereby contributing to better insight into the role of systemic immune profiles in tumor progression.

Background: Chemotherapy as an important tool for cancer treatment faces many obstacles such as multidrug resistance and adverse toxic effects on healthy tissues. Drug delivery systems has opened a new window to overcome these problems. There has been a strong interest development of new platform and system for delivof chemotherapeutic agents.
Purpose: In the present study, a green synthesis method was chosen and performed for preparation of a novel amphoteric calix[4]arene (Calix) macrocycle with low toxicity to the human body.
Materials and methods: The amphoteric Calix was coated on the surface of Fe
Results: In vitro biological studies including hemolysis assay, erythrocytes sedimentation rate, red blood cells aggregation, cyto cellular internalization, and apoptosis evaluations were performed. Based on results, the developed nanocarrier has many advantages and capability for an efficient codelivery of DOX and MTX, which has a highly potent ability to kill cancer cells.
Conclusion: All these results persuade us, this nanocarrier could be effectively used for cancer therapy of MCF7 breast cancer cells and is suitable for use in further animal studies in future investigations.

BACKGROUND AND OBJECTIVES: We investigated implant revision, implant failure, and amputation risk after limb-sparing bone tumor surgery using the Global Modular Replacement System (GMRS) tumor prosthesis in patients suffering from bone sarcomas (BS), giant cell tumors (GCT), or metastatic bone disease (MBD).
MATERIAL AND METHODS: A retrospective study of a nationwide consecutive cohort (n = 119, 47 [12-81] years, M/F = 65/54) having limb-sparing surgery and reconstruction using the GMRS tumor prosthesis due to bone tumors (BS/GCT/MBD = 70/8/41) from 2005 to 2013. Anatomical locations were as followed: distal femur (n = 49), proximal femur (n = 41), proximal tibia (n = 26), or total femur (n = 3). Kaplan-Meier survival analysis and competing risk analysis with death as a competing risk were used for statistical analysis.
RESULTS: For BS and GCT patients, 5-year patient survival was 72% (95% confidence interval [CI]: 59-85%) and for MBD 33% (95% CI: 19-48%). Thirty-two patients underwent revision surgery (5-year revision incidence 14%; 95% CI: 8-21%). Twelve patients had revision of bone-anchored parts (implant failure) with a 5-year revision incidence 6% (95% CI: 2-10%). Ten amputations were performed due to local relapse (n = 9) or recurrent infections (n = 1) with a 5-year incidence of amputation: 8% (95% CI: 3-13%).
CONCLUSIONS: We identified a low risk of revision and amputation when using the GMRS tumor prosthesis for limb-sparing bone tumor.

OBJECTIVES: To derive and validate a practical scoring system for identification of endometrial cancer (EC) or atypical hyperplasia (AH) using transvaginal ultrasonography (TVS) and gel infusion sonography (GIS) in women with postmenopausal bleeding (PMB).
STUDY DESIGN: Endometrial pattern was correlated with endometrial pathology in consecutive women with PMB in both a derivation study (N = 164) and a validation study (N = 711). Logistic regression was used to derive and validate two scoring systems (A and B) for prediction of EC/AH: scoring system A was Doppler score + interrupted endo-myometrial junction (IEJ) (2 points); and scoring system B was Doppler score + IEJ (1 point) + Irregular Endometrial Outline (IESO) by GIS (1 point); the Doppler score was based on the presence of more than one single or double vessel (1 point) + multiple vessels (1 point) + large vessels (1 point).
OUTCOME MEASURES: Diagnostic performance and calibration curves for identification of EC/AH.
RESULTS: Both scoring systems had good observer agreement.
VALIDATION DATA: Scoring was most effective with endometrial thickness (ET) ≥ 8 mm. Both scoring systems were well calibrated and performed satisfactorily in women with ET ≥ 8 mm. The sensitivity and specificity of a score of ≥ 2 points in system A were 92% and 84%; the respective values were 89% and 88% in system B.
CONCLUSIONS: Scoring was highly efficient in identifying EC/AH. Four risk groups of EC/AH may guide the management of women with PMB: very low (ET < 4 mm), low (ET 4-7.9 mm), intermediate (ET ≥ 8 mm and score < 2 points) and high risk (ET ≥ 8 mm and score ≥ 2 points).

This paper reviews the conceptual, methodological, and technical innovations underpinning strategies for adaptive target volume selection and risk-adapted dose prescription in cervical cancer. An adaptive target volume concept has been developed which reflects tumor shrinkage at the end of initial chemo-radiation, which serves for an image-guided boost delivered through brachytherapy, with a risk-adapted dose prescription to different gross tumor- and clinical target volumes defined at diagnosis and after 40-50Gy external beam radiotherapy, and adaptation of the treatment technique according to the topography of the tumor after response and adjacent organs at risk. Clinical results of these innovations are presented based on prospective and retrospective multi-center trials (IntErnational study on MRI-based BRachytherapy in locally Advanced CErvical cancer [EMBRACE], retroEMBRACE) with large patient cohorts (n = 1416, n = 731). The potential benefit of applying these strategies and using a specific multi-parametric dose prescription protocol are explored (EMBRACE-II) and overall current and future research strategies are outlined. The challenges of dissemination and implementation of these complex new techniques into clinical practice are discussed.

The world is embracing the information age, with real-time data at hand to assist with many decisions. Similarly, in cancer radiotherapy we are inexorably moving toward using information in a smarter and faster fashion, to usher in the age of real-time adaptive radiotherapy. The three critical steps of real-time adaptive radiotherapy, aligned with driverless vehicle technology are a continuous see, think, and act loop. See: use imaging systems to probe the patient anatomy or physiology as it evolves with time. Think: use current and prior information to optimize the treatment using the available adaptive degrees of freedom. Act: deliver the real-time adapted treatment. This paper expands upon these three critical steps for real-time adaptive radiotherapy, provides a historical context, reviews the clinical rationale, and gives a future outlook for real-time adaptive radiotherapy.

The selective expression of CD137 on cells of the immune system (e.g., T and DC cells) and oncogenic cells in several types of cancer leads this molecule to be an attractive target to discover cancer immunotherapy. Therefore, specific antibodies against CD137 are being studied and developed aiming to activate and enhance anti-cancer immune responses as well as suppress oncogenic cells. Accumulating evidence suggests that anti-CD137 antibodies can be used separately to prevent tumor in some cases, while in other cases, these antibodies need to be co-administered with other antibodies or drugs/vaccines/regents for a better performance. Thus, in this work, we aim to update and discuss current knowledge about anti-cancer effects of anti-CD137 antibodies as mono- and combined-immunotherapies.

Our previous studies have shown that diamond nanoparticles (NDs) exhibited antiangiogenic and proapoptotic properties in vitro in glioblastoma multiforme (GBM) cells and in tumors in vivo. Moreover, NDs inhibited adhesion, leading to the suppression of migration and invasion of GBM. In the present study, we hypothesized that the NDs might also inhibit proliferation and cell cycle in glioma cells. Experiments were performed in vitro with the U87 and U118 lines of GBM cells, and for comparison, the Hs5 line of stromal cells (normal cells) after 24 h and 72 h of treatment. The analyses included cell morphology, cell death, viability, and cell cycle analysis, double timing assay, and gene expression (

Paediatric radiotherapy comes at the expense of increased risk of late effects due to out-of-field dose caused not only by the treatment itself but also by image guidance. This study examined how the out-of-field dose to selected radiosensitive organs was affected by applying a 1 mm lead shielding during delivery of volumetric-modulated arc therapy (VMAT) for paediatric brain cancer. The study also investigated how the out-of-field dose to the same organs was affected by the use of flattening-filter free (FFF) beams. Out-of-field doses to the thyroid, breast and testes were measured using thermoluminescence dosimeters inserted in two anthropomorphic phantoms equivalent to a 1-year and 5-year old child. Coplanar VMAT plans were prepared for 6 MV and 6 MV FFF photon beams and delivered using a Varian TrueBeam linear accelerator, with and without lead shielding applied to the phantoms. The measured out-of-field doses were as large as 200,9 cGy for the whole treatment, with associated secondary cancer risk being as large as 1,1%. Shielding of the phantoms was found to decrease the out-of-field dose by up to 24%. The use of 6 MV FFF beams yielded a decrease in the dose to the testes by 21-42% compared to 6 MV, while in one case increasing the dose to the thyroid by 18%. The observation that only doses to organs distant to the primary irradiated volume were significantly decreased for FFF can be explained by an increase in internal scatter caused by the softer energy spectrum of the Varian FFF beam.

MicroRNA-21 (miR-21) is upregulated in many cancers including colon cancers and is a prognostic indicator of recurrence and poor prognosis. In colon cancers, miR-21 is highly expressed in stromal fibroblastic cells and more weakly in a subset of cancer cells, particularly budding cancer cells. Exploration of the expression of inflammatory markers in colon cancers revealed tumor necrosis factor alpha (TNF-α) mRNA expression at the invasive front of colon cancers. Surprisingly, a majority of the TNF-α mRNA expressing cells were found to be cancer cells and not inflammatory cells. Because miR-21 is positively involved in cell survival and TNF-α promotes necrosis, we found it interesting to analyze the presence of miR-21 in areas of TNF-α mRNA expression at the invasive front of colon cancers. For this purpose, we developed an automated procedure for the co-staining of miR-21, TNF-α mRNA and the cancer cell marker cytokeratin based on analysis of frozen colon cancer tissue samples (

BACKGROUND: In case of response to chemotherapy, unresectable liver metastases from colorectal cancer can be converted to resectable and thereby obtain a chance of cure. The primary aim of this trial was to evaluate the response rate with intrahepatic oxaliplatin in combination with systemic 5-FU +/- cetuximab. Secondary aims were to evaluate the conversion rate from unresectable to resectable liver metastases, median progression-free survival, median overall survival, and toxicity.
METHODS: Forty-five chemo-naïve patients with liver metastases from colorectal cancer were treated in a prospective phase II trial. Calcium folinate and 5-FU were delivered systemically while oxaliplatin was delivered alternating between systemic and intrahepatic administration. When oxaliplatin was delivered intrahepatic-ally, infusion time was reduced to 10 min followed by embolic material. In patients with KRAS wild-type tumors, cetuximab was added.
RESULTS: The treatment was well tolerated and only pain in the liver and a mild increase in liver enzymes were observed after intrahepatic oxaliplatin. The patients obtained a response rate of 82%. Further, 58% converted from having unresectable to resectable liver metastases. The median overall survival and progression-free survival were 38.7 months (95% confidence interval [CI] 33.0-44.3) and 12.9 months (95% CI 10.2-15.6), respectively.
CONCLUSIONS: Intrahepatic infusion of oxaliplatin in 10 min with systemic 5-FU to patients with chemo-naïve colorectal cancer is feasible and with low toxicity. A high response rate and long median overall survival were obtained.

Objective To explore whether gestational prolactin and breast increase are markers of metabolic health in pregnancy and on long-term, in PCOS. Design Follow-up study. Women with PCOS, according to the Rotterdam criteria (n = 239), former participants of the randomized controlled trial (RCT) PregMet were invited, 131 participated in the current follow-up study, at mean 8 years after pregnancy. Methods Metformin 2000 mg/day or placebo from first trimester to delivery in the original RCT. No intervention in the current study. Prolactin was analyzed in the first trimester and at gestational week 32 and metabolic characteristics which are part of the metabolic syndrome and measures of glucose homeostasis were examined. Metabolic health was also evaluated according to breast increase versus lack of breast increase during pregnancy. Results Prolactin increase in pregnancy was negatively correlated to BMI (P = 0.007) and systolic blood pressure (P ≤ 0.001) in gestational week 32. Prolactin at gestational week 32 was negatively correlated to BMI (P = 0.044) and visceral fat area (P = 0.028) at 8-year follow-up in an unadjusted model. Prolactin at gestational week 32 showed no associations to metabolic health at follow-up when baseline BMI was adjusted for. Women who reported lack of breast increase during pregnancy, had higher BMI (P = 0.034), waist-hip ratio (P = 0.004), visceral fat area (P = 0.050), total cholesterol (P = 0.022), systolic (P = 0.027) and diastolic blood pressure (P = 0.011) at 8-year follow-up. Conclusion High prolactin levels and breast increase in pregnancy were associated with a more favorable long-term metabolic health in women with PCOS. Both prolactin and breast increase may be mediated by gestational BMI.

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

INTRODUCTION: The EORTC QLQ-CR29 is a patient-reported outcome measure to evaluate health-related quality of life among colorectal cancer patients in research and clinical practice. The aim of this systematic review was to investigate whether the initial positive results regarding the measurement properties of the QLQ-CR29 are confirmed in subsequent studies.
METHODS: A systematic search of Embase, Medline, PsycINFO, and Web of Science was conducted to identify studies investigating the measurement properties of the QLQ-CR29 published up to January 2019. For the 11 included studies, data were extracted, methodological quality was assessed, results were synthesized, and evidence was graded according to the COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) methodology on the measurement properties: structural validity, internal consistency, reliability, measurement error, construct validity (hypothesis testing, including known-group comparison, convergent and divergent validity), cross-cultural validity, and responsiveness.
RESULTS: Internal consistency was rated as "sufficient," with low evidence. Reliability was rated as "insufficient," with moderate evidence. Construct validity (hypothesis testing; known-group comparison, convergent and divergent validity) was rated as "inconsistent," with moderate evidence. Structural validity, measurement error, and responsiveness were rated as "indeterminate" and could therefore not be graded.
CONCLUSION: This review indicates that current evidence supporting the measurement properties of the QLQ-CR29 is limited. Additionally, better quality research is needed, taking into account the COSMIN methodology.

OBJECTIVE: Little is known about long-term risk of depression in women treated for gynecological cancers. We aim to investigate risk for depression among these women compared to women without a history of cancer.
METHODS: We followed 16,833 women diagnosed with gynecological cancers between 1998 and 2013 and 138,888 reference women in nationwide registers for up to 19 years. Women with a history of severe psychiatric disorders, and those who had redeemed a prescription for antidepressants three years before study entry were excluded from analyses. Regression analyses were applied to compare the risk for antidepressant use among patients compared to reference women, and to investigate associations between socio-demographic as well as clinical risk factors and use of antidepressants.
RESULTS: We found an increased risk for antidepressant use among women treated for ovarian (HR 4.14, 95% CI 3.74-4.59), endometrial (HR 2.19, 95% CI 1.97-2.45), and cervical cancer (HR 3.14, 95% CI 2.74-3.61) one year after diagnosis. This increased risk persisted years after diagnosis in all three groups, with the longest (up to eight years) found for ovarian cancer. Advanced disease was strongly associated with antidepressant use followed by short education, and comorbidity.
CONCLUSIONS: Women diagnosed with gynecological cancer have an increased risk for depression compared to reference women. The risk remains increased for years after diagnosis throughout and beyond standard oncological follow-up care. Advanced disease, short education, and comorbidity are factors associated with antidepressant use in this patient group.

BACKGROUND: A growing body of evidence suggests that exercise training has beneficial effects in cancer patients. The aim of the present study was to investigate the molecular basis underlying these beneficial effects in skeletal muscle from cancer patients.
METHODS: We investigated expression of selected proteins involved in cellular processes known to orchestrate adaptation to exercise training by western blot. Skeletal muscle biopsies were sampled from ten cancer patients before and after 4-7 weeks of ongoing chemotherapy, and subsequently after 10 weeks of continued chemotherapy in combination with exercise training. Biopsies from ten healthy matched subjects served as reference.
RESULTS: The expression of the insulin-regulated glucose transporter, GLUT4, increased during chemotherapy and continued to increase during exercise training. A similar trend was observed for ACC, a key enzyme in the biosynthesis and oxidation of fatty acids, but we did not observe any changes in other regulators of substrate metabolism (AMPK and PDH) or mitochondrial proteins (Cyt-C, COX-IV, SDHA, and VDAC). Markers of proteasomal proteolysis (MURF1 and ATROGIN-1) decreased during chemotherapy, but did not change further during chemotherapy combined with exercise training. A similar pattern was observed for autophagy-related proteins such as ATG5, p62, and pULK1 Ser
CONCLUSIONS: Molecular signaling cascades involved in exercise training are disturbed during cancer and chemotherapy, and exercise training may prevent further disruption of these pathways.
TRIAL REGISTRATION: The study was approved by the local Scientific Ethics Committee of the Central Denmark Region (Project ID: M-2014-15-14; date of approval: 01/27/2014) and the Danish Data Protection Agency (case number 2007-58-0010; date of approval: 01/28/2015). The trial was registered at http//www.clinicaltrials.gov (registration number: NCT02192216; date of registration 07/17-2014).

Objectives: This study aims to assess the impact of surgical margin and malignancy grade on overall survival (OS) and local recurrence free rate (LRFR) for soft tissue sarcomas (STS) of the thoracic wall.
Methods: This retrospective cohort study identified 88 patients, diagnosed and treated surgically for a nonmetastatic STS located in the thoracic wall between 1995 and 2013, using the population based and validated Aarhus Sarcoma Registry and Danish Sarcoma Registry. The Kaplan-Meier method was used to estimate OS and LRFR. Multivariate Cox analyses were used to determine prognostic factors for OS and LRFR.
Results: The 5-year OS was 55% (95% confidence interval (CI): 0.44-0.65) and 5-year LRFR was 77% (95% CI: 0.67-0.85). High malignancy grade and intralesional/marginal resection were identified as negative predictors for OS. High grade was the only prognostic factor associated with a lower LRFR.
Conclusions: In this large, single institution, study tumor grade was the key predictor for OS and LRFR. Surgical margin only statistically significantly influenced mortality, not local recurrence.

BACKGROUND: Women with Polycystic Ovary Syndrome (PCOS) present a heterogeneous reproductive and metabolic profile with an increased lifetime risk of Type 2 Diabetes (T2D). Early biomarkers of these metabolic disturbances in PCOS women have not been identified. The abundance of circulating insulin gene promotor cell-free DNA (INS cfDNA) was shown to be valuable as a predictive biomarker of β-cell death in individuals with Type 1 diabetes (T1D) as well as with gestational diabetes. Since β-cell death is common to the development of T1D as well as in T2D, we aimed to investigate if insulin-coding DNA is more abundant in circulation of PCOS women (vs Controls) and if their levels change after 6 yr. follow-up as a potential measure to predict future T2D.
METHODS: A cohort of 40 women diagnosed with PCOS according to Rotterdam 2003 criteria and eight healthy controls were examined at baseline and 6 years follow-up. Clinical measurements for evaluation of glucose homeostasis as well as blood/serum samples were obtained at each visit. Methylated and unmethylated INS cfDNA were quantified using droplet digital PCR. Differences between groups were assessed using Kruskall-Wallis test and Wilcoxon Signed rank test.
RESULTS: At baseline, there was no detectable difference in copy number (copies/μL) of methylated (p = 0.74) or unmethylated INS cfDNA (p = 0.34) between PCOS and Control groups. At follow up, neither methylated (p = 0.50) nor unmethylated INScfDNA levels (p = 0.48) differed significantly between these groups. Likewise, when pooling the groups, there was no difference between baseline and follow up, in terms of copies of methylated or unmethylated INS cfDNA (p = 0.38 and p = 0.52, respectively). There were no significant correlations between counts of unmethylated or methylated cfDNA and the clinical measurements of β-cell function and pre-diabetes.
CONCLUSION: The circulating level of unmethylated and methylated INScfDNA is similar between PCOS and Controls and cannot be used to predict islet β-cell loss and progression to Type 2 diabetes in a 6-year follow-up.
TRIAL REGISTRATION: The Danish Data Protection Agency (REG-31-2016. Approval: 01-12-2015) and by the Danish Scientific Ethical committee of Region Zealand (Journal no. SJ-525. Approval: 13-06-2016), Clinicaltrials.gov, ( NCT03142633 , registered 1. March, 2017, Retrospectively registered).

AIM: The aim of the study was to examine if statin exposure during neoadjuvant chemoradiotherapy improves oncological outcomes in patients with rectal cancer.
PATIENTS AND METHODS: The study cohort consisted of patients who were undergoing neoadjuvant chemoradiotherapy and resection for rectal cancer. The statin users were matched 1:1 with non-users using propensity score-based matching. The primary outcome of the study was disease-free survival; secondary outcomes were recurrence-free survival and all-cause mortality.
RESULTS: A total of 704 patients were included in the study. Disease-free survival was not different between the two groups [hazard ratio (HR)=0.98, 95% confidence intervaI (CI)=0.77-1.25, p=0.88]. Both recurrence-free survival (HR=1.02, 95% CI=0.74-1.39, p=0.92) and all-cause mortality (HR=0.92, 95% CI=0.68-1.23, p=0.56) were similar for the two groups.
CONCLUSION: The study does not support that statin use is associated with response to neoadjuvant chemoradiotherapy in terms of disease-free survival, recurrence-free survival or all-cause mortality.