Patients with AR+ had better OS, 35.50 vs. 33.40 months, with p = 0.027. Moreover, PFS was prolonged for patients AR+, 32.60 vs. 30.50 months, with p = 0.38. Triple negative breast cancer (TNBC) patients had lower OS and no difference was observed for PFS. Conclusions: Both OS and PFS were favorably influenced by the presence of AR. TNBC had worse outcomes compared with patients with hormonal or/and Her 2/neu positive disease in terms of OS.Background: We investigated the correlation between the androgen receptor (AR) and immunohistochemistry (IHC) as a prognostic factor in breast cancer (BC). AR is expressed in 60–80% of BC. Methods: We evaluated the prognostic values of AR expression among 143 patients with BC for 36 months. The protocol was amended to measure androgen, estrogen and progesterone receptor expression by IHC and the percentage of hormone positive nuclei was quantified. We determined and quantified the Her2/neu status using IHC and in situ hybridization. The methodology consisted in using a Kaplan–Meier analysis and restricted mean survival time up to 36 months. The principal endpoints of the study were overall survival (OS) and progression free survival (PFS). Results: 57% of patients ( Breast cancer (BC) is the most frequent type of cancer among women worldwide. In this disease, although many/ most of the main risk factors are known, as well as the pathogenic pathways, the mechanism of metastasis and therapeutic strategies, death related cancer remains very high. The widespread possibilities of neo-adjuvant or adjuvant therapy have reduced mortality, but there are some patients over treated and others undertreated. For a complete characterization of a breast cancer, American Joint Committee on Cancer (AJCC) and World Health Organization (WHO) guidelines require classification of malignant tumors (TNM) and a minimal histo-pathological report that must include the grade of differentiation according to Nottingham scale and an immune-histo-chemical panel for prognostic and predictive factors for molecular classification in luminal or non-luminal subtypes. Those are hormone receptor expression, estrogen (ER) and progesterone (PR), proliferation index measured using antigen Ki 67 and the HER2neu oncogene status. Even with this stratification that allows an increasing specificity for certain treatments, novel expensive models of appreciating the opportunity of treatment in selected population , we consider that it would be of great value to have supplementary prognostic factors, economically reliable that may help the clinicians to personalize therapies ,2,3. By definition, a prognostic factor provides information on clinical outcome at the moment of diagnosis. Such markers are predominantly referred to the evolution of the tumor and can provide information related to growth, invasion and metastatic potential. Mammographic features, pathologic aspects or receptor status are prognostic factors used in clinical routine ,5,6.Estrogen, progesterone and androgen receptor (AR) are sex steroid hormone receptors, which have a primordial role in development and spread of BC. Even more, estrogen blockade using selective estrogen modulators and aromatase inhibitors are fundamental therapeutic strategies for BC patients ,8.The case of a patient where a receptor for androgen is identified and expressed in BC is very interesting considering the fact that the tumor is predominantly estrogen dependent. It has been noted that 70–90% of BC patients overexpress the AR with several studies indicating that AR might be a predictive or prognostic factor and a drug target in BC [Taking into account the heterogeneity of the disease, that could indicate the lack of response to hormonal treatments in some BC expressing hormones, the AR could turn up to be as a new marker and potential new therapeutic target, following the possibilities opened up by the AR inhibitors approved for the treatment of prostate cancer .An important aspect is to understand the locations of the AR and its functional significance to better reveal its complex role in BC. There is increasing evidence to suggest the existence of membrane ARs, however their exact mechanism and structure have still to be elucidated. Debate surrounds whether sex steroid receptors can be located in the cell membrane or localized at the cytoplasmic membrane. Some studies suggest that membrane AR is the classical AR receptor, but a modification such as palmitoylation enables translocation to the membrane ,12.Despite the location and the cell mechanism of AR, an important aspect is to demonstrate the impact of blood androgens. Studies reported in breast cancers a relation between mediation of gene transcription by conjugated testosterone (that does not cross the cell membrane) and non-conjugated ligand. It was discovered that in an AR negative cell line a large proportion of the genes modified by testosterone were also affected by the conjugated form of testosterone. However, in AR positive cells a significant number of genes were induced with testosterone and they were not observed with conjugated ligand treatment ,14.The fact that AR has a part to play in the development of BC seems to be indisputable and brought up by preclinical and clinical findings, even though the influence of circulating androgens in the progression of BC is not fully understood. Although the BC diagnosis is very accurate using the IHC protocols, there are some cases, especially the triple negatives which are challenging. Sry-related HMg-Box gene 10, GATA-binding protein 3, gross cystic disease fluid protein 15, mammaglobin and AR are useful IHC markers which may help on differential diagnosis of a metastatic disease .AR is one of the members of the steroid receptor family, which includes estrogen and progesterone receptors. It is expressed in both normal and malignant tissue, in about 60–80% of breast carcinomas, in different types of histology. While the estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor (Her 2/neu) are routinely assessed in BC for helping in prognosis and treatment decision- making, this is not the case for AR. Recently, clinical research has shifted the interest to AR as a possible therapeutic option in BC treatment, due to the high degree of presence on the tumor cells and lack of therapeutic drugs ,18,19.Preclinical and clinical data showed that the effect of AR is different for each hormonal status of cancer cells. In ER positive cells, in vitro models showed that AR has an antagonistic effect to the estrogens. This may occur through competition between ER and AR for binding sites, at estrogen response elements, or through competition for transcriptional co- regulators. In terms of survival, population- based studies support the hypothesis that there is an inverse association between tumor AR expression and mortality in women with ER positive BC ,14.Preclinical studies have surmised that AR may enact its protective role by blocking ERα gene transcription, however, other studies in triple-negative and apocrine BC indicate that AR may act as a pseudo- ERα in this setting. There has also been some confounding clinical data in which AR positivity indicates lack of complete clinical response to neo-adjuvant chemotherapy in contrast to patients who are negative for both AR and Erα ,21,22,23The oncoprotein Her 2/ neu and the AR are positive in approximate 60% of BC. In this population, about 10% of the tumors with co-expression of those receptors were associated with less aggressive tumors, , so with better outcome in terms of survival ,24.AR is expressed in about 10–35% of triple negative breast cancer (TNBC), which does not express ER, PR and Her2/neu and tends to be more aggressive than other subtypes of BC. In this group of patients, the positive of AR is associated with better PFS and OS. This response was also seen in patients in whom the pathological complete response was not present after neo-adjuvant chemotherapy .In addition to the diagnostic and therapeutic side, targeting AR represented an important aspect to take in consideration. For instance, the interest was carried on molecules which may block the receptors or the interaction with AR pathways that cause cell proliferation. Bandini et al. suggested that a specific uptake can help the purpose to customize miRNAs as therapeutics alone or in combination with other oncologic treatments .In recent years there has been a growing interest in targeting the AR in BC either by using AR agonists such as enobosarm or by antagonizing AR actions using drugs primarily developed as therapeutic agents for prostate cancer, specifically bicalutamide, enzalutamide and the CYP17 inhibitor, abiraterone. Results from these trials have been varied with better outcomes reported in AR positive triple negative tumors ,28,29,30In the following subsections, we aim to categorize BC from the standpoint of the molecular stratification based on the receptors displayed on the tumor cell surface. This study was designed to evaluate the use of AR and IHC subtypes as prognostic markers in early and advanced BC cohorts. Our aim is to demonstrate the importance of routinely assessing the AR, helping the clinicians to have a good overview regarding the prognosis and to deliver the best treatment choice for each case.IHC is valuable to identify the tumor lineage in patients with poorly differentiated cancer, to suggest the specific tumor type and the origin of the tissue. The antibodies used in this technique are directed to specific cell components or cell products including enzymes, hormones, normal tissues components or tumor markers. Overall, IHC offers clinicians’ aspects related to the tumor, but also information about the therapeutic possibilities ,32.In BC patients, the IHC testing provides information on the status of hormone receptors. ER and PR evaluation are essential for all newly diagnosed cases of breast cancer, and when applicable, for recurrent/metastatic ones. Positive ER and PR expression is associated with longer disease-free status and overall survival and is an indicator of responsiveness to endocrine therapy ,2.For Her2/neu (ISH) for IHC 1+ or 2+ is used in conjunction with in situ hybridization to ensure a description as accurate as possible. The results of this analysis are useful for assessing the prognosis of patients, but also for delivering targeted molecular treatment .The IHC classification correlates well with intrinsic gene expression microarray categorization: ER/PR+, Her2− with Luminal A; ER/PR+, Her2+ or / and Ki 67 > 20% with Luminal B; ER/PR− Her2+ and ER/PR−.Her2− with triple negative/basal-like tumors. Apart from lending itself to subtype analyses of tumor when fresh tissue is not available, the IHC classification has prognostic and therapeutic implications, is inexpensive and readily available [We conducted a retrospective, observational study on the early and locally advanced BC patients treated in Elias Emergency Hospital Bucharest, Romania, between January 2014 and December 2019. Our research was carried out with the approval and in accordance with the guidelines of the local Ethics Committee. All the procedures in the study respect the ethical standards in the Helsinki Declaration, and the protocol was approved by the Ethics Committee with the code 7423/2018.One hundred and forty-three patients newly diagnosed with BC without metastasis disease were recruited in our hospital and submitted in our study. The mean age was 52 .Eligible patients were ages 18 years or older with an Eastern Cooperative Oncology Group status of 0 or 1, unilateral breast tumor, absence of pregnancy in the last 6 months and locally advanced BC. From this group of patients, we excluded the Human Immunodeficiency Virus (HIV) positive, Venereal Disease Research Laboratory (VDRL) positive or infection with B or C hepatic viruses. We also did not enroll patients who had abnormalities in the Pap smear test, until the histo-pathological confirmation of the benign result or had been diagnosed with cervical cancer ,35,36.All patients had IHC assay with staining for ER, PR, AR and for Her 2/neu. A cut-off for positivity of 1% positively stained nuclei was applied for ER and PR. Regarding the Her 2/neu status initial with IHC and, for the samples with 1 or 2+, we performed fluorescence ISH to confirm the status.Tumor staging was performed clinically or pathologically (if surgery was performed before chemotherapy) using TNM staging. In our study only 4% of patients were eligible to receive only hormonal therapy after surgery; most of the patients were candidates for chemotherapy according to their stage or pathological features.n = 68) of patients were not eligible for surgery and had to receive neo-adjuvant chemotherapy. Subsequently, for approximately 80% of those patients the surgeon performed lumpectomy and after that the patients received radiotherapy.The chemotherapy schedules were delivered under international guidance consultation. 47% . Following assessment of tumor invasiveness using hematoxylin and eosin-stained slides, a semi-quantitative scoring of AR fractions  of positively stained nuclei, irrespective of nuclear staining intensity, was performed. Nuclear staining in tumor cells was considered positive. Although the activated AR has membrane localization, in our study we assessed 110 kDa protein using IHC methods in order to increase the sensitivity of the AR detection method.In the evaluation and quantification of positively immune-stained cells, the most prevalent method that we used was the manual counting performed by the pathologist using a conventional microscope. We measured the cellular density of the images with > 100 positive cells/image, For category variables, the absolute frequencies  and the relative ones (percentages) were calculated. We used bar plots and dot charts for graphical representation. For continuous  variables, the following were measured: central tendency , tendency to variability , deviation of the symmetry distribution  and peak of distribution (kurtosis). We also tested the deviation from the normal distribution by means of the Shapiro-Wilk test of normality.Immune-histo-chemical evaluation was performed according to the percentage and intensity of tumor cells with brown nuclear staining. The intensity of staining was graded semi quantitatively as mild, moderate and strong. Tumors with nuclear staining of 1% or more were accepted as AR-positive, while tumors with AR were scored by a dedicated pathologist, blinded for clinical data, and were considered positive in case of staining in at least 1% of fractions of tumor cells, consistently with most recent studies and specified in a statistical plan ,38.ER, Data regarding clinical examination with local evaluation, imagistic assessment, histopathologic and IHC exam were collected at baseline and reviewed at each subsequent visit. Follow-up visits were scheduled every three months and all patients were followed for a maximum of 36 months.Submission of tumor tissues for AR screening was allowed for the first sample, either core biopsy or surgical intervention. All the samples were collected before any cancer treatment. The IHC assay was performed for ER, PR and her2/neu in different laboratories, under the international protocols. After the cancer confirmation the patients received chemotherapy or hormonal according to clinical stage. The evolution and response were assessed with clinical examination and CT scan every 12 weeks for the first 12 months, then every 24 weeks for the second year and then annually. The disease progression defined by the guidelines Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 was requested to objectify progressive disease.For the statistical analysis we had two principal end points: OS and PFS considering androgen receptors and IHC aspects. OS was measured from the date of surgery or biopsy to the date of death or up to 36 months. PFS was measured from the date of surgery or biopsy until the first local or distant recurrence.p < 0.05, considered statistically significant.For statistical analysis we used the R program, version 4.0.2  and survminer package. The sensitivity level was 95%, with Our research was carried out with the approval and in accordance with the guidelines of the local Ethics Committee. All the procedures in the study respect the ethical standards in the Helsinki Declaration, and the protocol was approved by the Ethics Committee with the code 7423/2018 and 223/2019.Both OS and PFS were measured using restricted mean survival time (RMST). RMST quantifies the time until the event occurs, illustrated survival functions, and conventionally reported an alternative to hazard ratios to express the magnitude of the treatment effect when comparing between groups. Due to this short follow-up period, 36 months, the median survival could not be calculated .n = 39)Group I: triple negative breast cancer (TNBC) (n = 22)Group II: hormonal receptors negative, Her 2/neu positive (n = 68)Group III: hormonal receptors positive, Her 2/neu negative (n = 14).Group IV: hormonal receptors positive, Her 2/neu positive  on the entire group of patients, Considering the ≥ 1% cut-off, AR was present in 57% of patients . When we compared the positive versus negative AR, we observed that the presence of AR has a favorable impact on the PFS Group I: triple negative breast cancer (TNBC) (n = 22)Group II: hormonal receptors negative, Her 2/neu positive (n = 68)Group III: hormonal receptors positive, Her 2/neu negative (n = 14).Group IV: hormonal receptors positive, Her 2/neu positive . The better outcome, with no events, was achieved in the group with hormonal receptors (estrogen and progesterone) and her 2/ neu positive  and all decisions were taken in the multidisciplinary tumor board. In our clinic, special attention is paid to patients with comorbidities. Each case is discussed with the specialized doctor together with detailed research of the specialized literature ,41,42.The routinely testing of other asymptomatic diseases is mandatory in our clinic. First and foremost, the assessment for both sexually transmitted diseases and screening for other types of cancers was performed for all patients .Adherence to the treatment is very important to ensure the optimal therapeutic response. All the efforts were made to avoid delay, dose reduction or discontinuation of treatment. Even delay that has no relation to toxicity  was managed so that chemotherapy could be administered exactly when necessary. However, in about 10% of patients dose reduction or discontinuation of one of the cytostatic was required.We assessed AR expression in 143 BC patients of different ages and with localized tumors and we found that this single marker was effective at predicting the evolution of the patients. This marker may impact both the OS and the PFS, if it is positive. Notably however, this association was not significant when we compared the entire group of patients. The OS was improved with 2.1 months in the AR positive arm, compared with the AR negative group.A potential limitation of this study is the absence of the same treatment for this cohort, including the fact that treatment algorithms are likely to have been inconsistent over the six years’ time frame of this study. In addition, we have some patients with delayed scheduled treatment, so with less dose intensity and some patients with adverse events  for which it was necessary to postpone the treatment, to adjunct chemotherapy treatment or to interrupt it.The chemotherapy regimens used in the study were delivered according to the international protocols in force, published by European Society for Medical Oncology (ESMO) or by National Comprehensive Cancer Network (NCCN) at the time of presentation in our clinic. About 10% of patients reported grade 3 or 4 adverse events and required delay or discontinuation of treatment. The principal adverse event was neutropenia, primary prophylaxis of neutropenia fever was always preferred in the presence of intermediate overall risk after taking into consideration all the patients risk factors. In the case of febrile neutropenia, we pay special attention to harvesting all peripheral smears and to isolating the patients in order to promptly establish an antibiotic therapy ,45.Few studies have tested the impact of the presence of androgen receptors (AR) on the BC cells and the results were gathered in meta- analysis. Kim et al. suggested that AR expression benefited both PFS and OS . Special attention was paid to the triple negative BC patients (TNBC), taking into account the severe prognosis and the lack of therapeutic approaches. Study by Qu et al. found that AR positive was beneficial to PFS in the TNBC subgroup , but not for OS  ,47.AR may therefore be an interesting tool to select patients for clinical trials, using this marker for prognostic or as a targeted therapy. Moreover, there are studies in which this marker was used as a surrogate for tissue biopsies using imaging positron emission tomography with different radiotracers. In a study publish in 2017 by Venema et.al metastatic BC patients with ER positive were enrolled irrespective of the AR status. The purpose of the study was to find out if it is a concordance between flour-dihydro-testosterone and 8F-fluoroestradiol PET and tumor AR and ER expression measured by immunohistochemistry. The authors conclude that it is a correlation between the radiotracers and the hormone expression and this technique may be used especially for biopsy associated sampling errors ,48,49,50Although a clinical threshold that determines AR positively and negativity for BC patients has not been widely established, in this trial we consider that a positive result is more than 1%. We evaluated the impact of the expression and the absence of those receptors. Routine testing along with the classical triad IHC markers for BC appears to be an important prognostic factor for those patients.The use of AR as a potential therapeutic target in breast cancer has yet to be established due to the difficulties in both the identification of the patients who might be benefit from AR-targeted therapies and the development of the right combination of therapeutic agents based on AR targeted therapies ,14,24.According to our data, AR was present in 57% of our patients. The presence of those receptors was statistically significantly correlated with an improvement of overall survival and progression free survival. These findings confirm that AR may be used as a prognostic factor and further studies are necessary for developing therapeutic targeted therapies. Till now, a few drugs were tested in BC patients with promising results; with the targeted population especially triple negative breast cancer. Furthermore, medical IoT (Internet of Things) enables continuous monitoring of patients, enabling remote gathering of results during their treatment, which is especially useful in case of pandemic crises when access to medical facilities is difficult ,51.The role of androgens in female BC seems to have dual effect, both pro- and anti- tumorigenic roles have been reported. Blood androgens are ligands which bind the membrane AR, who is internalized in cytoplasm and subsequently transported to the nucleus where it exerts the effects. The activation of targeted gene transcription leads to mRNA synthesis and subsequent protein synthesis, which finally determine cell proliferation, angiogenesis, cell division and differentiation. Without the ligand, the unbound AR is found in cytoplasm in a complex together with heat shock proteins. Given these data, we consider it is important to correlate the blood androgen levels with the positivity of the AR, moreover the association between increased androgen levels and high BC risk in pre- and postmenopausal patients. We consider that this aspect may be taken into account for the screening of BC ,53,54.p = 0.02) compared with both hormonal and Her2/neu positive BC patients. In the group of patients with positive ER, PR and Her 2/neu, the OS reached the maximum follow-up period. These expected survival differences have meaningful implications for communication and care decisions between providers and their cancer patients. This subclassification should, however, be complemented with the many other important prognostic variables for the individual such as age, tumor size, lymph node status, comorbidity, and adjuvant therapy.In our clinic, we admit and deliver oncologic therapy only for patients with complete staging of the cancer disease. In this study, first and foremost, the tumor description with a complete histological and IHC report was mandatory. In order to demonstrate how hormone receptors may influence the prognosis in our group of patients, we divided the patients in four subgroups, according to the IHC results. We conclude that the TNBC molecular profile may have a negative impact on overall survival (32.30 vs. 36 months, While our study has the potential limitation of being retrospective and having a relatively small number of subjects, it has the advantage of consistency in immunostaining results. Using both biopsy and mastectomy specimens, that had been immediately fixed after sample collection, all processing steps and evaluations were performed in a single institution, an important feature of our study given that inconsistencies in the assessment of AR among institutions have yet to be resolved in order to ensure an accurate prognosis. Another important aspect is that the specimens were collected before receiving any oncological treatments.The key strength of this study is the investigation of well characterized diagnosis BC samples this allowing an objective assessment of androgen receptor markers for prognostication of the BC. PFS and OS between groups of patients with different levels of each biomarker have been compared using log-rank tests with a 5% level of statistical significance. The group of patients with positive AR had a better OS and PFS. Correlated with the observation that TNBC had the poorest outcomes of BC patients, further studies are needed in order to establish which biomarkers in which cases can be used as prognostic factors.New research studies along with advanced technological methods have shed light into the role of the AR in BC. Undoubtedly, the significance of the AR is getting clearer, as AR function and prognostic value had been elucidated over time. The proper identification of AR-partners and AR-target molecules will facilitate the understanding of BC pathogenesis. Further studies are needed to establish in which molecular types and menopausal status the AR may impact BC prognostic.Despite the use of chemotherapy and immunotherapy nowadays, mortality in BC patients, especially TNBC, remains high. Therefore, it is necessary to find new therapies and AR may be an option. Moreover, the assessed of the AR may be used for molecular diagnosis for unknown primary tumors, especially TNBC.


The SEM analyses supported associations between FMS, HRF and PA, with sound goodness-of-fit indices: (1) model-1: CFI = 0.95; RMSEA = 0.072; and (2) model-2: CFI = 0.95; RMSEA = 0.071, respectively. The relationship between FMS and PA was fully mediated by the HRF in both directions. The behavioral mechanism  provides meaningful insights to understand the obesity trajectory during middle childhood.The purposes of the study were: (1) to investigate the associations between fundamental motor skills (FMS), health-related fitness (HRF) and physical activity (PA) during middle childhood; and (2) to examine whether HRF serves as a mediator in these pathways. The participants were 342 children  recruited in Texas. Children’s FMS  were assessed. School-based PA that included light, moderate, and vigorous PA was captured by accelerometers. The FITNESSGRAM battery was used to measure children’s HRF, including body composition, cardiorespiratory fitness, and muscular fitness. Structural equation models were used to evaluate two proposed models . Both locomotor and ball skills were associated with all components of HRF ( It was well-documented that physical activity (PA) contributes to overall health and prevents childhood obesity, however, more than 70% of the children aged 6–11 years in the United States do not meet the recommended levels of PA, and less than half of the youth achieve adequate fundamental motor skills (FMS) and health-related fitness (HRF) levels ,3,4. PhyTo effectively combat the obesity epidemic, investigating the potential causal relationships between PA behavior and FMS competence or the mediators of this association may show a positive spiral of engagement identified in a conceptual theoretical foundation ,9. StoddRecent systematic reviews have also documented a positive relationship between FMS competence and HRF in children and adolescents ,18,19. FTM ). FMS explained 17% of variance in HRF (p < 0.01) and both locomotor and ball skills accounted for the variance explained in HRF. The direct effect between FMS and HRF  and between HRF and PA  were significant and stronger than that of between FMS and PA. The model fit indicated that FMS was fully mediated through HRF components to PA, since the direct effects between FMS and PA were not significant in the first model.According to the first SEM model . PA explained 4% variance in HRF (p < 0.001) and all components of HRF significantly contributed to the variance in both locomotor and ball skills . The direct effect of HRF on FMS  was significant and stronger than the direct effect of PA on FMS . The direct effect between PA and FMS was not significant in the second model, which suggests that the pathway from PA to FMS was fully mediated by all components of HRF.According to the second SEM model . This is consistent with findings showing that 77% of young children demonstrated delays in FMS . PreviouThe central finding of this study revolves around the antecedent-consequent behavioral mechanism of obesity trajectory in middle childhood. Several previous studies demonstrated the direct associations of FMS with PA and HRF in early childhood  ,38,39 anDuring third grade (around 9 years of age) is the first time that children are administered HRF testing in the U.S., thus, the findings of this study provide insights for school-based PE curriculum design and PA/PE program implementation. Specifically, enhancing skill learning and PA participation during school  should be emphasized, and a fitness routine should be implemented into a daily PA/PE program. Another variable interacting with the relationship between FMS and PA we explored was weight status (BMI). Studies hint at a strong relationship between weight status, FMS, and other variables. For example, children with higher HRF and FMS competence are less prone to overweight or obesity during childhood . From anLimitations of this study included that the FMS was assessed with only four different locomotor and ball skills. Children’s lack of familiarity with the testing procedures may have affected their performance (such as doing a push-up in the Fitnessgram) . In addiIn conclusion, the findings of this study demonstrated that the relationship between FMS and PA is not direct, but mediated by HRF among third grade children. These findings suggest that maintaining appropriate levels of HRF may benefit skill acquisition and promote PA in middle childhood. Taken together, these findings will assist in understanding the underlying mechanisms of behavioral change in order to strengthen effective intervention components and eliminate or adapt ineffective components. However, further research is needed to replicate the importance of HRF as a mediator between FMS and children’s engagement of different intensity levels of PA. This study provides empirical evidence for the inclusion of FMS development/acquisition as a mechanism of behavioral change and, thus, a strategy that should be included in interventions aimed at increasing children’s PA and HRF by age, gender, and race/ethnicity group.


We examined mRNA expression of androgen receptor (AR), AR splice variant‐7, intratumoral androgen synthesis enzyme‐encoding genes AKR1C3, CYP17A1, SRD5A1 and SRD5A2, AR protein expression, ERBB2 (HER2) gene amplification and DNA mutations in driver genes. Furthermore, functional AR pathway activity was determined using a previously reported Bayesian model which infers pathway activity from AR target gene expression levels. SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit from ADT compared to those without benefit. Survival analysis showed a trend toward a longer median progression‐free survival for patients with high SRD5A1 expression levels and high AR pathway activity scores. The AR pathway activity analysis, and not SRD5A1 expression, also showed a trend toward better disease‐free survival in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). In conclusion, we are the first to describe that AR pathway activity may predict clinical benefit from ADT in SDC patients, but validation in a prospective study is needed.Androgen deprivation therapy (ADT) is first‐line palliative treatment in androgen receptor‐positive (AR+) salivary duct carcinoma (SDC), and response rates are 17.6–50.0%. We investigated potential primary ADT resistance mechanisms for their predictive value of clinical benefit from ADT in a cohort of recurrent/metastatic SDC patients receiving palliative ADT  is a leading treatment strategy in the palliative care of patients with androgen receptor (AR)‐positive salivary duct carcinoma (SDC). However, while as many as half of patients may respond to ADT, resistance frequently emerges, undermining its use. In this investigation of primary ADT resistance mechanisms, expression of the androgen synthesis enzyme‐encoding gene  ADTandrogen deprivation therapyAKR1C3aldo‐keto reductase family 1 member C3ARandrogen receptorASCOAmerican Society of Clinical OncologyCAPCollege of American PathologistsCIconfidence intervalCRPCcastration‐resistant prostate cancerCYP17A1cytochrome P450 17A1DFSdisease‐free survivalFFPEformalin‐fixed paraffin‐embeddedFISHin situ hybridizationfluorescent H&Ehematoxylin and eosinHPRT1hypoxanthine phosphoribosyltransferase 1IQRinterquartile rangeLAlocally advancedOSoverall survivalPFSprogression‐free survivalR/Mrecurrent/metastaticROCreceiver operating characteristicSDCsalivary duct carcinomasmMIPsingle‐molecule molecular inversion probeSRD5A1/2steroid 5 alpha‐reductase 1/2p = 0.022) and OS  compared to 111 controls who did not receive adjuvant ADT.Salivary duct carcinoma (SDC) is an aggressive subtype of salivary gland cancer, which is often androgen receptor (AR) positive 66.7–96.4%).%.4 In paERBB2 (HER2) gene amplification (29.4–46.4%),Besides ADT, other treatment options are available for patients with R/M SDC. In the case of ication 2.4–46.4%,AR‐V7 expression is 20‐fold higher in castration‐resistant prostate cancer (CRPC) compared to hormone‐naïve prostate cancer, though in SDC the presence of AR‐V7 has also been shown in hormone‐naïve tumors.AKR1C3), cytochrome P450 17A1 (CYP17A1), steroid 5 alpha‐reductase 1 (SRD5A1) and SRD5A2. Finally, a low‐active or inactive AR signal transduction pathway, in which androgen stimulation does not result in (full) AR transcriptional activity, may cause primary ADT resistance, simply because no effective AR signaling is present. AR pathway activity can be quantified by a recently developed and validated method, in which expression of AR target genes is measured and subsequently converted into a pathway activity score (ranging between 0 and 100) using a Bayesian computational model.ERBB2 gene amplification or other tumor‐driving gene mutations. The aim of our study was to assess these potential primary ADT resistance mechanisms in a cohort of R/M SDC patients receiving palliative ADT and a cohort of LA SDC patients receiving adjuvant ADT. For those factors that differed significantly between R/M SDC patients with and without clinical benefit from ADT, the optimal cut‐off value and survival differences were assessed. Subsequently, this cut‐off value was used to evaluate DFS differences in the LA cohort.Despite the efficacy of ADT in the palliative and adjuvant setting, ADT is only effective in a subgroup of patients and little is known about primary resistance mechanisms. Although AR expression, determined by immunohistochemistry, is a hallmark of SDC, intratumoral and intertumoral variation of AR expression is frequently observed.n = 30) and a cohort of LA AR‐positive SDC patients receiving adjuvant ADT (n = 14) after surgical tumor resection, and in most cases a neck dissection (13/14 patients) and postoperative radiotherapy (13/14 patients). ADT consisted of bicalutamide or LHRH‐analog plus bicalutamide following shared decision making.Clinicopathological characteristics and potential ADT resistance mechanisms were assessed in a cohort of R/M AR‐positive SDC patients receiving palliative ADT . Clinical data were collected from the medical records. A no‐objection system was used for secondary use of human tissue and medical data in accordance with the code of conduct of the Federation of Dutch Medical Scientific Societies . For all patients who were alive at the start of our study, written informed consent was obtained.n = 36). If primary tumor material was unavailable, tumor material of locoregional lymph node metastases or distant metastases prior to treatment was used . Nonstained FFPE sections were cut and used for DNA/RNA isolation, AR immunohistochemistry (IHC) and ERBB2 FISH. Before and after these sections, hematoxylin and eosin (H&E) stained sections were prepared for pathological confirmation of SDC and for tumor annotation. Median percentage of neoplastic cells in tissue sections used for further analysis was 70.0% (range 25.0–90.0%) in the R/M cohort and 70.0% (range 30.0–80.0%) in the LA cohort.Formalin‐fixed paraffin‐embedded (FFPE) tissue samples of the primary tumor prior to treatment were collected . RNA was eluted in 100 μl buffer according to the instructions. After DNase treatment  RNA was stored at −80°C. RNA concentration was measured using the Qubit® RNA HS Assay Kit  on a Qubit® Fluorometer.AR, AR‐V7, AKR1C3, CYP17A1, SRD5A1 and SRD5A2 were calculated using the ΔΔCt method using the hypoxanthine phosphoribosyltransferase 1 (HPRT1) gene for normalization. Primer sequences are listed in Supporting Information Table One microgram of total DNase‐treated RNA was used for cDNA synthesis. Random‐primed cDNA was synthesized using SuperScript II reverse transcriptase . Gene expression levels were determined by SYBR Green qPCR  using a LightCycler LC480 instrument (Roche). Relative gene expression levels of Androgen receptor expression was determined using the AR specific polyclonal antibody N‐20 . FFPE sections were pretreated with citrate pH 6.0) for 10 min in a pretreatment module. Immunostaining was carried out using a 1:200 dilution of the primary antibody, and staining was performed according to the Powervision method by Immunologic. The AR staining was scored considering the staining intensity  and the percentage of positive nuclei . The final staining score was recorded as the sum of the staining intensity and the staining extent..0 for 10p), the odds for AR pathway activity was provided by the Bayesian model (p/1 − p), and this was transformed into a (base 2) logarithmic scale and then normalized to scores ranging from 0 to 100, where 0 corresponds to the lowest and 100 corresponds to the highest odds in favor of an active AR pathway that a specific model can infer. For each analyzed sample, this normalized AR pathway activity score between 0 and 100 was calculated.To quantitatively assess the AR pathway activity a qPCR‐based AR pathway test was used, that was adapted from the previously described biologically validated AR pathway analysis method developed for Affymetrix U133Plus2.0 microarray.ERBB2 fluorescent in situ hybridization (FISH) according to standard ISH protocol using the ERBB2 probe of Kreatech . Scoring was performed according to breast cancer guidelines of the American Society of Clinical Oncology (ASCO) and the College of American Pathologists (CAP).HER2 status was determined by For all patients in the R/M cohort, oncogenic driver gene mutations were assessed using single‐molecule molecular inversion probes (smMIPs) analysis and Next‐Generation Sequencing.t‐test with equal variance assumed. Equal variance was confirmed by Levene's test for equality of variances. A log transformation, using the natural logarithms, was performed on gene expression data before t‐tests were conducted in order to satisfy the assumption of normal distribution. AR protein expression levels in tumor tissue of patients with and without clinical benefit were compared using the Mann–Whitney U test. HER2 status and the presence or the absence of a driver mutation in patients with and without clinical benefit were compared using Fisher's exact test. Values of p < 0.05 were considered statistically significant without correction for multiple testing, as these analyses are considered exploratory.Clinical ADT response in the R/M cohort was classified into five categories according to RECIST criteria: complete response, partial response, stable disease longer than 6 months, stable disease shorter than 6 months and progressive disease.AR and AR‐V7 gene expression levels, and for SRD5A1 gene expression levels and AR pathway activity scores. Analyses were performed using IBM SPSS version 25.0.For those factors that differed significantly between patients with and without clinical benefit, receiver operating characteristic (ROC) curves were constructed to establish the optimal cut‐off value to predict clinical benefit. Subsequently, Kaplan–Meier survival curves were constructed for patients above and below the cut‐off value. The log‐rank test was used to compare survival data. Finally, Pearson correlations were calculated for In the R/M cohort, 30 patients  who received palliative ADT were analyzed. Median age at the start of ADT was 62 years (range 36–79 years). Seven patients were treated with a LHRH‐analog plus bicalutamide, and 23 patients with bicalutamide monotherapy. Of these 30 patients, 5 had a partial response 16.7%), 4 had stable diseases for more than 6 months (13.3%), 3 had stable diseases for less than 6 months (10.0%) and 18 (60.0%) had progressive disease at first evaluation. Median FFPE tissue storage time was 49 months (range 7–195 months), and 23 samples were obtained from primary tumor, four from regional lymph nodes metastases and three from distant metastases. Further patient characteristics are listed in Table 6.7%, 4 hIn the adjuvant ADT treated LA cohort, 14 patients  were analyzed. Median age at the start of ADT was 61 years (range 36–84 years). Two patients were treated with an LHRH‐analog plus bicalutamide and 12 patients with bicalutamide monotherapy. Median FFPE tissue storage time was 13.5 months (range 3–108 months), and 13 samples were obtained from primary tumors and 1 from a regional lymph node metastasis. Further patient characteristics are listed in Table vs. 6.0, IQR 4.0–6.0, p = 0.29). Also, expression levels of AR , AR‐V7 , AKR1C3 , SRD5A2 , and CYP17A1  mRNA were not significantly different between patients with and without clinical benefit. However, SRD5A1 mRNA expression levels were significantly higher (p = 0.008) in patients with clinical benefit  compared to those without . Moreover, the difference in AR pathway activity scores between patients with clinical benefit  and those without  was significant (p = 0.017). Box plots of ADT resistance mechanisms in patients with and without clinical benefit are shown in Supporting Information Figure AR‐V7 expression levels were not significantly different in both groups, 41 of 43 evaluated patients in both cohorts (95.3%) had detectable AR‐V7 levels, and a significant correlation between AR and AR‐V7 expression levels was found . The area under the curve was 0.75 . The optimal cut‐off value for predicting clinical benefit was an AR pathway activity score of 52.9, which resulted in a sensitivity of 55.6%, a specificity of 95.2%, a positive predictive value of 83.3% and a negative predictive value of 83.3%. Using this cut‐off value, Kaplan–Meier survival curves were constructed for PFS  and OS  in the R/M cohort. The median PFS after treatment with palliative ADT was 2.9 months (95% CI 2.7–3.1 months) for patients with an inactive AR pathway and 9.9 months (95% CI 1.5–18.3 months) for patients with an active AR pathway (p = 0.13). The median OS was 25.9 months (95% CI 8.9–42.9 months) for patients with an inactive AR pathway and 43.6 months (95% CI 0.9–86.3 months) for patients with an active AR pathway (p = 0.39). Subsequently, this cut‐off value was applied to the LA cohort and the median DFS was 17.7 months (95% CI 8.4–27.0 months) for patients with an inactive AR pathway and 22.8 months  for patients with an active AR pathway . In the LA cohort, differences in OS were not calculated because of insufficient follow‐up.Patients with clinical benefit in the R/M cohort had a significantly higher AR pathway activity score compared to those without. A ROC‐curve of the AR pathway activity score to predict clinical benefit in the R/M cohort was constructed Fig. a. The aSRD5A1 mRNA expression of the primary tumor tissue and clinical benefit was found. The area under the ROC curve for SRD5A1 in the R/M cohort  was 0.79 . The optimal cut‐off value for predicting clinical benefit was an SRD5A1 expression of 2.75, which resulted in a sensitivity of 77.8%, a specificity of 75.0%, a positive predictive value of 58.3% and a negative predictive value of 88.2%. Using this cut‐off value, Kaplan–Meier survival curves were constructed for PFS  and OS  in the R/M cohort. The median PFS after treatment with palliative ADT was 2.8 months (95% CI 2.3–3.3 months) for patients with a low SRD5A1 expression and 5.6 months (95% CI 0.0–13.2 months) for patients with a high SRD5A1 expression (p = 0.008). The median OS was 24.2 months (95% CI 2.9–45.5 months) for patients with a low SRD5A1 expression and 46.3 months (95% CI 0.0–92.8 months) for patients with a high SRD5A1 expression (p = 0.069). Subsequently, this cut‐off value was applied to the LA cohort and the median DFS was 17.7 months  for patients with a low SRD5A1 expression and 22.8 months (95% CI 6.3–39.3 months) for patients with a high SRD5A1 expression . In the LA cohort, differences in OS were not calculated because of insufficient follow‐up.A significant correlation between ort Fig. b was 0.SRD5A1 expression (>2.75) vs. negative cases for both factors. Discrepant cases were left out. This resulted in a median PFS of 10.6 months (95% CI 3.1–18.1 months) and 2.8 months , a median OS of 46.3 months (95% CI 9.6–83.0 months) and 24.2 months , and a median DFS of 22.8 months  and 17.7 months , respectively. Furthermore, a significant correlation between the AR pathway activity score and SRD5A1 expression factors was found  and DFS (LA cohort) for patients with a high AR pathway activity score (>52.9) and high SRD5A1 expression levels and AR pathway activity scores were not significantly different between primary tumor tissue, lymph node metastatic tissue and distant metastatic tissue  vs. 0.85 (IQR 0.71–1.13), p < 0.001 and median AR pathway activity 63.7 (IQR 61.8 – ‐) vs. 43.7 (IQR 37.6–51.5), p = 0.019, respectively. Supporting Information Fig. p = 0.064 and 95% CI 1–1, p = 0.053, respectively, Supporting Information Fig. SRD5A1 expression levels  and high AR pathway activity scores . Median OS was not different for both factors. For primary tumor tissue (n = 23), the SRD5A1 expression levels and AR pathway activity scores were higher in patients with clinical benefit, but significance was lost .In the R/M cohort, primary tumor tissue was used in 23 patients, and tissue for regional lymph node metastases and distant metastases prior to ADT in 4 and 3 patients, respectively. ERBB2) amplification was determined in all patients in the R/M cohort and 10 of 14 patients in the LA cohort. Of these 40 patients, 14 patients (35.0%) had a tumor with an ERBB2 amplification  or OS .HER2 gene (TP53 (n = 11), PIK3CA (n = 5), HRAS (n = 4), PTEN (n = 2), BRAF (n = 2), AKT1 (n = 1) and ERBB2 (n = 2) genes  or OS .Mutation analysis was performed in all 30 patients in the R/M cohort. In 12 tumors (40.0%), no driver mutations were found. In the other 18 tumors, mutations were detected in the es Table . In the vs. 1.5 in patients with an active AR pathway. Patients with an inactive AR pathway more often received second‐line ADT (37.5% vs. 16.7%), third‐line ADT (8.3% vs. 0.0%), chemo and/or targeted therapy (37.5% vs. 33.3%) and immunotherapy (4.2% vs. 0.0%).Besides first‐line ADT, patients in the R/M cohort received other palliative systemic treatments after PD on ADT. An overview of the treatments is listed in Supporting Information Table SRD5A1 expression levels and AR pathway activity scores were significantly higher in patients with clinical benefit compared to those without. Survival analysis in the R/M cohort revealed that median PFS was longer for patients with high SRD5A1 expression levels (2.8 vs. 5.6 months) and high AR pathway activity scores (2.9 vs. 9.9 months). Differences in OS were not found, but many patients received additional palliative systemic treatments, follow‐up was relatively short and the cohorts were relatively small. The threshold for elevated SRD5A1 expression and for high AR pathway activity was set (discovered) on the R/M cohort, and subsequently evaluated for differences in DFS in an independent cohort of locally advanced SDC patients receiving adjuvant ADT (n = 14). For the AR pathway activity analysis and not SRD5A1 expression, a trend toward a better DFS was found. Therefore, the AR pathway activity score is most promising as predictive factor for clinical benefit from ADT, but validation in a prospective study is needed before this method can be put into daily practice. Furthermore, it would be interesting to evaluate the prognostic value of AR‐pathway activity and SRD5A1 expression, as the survival differences may also be a result of a more indolent (well‐differentiated) tumor.In our study, potential mechanisms of primary ADT resistance in SDC patients were investigated in order to predict clinical benefit from ADT. We are the first to describe that SRD5A1 expression levels and AR pathway activity scores were still significant between patient with and without clinical benefit.The predictive value of the AR pathway analysis may be further improved by using metastatic tissue only. In our study, only 7 of 30 samples in the R/M cohort were obtained from regional lymph node metastases or distant metastases prior to treatment. Nonetheless, the differences in SRD5A1 expression and AR pathway activity score showed a modest improvement in the prediction of clinical benefit in the R/M cohort, but worse prediction compared to the AR pathway activity score alone in the LA cohort. The most logical explanation for the lack of added value is that both biomarkers are either directly (the AR pathway activity score) or indirectly (SRD5A1 gene expression) associated with activity of the AR pathway, as SRD5A1 overexpression results in increased production of androgens in prostate cancer,SRD5A1 expression levels and AR pathway activity in SDC. More importantly, the level of SRD5A1 expression may have therapeutical consequences, as ADT response in SRD5A1 overexpressing tumors may be further enhanced by adding the SRD5A1 and SRD5A2 inhibitor dutasteride to the ADT regimen. In prostate cancer models, it was shown that dutasteride synergistically suppresses tumor cell proliferation when combined with enzalutamide .SRD5A1 expression levels and/or AR pathway activity scores as predictive biomarkers are confirmed, preferably on metastatic tissue.Combining AR‐V7 mRNA expression in 95.3% of primary tumor samples, which is more frequent than the 37–70% of AR‐V7 positive SDC cases reported earlier.AR‐V7 expression is elevated in response to ADT.AR‐V7 expression prior to ADT. Whether expression levels of AR or AR‐V7, or other genes, change during ADT in SDC remains to be investigated. Finally, genetic alterations such as ERBB2 amplification and functionally relevant mutations in oncogenes and tumor suppressor genes were found in 35.0 and 60.0% of patients, respectively, which is in accordance with the literature.The other potential primary resistance mechanisms were not significantly different between patients with and without clinical benefits from ADT and therefore cannot be used as predictive factors. However, some noteworthy findings were done. Although AR protein expression was in general high, one tumor lacked AR protein expression. This patient started palliative ADT based on an AR‐positive lung metastasis but had an AR negative epidural metastasis. This case shows the possible heterogeneity in AR expression in SDC metastases and could explain treatment resistance in such cases. Furthermore, we detected The positive results in our study are remarkable since our study has several limitations. First, the cohorts were relatively small, which is typical for a rare cancer but troublesome for elucidating predictive factors for clinical benefit. Second, not all patients received the same ADT, and compliance to ADT may differ, all of which could influence ADT response independent of AR pathway activity scores. Furthermore, for most patients, prediction of clinical benefit was based on primary tumor tissue samples, while treatment was installed when patients developed metastatic disease, with a varying time interval between primary tumor resection and development of metastases. It is well known that molecular characteristics frequently vary between primary tumors and metastases.SRD5A1 expression and low AR pathway activity scores as potential primary ADT resistance mechanisms in SDC patients. We speculate, based on our findings and studies in prostate cancer, that ADT response in SRD5A1 overexpressing tumors may be further enhanced by adding the SRD5A1 inhibitor dutasteride to the ADT regimen. The AR pathway activity score is a promising predictive biomarker for clinical benefit from ADT in SDC. Validation in a prospective study is needed, preferably in metastatic tissue samples.In conclusion, in our study, potential intrinsic ADT resistance mechanisms were studied in AR‐positive SDC patients that received ADT. We are the first to describe low Appendix S1: Supporting InformationClick here for additional data file.


Despite availability of clinical guidelines, underdiagnosis, undertreatment, and poor adherence are still significant concerns in allergic rhinitis (AR) therapeutic management. We investigated clinical practice patterns and prescribing behavior of Italian healthcare professionals (HCPs) specialized in AR.One-hundred allergologists, 100 ear, nose and throat (ENT) specialists, and 150 general practitioners (GPs) were recruited. The survey assessed: socio-demographic, work experience, monthly caseload, prescription drivers. Next, HCPs were invited to retrospectively recover patients’ clinical data to investigate: AR clinical characteristics, therapy management, prescription patterns, patient adherence. Descriptive statistics, Chi square, One-Way analysis of variance, and Two-Way Analysis of Variance were performed.Allergologists visited more AR patients (31% of monthly caseload) than ENTs , while GPs’ caseload was the lowest (6%). Clinical information of 2823 patients were retrieved of whom 1906 (67.5%) suffered from moderate/severe AR (discomfort score: 7.7 ± 1.3) and 917 (32.4%) from mild AR (5.7 ± 1.9). About one-third of mild patients had a discomfort score ≥ 7. Main prescription drivers were “effective on all symptoms” (54.3% patients) and “quick symptom relief” (47.8%), whereas minor drivers were “affordable price” (13.4%) and “refundable” (8.7%). The most prescribed drugs were antihistamines and intranasal corticosteroids (79% and 55% prescriptions), followed by fixed-dose-combination of intranasal azelastine/fluticasone (19%). Polytherapy was the most common treatment strategy (59.6%). HCPs’ believe that the majority of the patients was adherent to treatment (88% with score > 7).This survey describes the therapeutic approach adopted by Italian physicians to cope with AR and shows that HCPs underestimated AR severity and had a non-realistic perception of patients’ adherence. These findings suggest that further efforts are required to improve AR clinical management in Italy. Allergic rhinitis (AR) is one of the most common disease affecting adults worldwide with increasing incidence and prevalence in almost all western countries –5. ThougDespite international and national are continuously reviewed and updated to optimize patient care guidelines  –19, AR cIn Italy, prevalence of AR has increased over the last 20 years from 16.8 to 25.8% , 29. A sThe present research investigated the current clinical practice patterns and prescribing behaviour of Italian healthcare professionals (HCPs) specialized in AR management. Allergologists, ear, nose and throat (ENT) specialists, and GPs were asked to retrospectively recover clinical data of real-life cases to assess: (1) prescribing behaviour based on patients’ characteristics; (2) AR therapeutic management; (3) opinions toward patients’ adherence.We carried out a survey among a total of 350 Italian HCPs treating patients suffering from AR. The survey sample included 100 allergologists, 100 ENT specialists, and 150 GPs. HCPs were randomly selected from a national database. Exclusion criteria were: < 5 years of clinical practice, < 5 AR patients visited over the last month, participation to another market research in the previous 6 months. Recruitment was carried out via mail and it was planned to equally represent physicians from all Italian geographical macro-regions in each specialty area. The interviews were performed in April 2019 and data were collected through Computer Assisted Web Interviewing (CAWI) lasting 20 min.The questionnaire used in the present research was designed based on findings from a systematic literature review and included two sections. The first section collected the HCPs’ socio-demographic data, such as age, gender, years of work experience, and number of monthly visited patients with AR. HCPs’ attitude toward relevant prescription drivers was likewise investigated  and symptoms-related discomfort experienced by patients and disease severity  when appropriate. Kruskal–Wallis One Way Analysis of Variance on Ranks followed by Dunn’s post hoc test were likewise used. Two Way ANOVA was used to investigate significance between specialty area and patient assignment to the different classes of AR severity. Tukey’s post hoc test was used for pairwise multicomparison procedure.Differences in variable distributions across specialists were tested with ΧA p < 0.05 was considered statistically significant. The data were analyzed using the statistics software SigmaPlot 11.0 .Relevant characteristics of the 350 respondents are described in Table All the prescription drivers presented through the questionnaire  were allergic only to pollens, 439 (15.6%) only to dust, 222 (7.9%) to other causes, 849 (30.1%) to more than one cause. About a quarter of the cases  suffered from concomitant asthma and the majority of these patients  took a specific drug for asthma treatment. Among asthmatic patients, 213 were only allergic to pollens, 117 only to dust, 36 only to other causes.As shown in Table From a physicians’ perspective, distribution of AR severity in the patients’ sample was: 1906 (67.5%) patients with moderate/severe AR and 917 32.4%) patients with mild AR  reported reduced productivity due to AR , while monotherapy was used in 41.4% of cases (1170 patients)  followed by fixed-dose combination of intranasal azelastine/fluticasone (Aze/flu) (543 prescriptions)  has good adherence to treatment, even in the cases of severe AR Fig. a. In HCPThe present survey investigated the current clinical practice scenario of AR management in Italy. In addition to provide an extensive description of Italian HCPs’ prescribing behaviour, this study discloses clinicians’ perspective about patients’ symptom discomfort and adherence.AR is characterized by substantial medical and social burden with high use of healthcare resources worldwide , 11, 34.In our survey, allergologist emerged as the main reference specialist for the disease in Italy, followed by ENTs. GPs visited more cases suffering from mild AR compared to both allergologists and ENTs. Prescription attitude was similar between HCPs. Attributes related to medication efficacy, safety, and patient adherence were considered more relevant prescription drivers than ease of use and cost-related items.Consistent with previous Italian studies , 32, theA remarkable finding of the present survey is that AR severity is underestimated by physicians, irrespective of the specialty area in which they operate. In fact, about half of the patients assigned to the mild class of severity actually experienced particularly bothersome symptoms. This observation is consistent with data reported by the European survey carried out in Germany, France, Italy, Spain, and UK, in which clinicians not only underestimated the severity of disease but also misdiagnosed the nature and discomfort of symptoms . As a coWith regard to HCPs’ opinions about patient adherence, our investigation disclosed that clinicians believe all the patients are compliant, even in the cases of severe AR. This perception does not reflect the real scenario of patients’ adherence in the AR settings. In fact, it is widely accepted that adherence in AR patients is very low , 47, 48.According to the interviewed physicians, the main cause of low compliance was relief of AR symptoms, followed by cost-related issues. Lack of efficacy, adverse effects, treatment duration, and costs are generally associated with lower compliance . PatientAR still represents a significant health problem because of the high burden of symptoms and the significant impact on patients’ QoL. The various available clinical guidelines state that accurate diagnosis, thorough patient evaluation, and adequate follow-up monitoring are a prerequisite to ensure optimal patient care.The present research showed severity of AR symptoms is underestimated by Italian physicians, regardless of the specialty area in which they operate. This could lead to inadequate control of the disease. In addition, HCPs are not fully aware of the poor adherence to treatment.These findings suggest that further efforts should be made to promote physicians’ adherence to clinical guidelines in order to improve AR management in Italy. Design of educational interventions for both GPs and specialists could improve characterization of the disease, help clinicians in the selection of the best treatment option, and promote a better patient-physician communication on the nature, severity, and impact of symptoms.Additional file 1. Supplementary methods and results.


Current guidelines against spread of coronavirus (COVID-19) interrupt non-essential rehabilitation services. Thus, individuals with physical disabilities such as children with cerebral palsy can no longer benefit from physical rehabilitation during this undetermined period. Using either a synchronous or asynchronous format, in collaboration with a therapist via telerehabilitation, we suggest that active video games and low-cost virtual reality are a promising delivery mode for at-home rehabilitation in the context of a global pandemic. This therapeutic modality, incorporated into an at-home individualized treatment plan, provides a means to lessen the impact of an interruption in rehabilitation services while not loosing the pre-pandemic, in-person physical activity gains. Growing evidence supports active video games and low-cost virtual reality as viable therapeutic interventions for children with physical disabilities. These technologies are especially well-accepted by pediatric populations for the ludic and motivating features that lend themselves to nearly seamless incorporation into telerehabilitation. Advantages for rehabilitation of active video games and low-cost virtual reality include a rich, challenging, multi-modal training environment in which high numbers of movement repetitions can be accomplished, and a unique opportunity to foster engaged practice actions that go beyond household activities. We offer suggestions for the clinician about how to adopt active video games and low-cost virtual reality into your practice during a global pandemic. Current strategies to combat the Coronavirus COVID-19) involve flattening the incidence curve and reducing the rate of spread, such as social distancing, school closures, and confinement of the population 9 involve. While tAmong children with physical disabilities typically followed by rehabilitation specialists, cerebral palsy (CP) is the most common neuromotor disorder in children  with a pAside from sensorimotor impairments, limited participation is attributed to a number of obstacles including: personal, socioeconomic status and environmental factors . Other hRecently, an expert group of clinicians, researchers and outpatient health program leaders proposed telerehabilitation as a promising strategy to maintain rehabilitation services during this unprecedented time . TelerehActive video games and low-cost virtual reality have the potential to engage school-age children and adolescents afflicted by physical disabilities to be physically active while sheltered at home and to continue their engagement with rehabilitation using technology-enhanced game-like interventions. Video games has a large penetration rate in the general population, with over 70% of U.S. families including a child who plays video games . VirtualAVG/VR, grounded in principles of experience-dependent neural plasticity and motor learning, offers many advantages to deliver rehabilitation interventions at home. These include: intrinsic motivation, task salience, number of repetitions, intensity and duration, and challenging practice along with the provision of augmented feedback . Amidst Despite the advantages of AVG/VR for rehabilitation, commercially available active video games are primarily designed for the general population and have limitations that should be acknowledged . ForemosThere is growing evidence that supports the use of AVG/VR in children with physical disabilities to achieve improvements across the domains of the International Classification of Functioning, with the bulk of evidence coming from studies of children with CP , 49–52. More than ever, children with physical disabilities whose accessibility to rehabilitation services is limited, are more likely to adopt sedentary behaviors . SedentaTM game analysis (Clinicians play a crucial role in selection of an appropriate platform and games to meet individual rehabilitation needs and goals. Clinicians can work with parents and children to explore suitability of various games and consoles already available to the home environment. While frequent follow-up may not be possible, clinicians can offer guidelines on intensity of physical activity, the nature of movement, amount and frequency of active movement and adjustment to the therapeutic goals for each child . Resultsanalysis  can be uanalysis , and theanalysis . As an eanalysis  to illusanalysis . The choanalysis , 77. To The past few months taught us that people around the world can develop creative solutions to adapt to the COVID-19 pandemic. The use of AVG/VR could be one creative and evidence-based solution to guide clinicians in the delivery of challenging and motivating in-home physical rehabilitation activities to drive a positive impact on the lives of children with physical disabilities.The original contributions generated for the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.MD and MR conceived the presented idea. MD, OM, and MR critically reviewed the literature. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Breast cancer (BC) and related treatment are associated with the risk of developing a wide range of persistent disabling impairments. Despite extensive research in the field and an enhanced focus on BC rehabilitation, up to 34–43% of these patients are at risk of developing chronic distress. In addition, it is known that these patients repeatedly report unmet needs, which are strongly associated with reduced quality of life. However, despite knowledge that patients’ needs for support during BC rehabilitation varies greatly, individualized rehabilitation is often lacking. Therefore, this study aimed to explore health care professionals’ (HCPs) experiences of current rehabilitation practice and describe current barriers and facilitators for individualized rehabilitation for patients following BC treatment.A total of 19 HCPs were included, representing various professions in BC care/rehabilitation within surgical, oncological and specialized cancer rehabilitation units at a university hospital in Sweden. Five semi structured focus group interviews were conducted and inductively analysed using conventional qualitative content analysis.Three categories were captured: (1) varying attitudes towards rehabilitation; (2) incongruence in how to identify and meet rehabilitation needs and (3) suboptimal collaboration during cancer treatment. The results showed a lack of consensus in how to optimize individualized rehabilitation. It also illuminated facilitators for individualized rehabilitation in terms of extensive competence related to long-term experience of working with patients with BC care/rehabilitation. Further, the analysis exposed barriers such as a great complexity in promoting individualized rehabilitation in a medically and treatment-driven health care system, which lacked structure and knowledge, and overarching collaboration for rehabilitation.This study suggests that the cancer trajectory is medically and treatment-driven and that rehabilitation plays a marginal role in today’s BC trajectory. It also reveals that structures for systematic screening for needs, evidence-based guidelines for individualized rehabilitation interventions and structures for referring patients for advanced rehabilitation are lacking. To enable optimal and individualized recovery for BC patients’, rehabilitation needs to be an integrated part of the cancer trajectory and run in parallel with diagnostics and treatment. Despite a favourable prognosis and extensive evidence of the positive effects of cancer rehabilitation, patients with breast cancer (BC) still suffer from unmet rehabilitation needs . This maBC is the most common cancer in women worldwide and is responsible for about 28% of all cancer diagnoses  and prolThis means that rehabilitation is essential for patients’ suffering from BC as cancer rehabilitation aims to prevent and reduce the physical, psychological, social and existential consequences of cancer . StudiesFor cancer rehabilitation to be successful, teamwork is needed to prevent and reduce the physical, psychological, social and existential consequences of cancer and its treatment . In SwedDespite extensive research related to BC rehabilitation, the reasons behind patients’ unmet rehabilitation needs are still unclear. Therefore, interviewing HCPs about barriers and facilitators for individualized rehabilitation is needed to gain a deeper understanding of reasons for patients’ lack of access to rehabilitation.The aim of this study was to explore HCPs’ experiences of current rehabilitation practice and describe current barriers and facilitators for individualized rehabilitation for patients following BC treatment. This explorative qualitative focus group study is a part of the ReScreen complex intervention study  focusing on screening-based individualized rehabilitation following BC treatment. The overall project is developed according to the Medical Research Councils (MRC) framework for complex interventions . The preThis study was conducted at the Departments of Surgery and Oncology of a university hospital in southern Sweden where approximately 670 patients are diagnosed with BC annually. In Sweden, rehabilitation in this context, is performed at different levels depending on available competence and resources. Patients with BC are depending on initial treatment regime treated and followed-up at the surgical or at the oncological outpatient unit. These outpatient units represent the basic rehabilitation level. At the basic rehabilitation level contact nurses working specifically with BC patients are the patients primary care contact and are available during the pre and post treatment phase. These units also include rehabilitation resources such as physiotherapists, occupational therapists and social workers. Some rehabilitation follow-ups are structured, for example all patients with axillary lymph node dissection, by default see a physiotherapist before and after surgery focusing on lymphedema prevention, while rehabilitation in general is based on patients’ initiatives. Patients that, at the basic rehabilitation level, are identified as having complex needs can be referred to a specialized cancer rehabilitation unit (hereafter referred to as the advanced rehabilitation level). The unit for advanced rehabilitation is organized under the Department of Oncology and include a multi professional team with e.g. physicians, psychologist, social workers, physiotherapists and occupational therapists that exclusively focus on rehabilitation of patients with cancer.n = 11) and Oncology (n = 8) were included representing nurses (n = 7), nurse assistants (n = 1), physicians (n = 1), psychologists (n = 1), physiotherapists (n = 5), social workers (n = 3) and occupational therapists (n = 1). Four of the participants had worked in the field for 1–5 years, three for 6–10 years, five for 11–20 years, three for 21–30 years and four for 30 years or more.Different HCPs working within BC care or specific cancer rehabilitation, at the Departments of Surgery and Oncology and in various parts of the cancer trajectory, were considered eligible for inclusion. Participants were purposefully included through key persons, by mail or face-to face, at each unit to achieve maximum variation regarding type of profession, workplace, and years of working with BC/in cancer rehabilitation. A total of 19 HCPs from the Departments of Surgery .Rehabilitation, in the context of follow-up, were on the basic level predominately described as organized based on medical indicators such as risk of developing lymphoedema or risk of side effects associated with specific treatments. However, the participants stressed that the assessments of patients’ rehabilitation needs should be based on a combination of personal characteristics, such as the patient’s social network, personality and life situation. Therefore, the importance of exploring the patient’s life situation and resources at an early stage was repeatedly emphasized. At the advanced cancer rehabilitation level, a more comprehensive approach to rehabilitation was adopted, allowing for screening for both needs and resources as a base for a rehabilitation plan.they should contact us. Therefore, we have to make sure that they know where to go… …the health care service has a great responsibility to at least make sure of it [that patients know when to call], because it is very much based on the fact that The participants emphasized the importance of preparing patients for potential problems by giving them information in advance e.g. about risk of developing fatigue. They also stressed the importance of empowering patients to call the contact nurse if needed. However, participants also described the risk of patients not knowing when to call as they might be unaware of symptoms and problems that might prompt a contact.And the most important thing is not that [rehabilitation]; the important thing is to get them to understand the diagnosis and support them during the treatment. Then, if you feel during these meetings that ‘there seems to be a problem here’ then of course you can document it /…/ but it is not primary, that we need to identify their rehabilitation needs. The approach towards rehabilitation varied depending on the participants’ individual knowledge about and interest in rehabilitation, and on what rehabilitation level the HCP worked. It was evident that patients could be given different advice and support depending on which HCP they see. This indicate that lack of knowledge and consensus about timing and strategies for rehabilitation is a barrier. The HCPs expressed diverse views on the best time to initiate a rehabilitation plan. Some participants felt it was insulting to discuss rehabilitation when the patient is facing a life-threatening illness and stressed that patients should take it easy and slowly adjust to the new situation with as little interference from the HCPs as possible.On the other hand, it was also emphasized that a proactive approach promoting rehabilitation at an early stage was fundamental to recovery. At the same time HCPs repeatedly described rehabilitation as driven by patients’ initiatives indicating an inactive rather than proactive rehabilitation. Altogether, this indicated a lack of consensus regarding the meaning of and approach towards rehabilitation.It [the rehabilitation] starts there in the screening moment /…/ but above all … The approach is always that ‘You are going back [to recover]’, and how do we best achieve this? Participants sometimes described specific goals, both for rehabilitation in general and for establishing goals for each patient. However, at the basic rehabilitation level goal setting was often not described as a part of clinical routines and were rarely discussed at a team level. Specific patient-related goals were highlighted as important, such as being able to touch the breast or to get back to work but were rarely developed in conjunction with the patient. It was also stressed that there was a need for an integrated individual rehabilitation plan in which the patient’s goals were clearly documented, and which followed the patient throughout the cancer trajectory to optimize rehabilitation.The importance of identifying patients’ needs throughout the cancer trajectory was stressed. Still, a lack of structure for continuous screening for rehabilitation needs was repeatedly described as a barrier and consensus about the need for systematic needs assessments was lacking. Rather, HCPs identified signs of vulnerability as indicators for rehabilitation needs based on clinical experience.It comes naturally; I can see if a patient has small children or not … or if a patient has a chaotic relationship or if her husband has just left her …// It just something you catch in the moment … Based on experience, the HCPs were attentive to signs of vulnerability by looking beyond the merely obvious and medical aspects. These signs varied and could include specific patient groups such as younger women with children, women that were alone in their situation or did not seem to understand the situation:By identifying signs of vulnerability, the participants extended the understanding of patients’ needs. For example, if a patient had a history of burn-out the HCPs would ask how this might influence her rehabilitation or, in women with children, to explore the plans for telling their children about the cancer. However, the participants also described the risk of potential signs being neglected if they were considered “sensitive”  or if the HCP was unaware of specific signs.I think teamwork is everything in this, because you [the nurses] see it [the needs], you are the ones who meet the patient first. And then the rest of us come in. The participants described that the contact nurses at the basic levels were best positioned to identify signs of vulnerability. The other HCPs corroborated this, saying they had faith in the contact nurses’ ability to identify and refer patients in need of their interventions.The participants highlighted that patients’ needs vary greatly and that HCPs need to be aware of and responsive to patients’ needs throughout the cancer trajectory, which was described as a complex task.Some HCPs like to have a sheet and be able to count and measure, while other colleagues believe that /… / it should come naturally and that establishing a relationship is needed for concerns to emerge. Even if the participants at the basic level mainly described similar potential signs of vulnerability there were no consensus about or structure for how or when these potential signs should be identified. Various opinions were expressed about the importance of adopting a more structured way of screening. Some participants expressed that the most important issue was the relational aspects of support; they said that a more structured approach towards rehabilitation (e.g. through screening) could compromise the patient–HCP relationship, as the approach became instrumental and objective.We have tried to convey this [earlier needs assessment] //, that this should be done before they [the patients] come to us. // They come, as I see it, too late. Others stated that there was a great need for an improved and reliable way of identifying patients’ needs. These participants argued that a structured screening procedure would make it possible to identify and act upon each patient’s needs and would provide better prerequisites for individualized rehabilitation. On the other hand, participants at the advanced level stressed that patients often were referred too late indicating the need of earlier identification of patients’ needs.The participants described that when signs of vulnerability were identified and a patient was considered to be in need of extended rehabilitation, this triggered various actions. If the needs were practical (e.g. economic issues), psychological (e.g. anxiety) or physical (e.g. swollen arm) there was usually a clear routine for referral to a social worker or physiotherapist at the basic rehabilitation level. By contrast, if the trigger was based on personal characteristics or health behaviours , a structure for initiating supportive interventions or referring patients for extended support was often lacking.It was evident that barriers for rehabilitation existed at an organizational level, in terms of lack of interprofessional (between HCPs at the same department) and interdisciplinary (between the departments) collaboration. This was described as hindering a comprehensive rehabilitation process in which a team-based rehabilitation plan follows the patient throughout the cancer trajectory.There is probably no one, I believe, who thinks that it [team-based evaluations] would be impossible, but there could be purely practical conditions, obstacles, organizational barriers for it to happen spontaneously. //. But right now, there is no structure for it … // You make the best out of what you have. “Interprofessional collaboration” was often referred to as gathered professional competences within a specific unit, meaning that the team collaboration was related to one part of the cancer trajectory. It was stressed that interprofessional discussions about patient cases were important to keep updated, to enhance knowledge and to ensure that rehabilitation recommendations were valid, and evidence based. Still, at the basic rehabilitation level, the structure for team collaboration was limited. To enhance such collaboration, geographic and resource aspects were highlighted as important. For example, working geographically close made it easier to discuss individual patients and to share experiences in an informal way while the HCPs working in several units often described their role as consultative.Rehabilitation should really run through it all. From day one when you get your diagnosis, until you return to your normal everyday life. Interdisciplinary collaboration was often described as unsatisfactory. The ineffective collaboration was described as a process where the next instance “started over instead of taking over”, leading to a potential risk of prolonged waiting times, inefficient communication, and sub-optimal rehabilitation. To enable optimal rehabilitation, it was stressed that the recovery period should be (but often was not) seen from a comprehensive continuous perspective.There is not much to offer … who should we refer them to? One example of the lack of collaboration between disciplines was that despite extensive available competence at the advanced rehabilitation level many participants at the basic level was either unaware of the unit’s existence or of how or when to refer patients. The participants also expressed that they were working in a quickly changing health care system within an area where new evidence rapidly emerged, which made it difficult to keep up to date with both evidence and available rehabilitation resources. Therefore, they expressed that there was a need for a support tool that included information about which interventions might be effective for different problems and information about locally available rehabilitation resources.Therefore, implementation of evidence-based guidelines that are adopted throughout the cancer trajectory was expressed as having potential to bridge the gap between different disciplines.Despite national guidelines and initiatives to integrate rehabilitation throughout the cancer trajectory, this study shows that rehabilitation plays a marginal role in today’s BC care in Sweden. The results demonstrate a prominent lack of consensus regarding HCPs approach towards rehabilitation. It also demonstrates that the responsibility for identifying patients with extended rehabilitation needs is on the basic level where structures for systematic needs assessments and evidence-based guidelines often are lacking. This imbalance is likely to be a barrier for individualized rehabilitation. Altogether, these results clearly show that there is a gap between rehabilitation research and clinical practice leaving patients with sub-optimal rehabilitation and emphasizing the need for implementation of guidelines for individualized rehabilitation.This study shows that rehabilitation often is organized based on medical or treatment-related indicators meaning that patients with more advanced or specific treatments are more actively monitored. This way of organizing rehabilitation and survivorship care has also been demonstrated in a Danish study  where caEarlier studies have shown that HCPs avoid structured assessments because of insufficient implementation of a needs assessment form, uncertainty , or becaIdentifying women with extensive rehabilitation needs is a complex but fundamental task when aiming to ensure optimized BC rehabilitation. In this study, specialist and profession-specific competence were highlighted as important for enabling individualized rehabilitation. It was clearly stated that the responsibility for identifying women with extended needs was dependent on the contact nurses on the basic rehabilitation level. However, it was unclear who had the overall responsibility for the rehabilitation process, and an overall plan and structure for when and how patients should be referred within the system was lacking. Studies stress the importance of a multidisciplinary approach to meet the wide range of rehabilitation needs of patients with BC , 32 whicThis study shows that despite an extensive amount of research within the field structures for individualized rehabilitation is lacking. It is also well known that research often fail to translate into meaningful patient care outcomes. Key domains that are fundamental to consider to successfully implement research findings into clinical practice include understanding barriers and facilitators related to the characteristics of the intervention and the involved individuals, the inner and outer setting and the process of implementation . This emThis qualitative focus group study is, to our knowledge, the first of its kind exploring HCPs’ experiences of current practice and barriers and facilitators for individualized rehabilitation for patients treated for BC. Including HCPs who represent various professions and disciplines allowed for variation in perspectives, which can be considered a strength of this study. The design also enabled a deeper understanding of the mechanisms behind the current routines. However, this also means that narratives from different parts of the trajectory were included which might be related to conditions that are unique to that specific specialty and this should be considered when interpreting the results. When participant have intense or lengthy experience within the topic smaller focus groups are often recommended . In thisTo increase the trustworthiness of the study  the HCPsTransferability of qualitative studies is related to the degree of similarity between the study context and the clinical setting. Authors may make suggestions about transferability but due to contextual differences it is always the readers’ responsibility to determine however or not it is transferable . This stDespite the participants’ extensive individual knowledge in the field, this study clearly shows that the cancer trajectory is medically and treatment-driven and that rehabilitation plays a marginal role in the earlier parts of the trajectory. It also demonstrates a prominent imbalance in the role and structure of rehabilitation as the responsibility for identifying patients with extended rehabilitation needs is at the basic level where rehabilitation is often not an integral part. Structures for systematic screening for needs, evidence-based guidelines for individualized rehabilitation interventions and structures for referring patients for advanced rehabilitation are often lacking. To enable optimal and individualized recovery for BC patients’, rehabilitation needs to be an integrated part of the cancer trajectory and run in parallel with diagnostics and treatment.Additional file 1. Interview guide.