Steroid responsiveness predicts olfactory function recovery in dupilumab treated CRSwNP.

BACKGROUND: There is no known predictor for olfactory function recovery with dupilumab treatment in chronic rhinosinusitis with nasal polyps (CRSwNP). This study assessed whether patient-reported recovery of olfactory function on oral corticosteroids (OCS) is a prognostic factor. METHODS: Retrospective analysis of pre-biological OCS-responsiveness on olfactory functioning (OCS-responsive or OCS-unresponsive; OCS-r and OCR-u, respectively) as predictor for olfactory functioning after 6 months of dupilumab therapy for severe CRSwNP. RESULTS: 212 CRSwNP patients treated with dupilumab were divided between OCS-r (reported improvement of olfactory function with OCS before dupilumab treatment, n = 152), and OCS-u (OCS-unresponsive; no such improvement, n = 60). Olfactory function was tested with Sniffin' Sticks Identification Test (12 pens; SSIT-12). At baseline, both groups had a median SSIT-12 score of 3 / 12 indicating anosmia. Hyposmia and normosmia rates were also comparable (5.9% and 3.3% in OCS-r, respectively; 5.0% and 1.7% in OCS-u, respectively). After 6 months of dupilumab treatment, OCS-r showed higher olfactory scores (median SSIT-12: 8/12; 52.6% hyposmia and 17.8% normosmia) than OCS-u (median SSIT-12: 5/12; 31.7% hyposmia and 3.3% normosmia). The positive predictive value of OCS-responsiveness on scoring ≥7 (normosmia/hyposmia) on the SSIT-12 after 6 months of dupilumab treatment was 70.4%. Conversely, the negative predictive value of OCS-unresponsiveness on scoring.

Eosinophils are the dominant type2 marker for the current indication of biological treatment in severe uncontrolled chronic rhinosinusitis with nasal polyps.

The latest European Position Paper on Rhinosinusitis and Nasal Polyps (EPOS2020) defines markers for type2 inflammation in the context of indicating biological therapy in severe uncontrolled chronic rhinosinusitis with nasal polyps (CRSwNP) as either a total serum immunoglobulin E (total-IgE) <100 kU/L, a blood eosinophil count (BEC, expressed as -109 cells / L) >=0.25, or a tissue eosinophil count >=10 per high power field (HPF) (1). Recently, an EPOS/EUFOREA expert panel advised to lower the threshold for BEC from >=0.25 (EPOS2020) to >=0.15 (EUFOREA2023) to align with thresholds used for biological indication in asthma patients (2). As far as we know, there is no literature supporting the cut-off value for total-IgE.

Hypereosinophilia during dupilumab treatment in patients with chronic rhinosinusitis with nasal polyps.

BACKGROUND: Increased blood eosinophil count (BEC) is common in patients under dupilumab treatment for chronic rhinosinusitis with nasal polyps (CRSwNP). This study investigated the prevalence and consequences of hypereosinophilia and to help define patients at risk. METHODS: Real-life, prospective observational cohort study of patients treated with dupilumab for severe CRSwNP. Eligible patients were adult and biological-naive (N=334). All BEC values at baseline and during treatment were reported. Patients with a follow-up of >= 1 year were included to define patients at risk for hypereosinophilia by comparing baseline BEC values (N=218). Furthermore, clinical characteristics and therapeutic consequences for patients with BEC >= 3.0 were noted. RESULTS: Hypereosinophilia developed in a minority of patients, with a peak at week 12 (16.2% with BEC >= 1.5, and 1.7% >= 3.0) in cross-sectional analysis. BEC >= 1.5 developed in 28.9% and BEC >=3.0 in 4.6% of cases with a minimal 1-year follow-up. Baseline BEC was significantly higher for patients developing BEC >= 1.5 and BEC >=3.0, with an optimal cut-off point of 0.96 to predict developing BEC >= 3.0. CONCLUSIONS: Blood eosinophil count (BEC) >= 1.5 is transient and usually abates with no therapeutic interventions and BEC >= 3.0 is rare. Hypereosinophilic syndrome did not occur and switching to a different biological was rarely employed. A baseline BEC of >=1.0 can be a reason for extra caution.

Trends in three major histological subtypes of cutaneous melanoma in the Netherlands between 1989 and 2016.

BACKGROUND: Time trend analysis of cutaneous melanoma (CM) mortality in fair skin populations shows both a gradual decrease and/or an increase. To explain these differences, we analyzed long-term time trends in the incidence of the most common histological subtypes of CM: superficial spreading melanoma (SSM), lentigo maligna melanoma (LMM), and nodular melanoma (NM). METHODS: Using data from the Netherlands Cancer Registry and Statistics Netherlands, the number and rates of cases diagnosed with SSM, LLM, and NM from 1989 to 2016 were analyzed by age, calendar period, and birth cohort of people born in successive periods from 1925 to 1973. RESULTS: Primary CM was diagnosed in 52,000 men and 66,588 women in the study period. The annual age-standardized incidence rate increased three-fold from 14 to 42 per 100,000 person-years. The most common subtype was SSM (50%), followed by LMM (23%) and NM (14%). Age-specific subtype rates showed an upward trend over time for both men and women. Younger birth cohorts had higher rates of SSM and LMM diagnosis than older birth cohorts. This birth cohort pattern was not observed for NM. CONCLUSIONS: We observed a strong increase in the melanoma epidemic curves in the light-skinned Dutch population over the last three decades. This increase is explained by younger generations having higher rates of SSM and LMM than older generations.

Effect of the New Nordic Diet compared with usual care on glucose control in gestational diabetes mellitus: Study protocol for the randomized controlled trial intervention with new Nordic DIet in women with GestatiOnal diabetes mellitus (iNDIGO).

BACKGROUND: Gestational diabetes mellitus (GDM) is a pregnancy complication associated with short- and long-term health consequences for mother and child. First line treatment is diet and exercise but there is a recognized knowledge gap as to what diet treatment is optimal. A healthy Nordic diet has been associated with improved health but no studies in women with GDM exist. The New Nordic Diet (NND) is an initiative with the purpose to develop a healthy Nordic diet including foods with the potential to grow in Nordic countries; including fruit, berries, vegetables, whole-grain cereal products, nuts, fish, and rapeseed oil. The purpose of the intervention with new Nordic DIet in women with GestatiOnal diabetes mellitus (iNDIGO) is to test if the NND compared with usual care improves glucose control in women with GDM. METHODS: The iNDIGO study is a randomized parallel controlled trial where 50 women with GDM will be randomized to either an NND or usual care for 14 days (30-32 weeks of gestation). Participants in the NND group will receive menus and food bags containing foods to be consumed. Primary outcome is glycemic control (time in target) measured using continuous glucose monitoring. Compliance to the dietary intervention will be tested using dietary biomarkers and adherence questionnaires. CONCLUSION: Diet treatment represents first line treatment in GDM but it remains unclear what type of diets are effective. iNDIGO is an efficacy study and will provide evidence as to whether a healthy Nordic diet can improve glucose control in women with GDM. TRIAL REGISTRATION: ClinicalTrials.gov registration Number: NCT04169243. Registered 19 November 2019, https://clinicaltrials.gov/ct2/show/NCT04169243.

Introduction of routine hepatitis B screening for all patients receiving cancer treatment.

BACKGROUND: Patients with a chronic hepatitis B virus (HBV) infection or patients who have recovered from an HBV infection are at risk for HBV reactivation (HBVr), especially if they need treatment with chemotherapy. International guidelines recommend routine HBV screening for all patients starting with chemotherapy. This study evaluates the implementation of a routine HBV screening protocol. METHODS: A retrospective study was performed between January 2015 and October 2016 at the Medical Centre Slotervaart Amsterdam. All patients with a solid or hematological malignancy starting intravenous chemotherapy were included. In September 2015, a protocol for routine HBV screening was introduced. HBV screening results were evaluated before and after implementation of the screening protocol. RESULTS: In total, 184 patients were included, of which 129 patients were actually screened; 37 of the 70 (53%) patients were screened in the group before implementation of the protocol and 92 of the 114 (81%) after implementation. Before routine HBV screening, 8/37 (21.6%) patients tested anti-HBc positive; after introduction of routine screening, 13/92 (14.1%) patients tested anti-HBc positive. After implementation of the screening protocol, no HBVr occurred. CONCLUSION: Implementation of routine HBV screening in patients starting chemotherapy increases identification of the number of patients identified as at risk for HBVr and contributes to prevention of HBVr. A high prevalence of anti-HBc positive patients was found during routine HBV screening, indicating the importance of screening. Awareness and implementation of routine HBV screening, together with knowledge of existing guidelines is necessary to increase the HBV screening rate in patients treated with chemotherapy.

[Whether or not to use thromboprophylaxis in patients treated with chemotherapy for malignant disease]. / Wel of geen tromboseprofylaxe bij oncologische patiënten gedurende de chemotherapie?

CASE DESCRIPTION: A 55-year-old patient with locally advanced pancreatic carcinoma will start Folfirinox. Should he get thromboprophylaxis? CONSIDERATION: Patients with malignant disease have increased risk of venous thromboembolism (VTE). Several types of malignancy, surgery, chemotherapy and metastasis lead to increased risk. VTE is an underdiagnosed phenomenon and the second cause of death in patients treated with chemotherapy. Therapeutic doses increase the risk of bleeding compared to prophylactic anticoagulant treatment. Even though they are less than perfect, several risk scores are able to identify patients with high risk of VTE. The AVERT and CASSINI trials showed that prophylactic doses of DOACs in cancer patients with high risk of VTE are able to significantly reduce this risk. CONCLUSION: Even though there are many unresolved questions, it seems rational to start thromboprophylaxis in patients with aggressive types of cancer, preferably using DOACs, but low molecular weight heparins are possible as well. Risk scores may be helpful when selecting patients.

Genes associated with venous thromboembolism in colorectal cancer patients.

Essentials The underlying pathophysiological mechanisms behind cancer-associated thrombosis are unknown. We compared expression profiles in tumor cells from patients with and without thrombosis. Tumors from patients with thrombosis showed significant differential gene expression profiles. Patients with thrombosis had a proinflammatory status and increased fibrin levels in the tumor. SUMMARY: Background Venous thromboembolism (VTE) is a frequent complication in patients with cancer, and is associated with significant morbidity and mortality. However, the mechanisms behind cancer-associated thrombosis are still incompletely understood. Objectives To identify novel genes that are associated with VTE in patients with colorectal cancer (CRC). Methods Twelve CRC patients with VTE were age-matched and sex-matched to 12 CRC patients without VTE. Tumor cells were isolated from surgical samples with laser capture microdissection approaches, and mRNA profiles were measured with next-generation RNA sequencing. Results This approach led to the identification of new genes and pathways that might contribute to VTE in CRC patients. Application of ingenuity pathway analysis indicated significant links with inflammation, the methionine degradation pathway, and increased platelet function, which are all key processes in thrombus formation. Tumor samples of patients with VTE had a proinflammatory status and contained higher levels of fibrin and fibrin degradation products than samples of those without VTE. Conclusion This case-control study provides a proof-of-principle that tumor gene expression can discriminate between cancer patients with low and high risks of VTE. These findings may help to further unravel the pathogenesis of cancer-related VTE. The identified genes could potentially be used as candidate biomarkers to select high-risk CRC patients for thromboprophylaxis.

Strong and persistent effect on liver fat with a Paleolithic diet during a two-year intervention.

BACKGROUND/OBJECTIVES: Our objective was to investigate changes in liver fat and insulin sensitivity during a 2-year diet intervention. An ad libitum Paleolithic diet (PD) was compared with a conventional low-fat diet (LFD). SUBJECTS/METHODS: Seventy healthy, obese, postmenopausal women were randomized to either a PD or a conventional LFD. Diet intakes were ad libitum. Liver fat was measured with proton magnetic resonance spectroscopy. Insulin sensitivity was evaluated with oral glucose tolerance tests and calculated as homeostasis model assessment-insulin resistance (HOMA-IR)/liver insulin resistance (Liver IR) index for hepatic insulin sensitivity and oral glucose insulin sensitivity (OGIS)/Matsuda for peripheral insulin sensitivity. All measurements were performed at 0, 6 and 24 months. Forty-one women completed the examinations for liver fat and were included. RESULTS: Liver fat decreased after 6 months by 64% (95% confidence interval: 54-74%) in the PD group and by 43% (27-59%) in the LFD group (P<0.01 for difference between groups). After 24 months, liver fat decreased 50% (25-75%) in the PD group and 49% (27-71%) in the LFD group. Weight reduction between baseline and 6 months was correlated to liver fat improvement in the LFD group (rs=0.66, P<0.01) but not in the PD group (rs=0.07, P=0.75). Hepatic insulin sensitivity improved during the first 6 months in the PD group (P<0.001 for Liver IR index and HOMA-IR), but deteriorated between 6 and 24 months without association with liver fat changes. CONCLUSIONS: A PD with ad libitum intake had a significant and persistent effect on liver fat and differed significantly from a conventional LFD at 6 months. This difference may be due to food quality, for example, a higher content of mono- and polyunsaturated fatty acids in the PD. Changes in liver fat did not associate with alterations in insulin sensitivity.

A mimic of soft tissue infection: intra-arterial injection drug use producing hand swelling and digital ischemia / 世界急诊医学杂志（英文）

BACKGROUND: Inadvertent intra-arterial injection of illicit substances is a known complication of injection drug use and can lead to severe complications, including infection, ischemia and compartment syndrome. Identifying complications of intra-arterial injection can be difficult, as clinical manifestations overlap with other more common conditions such as cellulitis and soft tissue infection, and a history of injection drug use is frequently not disclosed. METHODS: A 37-year-old male patient presented with 24 hours of right hand pain, erythema and swelling. Despite classic "track marks", he denied a history of injection drug use, and vascular insults were not initially considered. After failing to respond to three days of aggressive treatment for suspected deep-space infection, an arteriogram demonstrated findings consistent with digital ischemia of embolic etiology. RESULTS: As a result of the delay in diagnosis, the lesion was not amenable to reperfusion and the patient required amputation of the distal digit. CONCLUSION: Practitioners should be alert to the possibility of intra-arterial injection and resulting complications when evaluating unusual extremity infections or unexplained ischemic symptoms, even in the absence of a definite history of injection drug use.

Molecular diagnosis in autoimmune skin blistering conditions.

Blister formation in skin and mucous membranes results from a loss of cell-cell or cell-matrix adhesion and is a common outcome of pathological events in a variety of conditions, including autoimmune and genetic diseases, viral and bacterial infections, or injury by physical and chemical factors. Autoantibodies against structural components maintaining cell-cell and cell-matrix adhesion induce tissue damage in autoimmune blistering diseases. Detection of these autoantibodies either tissue-bound or circulating in serum is essential to diagnose the autoimmune nature of disease. Various immunofluorescence methods as well as molecular immunoassays, including enzyme-linked immunosorbent assay and immunoblotting, belong to the modern diagnostic algorithms for these disorders. There is still a considerable need to increase awareness of the rare autoimmune blistering diseases, which often show a severe, chronic-relapsing course, among physicians and the public. This review article describes the immunopathological features of autoimmune bullous diseases and the molecular immunoassays currently available for their diagnosis and monitoring.

Immediate and delayed effects of mammographic screening on breast cancer mortality and incidence in birth cohorts.

BACKGROUND: Trend studies investigating the impact of mammographic screening usually display age-specific mortality and incidence rates over time, resulting in an underestimate of the benefit of screening, that is, mortality reduction, and an overestimate of its major harmful effect, that is, overdiagnosis. This study proposes a more appropriate way of analysing trends. METHODS: Breast cancer mortality (1950-2009) and incidence data (1975-2009) were obtained from Statistics Netherlands, 'Stg. Medische registratie' and the National Cancer Registry in the Netherlands for women aged 25-85 years. Data were visualised in age-birth cohort and age-period figures. RESULTS: Birth cohorts invited to participate in the mammographic screening programme showed a deflection in the breast cancer mortality rates within the first 5 years after invitation. Thereafter, the mortality rate increased, although less rapidly than in uninvited birth cohorts. Furthermore, invited birth cohorts showed a sharp increase in invasive breast cancer incidence rate during the first 5 years of invitation, followed by a moderate increase during the following screening years and a decline after passing the upper age limit. CONCLUSION: When applying a trend study to estimate the impact of mammographic screening, we recommend using a birth cohort approach.

Likelihood of early detection of breast cancer in relation to false-positive risk in life-time mammographic screening: population-based cohort study.

BACKGROUND: Women require balanced, high-quality information when making an informed decision on screening benefits and harms before attending biennial mammographic screening. PATIENTS AND METHODS: The cumulative risk of a false-positive recall and/or (small) screen-detected or interval cancer over 13 consecutive screening examinations for women aged 50 from the start of screening were estimated using data from the Nijmegen programme, the Netherlands. RESULTS: Women who underwent 13 successive screens in the period 1975-1976 had a 5.3% cumulative chance of a screen-detected cancer, with a 4.2% risk of at least one false-positive recall. The risk of being diagnosed with interval cancer was 3.7%. Two decades later, these estimates were 6.9%, 7.3% and 2.9%, respectively. The chance of detection of a small, favourable invasive breast cancer, anticipating a normal life-expectancy, rose from 2.3% to 3.7%. Extrapolation to digital screening mammography indicates that the proportion of false-positive results will rise to 16%. CONCLUSION: Dutch women about to participate in the screening programme can be reassured that the chance of false-positive recall in the Netherlands is relatively low. A new screening policy and improved mammography have increased the detection of an early screening carcinoma and lowering the risk of interval carcinoma.

The attitude of Flemish paediatricians regarding informed consent of adolescents.

BACKGROUND: Since 2002 the Belgian law requires an informed consent of the patient before each medical intervention. This provision applies also for adolescent patients on condition that the physician considers the young patient as competent to autonomously participate in the decision making process. AIM: The purpose of this study is to evaluate to what extent Belgian paediatricians from the Flemish part of the country have implemented the legal requirements for informed consent of adolescent patients, in particular when they consult alone. METHODS: In the frame of a larger study regarding the relation between paediatricians and their patients, a questionnaire was sent via regular mail to 570 Flemish paediatricians, evaluating how and how often they obtain an informed consent of the adolescent when consulting a physician unaccompanied. RESULTS: In only 1% of all consultations an adolescent consulted the physician alone and agreed to a medical intervention on his/her own. The information given by the paediatrician did not differ if the adolescent consulted alone or was accompanied by (one of) his/her parents for the following items: purpose and type of treatment (100% vs 100%), duration of treatment (92% vs 94%) and aftercare (89% vs 93%). However, the information differed with regard to alternatives to the treatment (65% vs 76%), degree of urgency (89% vs 95% ), treatment related risks (82% vs 90%) and cost (21% vs 45%). 18.6% of the paediatricians consider age as the single criterion to evaluate the competence of the adolescent to provide an informed consent; other criteria that are considered: experience (92%), insight into and factual understanding of the clinical picture (84%). To fulfil the tasks of providing information and asking for consent, paediatricians rarely had recourse to prior established protocols (14%), they preferred to rely on proper experience and expertise (81%). Fifty percent appealed to the opinion of other health care providers. CONCLUSIONS: Although the Belgian law stipulates regulations that should be complied with by the physician during the decision making process about any medical intervention on adolescents, this legislation has rarely been put into practice, as the adolescents used their right to autonomously consent in barely 1% of all paediatric consultations. For the majority of the respondents other criteria than age were taken into account to consider an adolescent as able to provide informed consent.

[Effects of the population screening into breast cancer]. / Effecten van het bevolkingsonderzoek naar borstkanker.

Annually, in the Netherlands around 900,000 women between the ages of 50-75 years undergo mammography as part of a population screening into breast cancer. In this way more than 5000 cases of breast cancer are detected (0.6% of women screened); 70% of these malignancies are < stage II, which is prognostically favourable. Due to the early detection and treatment of breast cancer, the breast cancer death risk in those women who participate in the population screening is half that of women who choose not to be screened. The downside of the population screening is that participants are relatively often referred to a hospital for a diagnostic work-up (around 2%), and 70% of them are ultimately found not to have cancer. The positive predictive value of the population screening is 30%. Early discovery also leads to over-diagnosis in patients with breast cancer that without screening would never have manifested itself. Based on computer simulations it has been estimated that in the Netherlands over-diagnosis occurs in 9% of patients in whom breast cancer is detected during a population screening.

Adherence to a low-fat vs. low-carbohydrate diet differs by insulin resistance status.

Previous research shows diminished weight loss success in insulin-resistant (IR) women assigned to a low-fat (LF) diet compared to those assigned to a low-carbohydrate (LC) diet. These secondary analyses examined the relationship between insulin-resistance status and dietary adherence to either a LF-diet or LC-diet among 81 free-living, overweight/obese women [age = 41.9 ± 5.7 years; body mass index (BMI) = 32.6 ± 3.6 kg/m(2)]. This study found differential adherence by insulin-resistance status only to a LF-diet, not a LC-diet. IR participants were less likely to adhere and lose weight on a LF-diet compared to insulin-sensitive (IS) participants assigned to the same diet. There were no significant differences between IR and IS participants assigned to LC-diet in relative adherence or weight loss. These results suggest that insulin resistance status may affect dietary adherence to weight loss diets, resulting in higher recidivism and diminished weight loss success of IR participants advised to follow LF-diets for weight loss.

Limitations of screening for occult cancer in patients with idiopathic venous thromboembolism.

BACKGROUND: Idiopathic venous thrombosis (IVT) is associated with occult malignancy in 10% of patients. The Trousseau study investigated whether extensive screening using abdominal and chest computed tomography (CT) scans and mammography in women would decrease mortality, compared with limited screening. Here, the costs and test characteristics of these screening strategies are presented, including true- and false-positive findings, sensitivity and specificity. METHODS: All investigations performed because of a suspicion of malignancy in the limited or extensive screening groups were collected. Costs were calculated using Dutch healthcare tariffs. RESULTS: A total of 342 and 288 patients with IVT were included in the extensive and the limited screening group, respectively. The prevalences of malignancy and mortality were comparable between these two groups, as were the abnormal findings during routine screening. In 30% of the extensively screened patients, the CT scans or mammography showed abnormalities necessitating further diagnostic work-up; this yielded six malignancies and resulted in a positive predictive value of 6.6%, sensitivity of 33% and specificity of 70%. Mean costs per patient were €165.17 for the routine and €530.92 for the extensive screening. CONCLUSION: Screening using CT scans and mammography results in extra costs due to the high percentage of false-positive findings for which a further diagnostic work-up is indicated.

[Sensibility changes of the infraorbital nerve after primary surgery on patients with unilateral cleft lip according to J. Delaire]. / Évaluation à long terme de la sensibilité du nerf infraorbitaire chez les patients porteurs de fente labiale unilatérale complète après traitement primaire selon la technique de J. Delaire.

OBJECTIVE: The aim was to determine the overall sensibility changes in the area of the infraorbital nerve on patients with unilateral clefts lips and unilateral clefts lips and palate who had undergone primary surgical correction according to the principles of Delaire. PATIENTS AND METHOD: Twenty patients (7-20years) with unilateral cleft lips (and palate) who had undergone surgery in infancy according to Delaire were included. Cutaneous sensibilities of the nasolabial fold and of the upper lip were tested using four cutaneous modalities. A tactil superficial sensibility light touch test, a two-point discrimination test (McKinnon-Dellon Disk-Criminator), and the determination of cold and warm detection thresholds (Quantitative Sensory Testing, Medoc Thermal Sensory Analyser). The possible difference of the sensibility between operated and controlateral sides of the face were compared. Results were finally compared to a control group of twenty healthy volunteers. RESULTS: No significant difference could be found between the operated and non-operated side of the cleft group. There was also no difference between the cleft and the control group. Specific difference of perception between nasolabial fold and lip encountered in the literature were confirmed by the experiments. CONCLUSION: The large subperiostal approach according to Delaire during the primary surgical procedure have not affected long term infraorbital sensibility of patients with unilateral complete cleft lip.

Less mammographic density after nasal versus oral administration of postmenopausal hormone therapy.

OBJECTIVE: Nasal administration gives a more acute but shorter rise in serum hormone levels than oral administration and may therefore have less effect on the fibroglandular tissue in the breasts. We studied the change in mammographic breast density after nasal vs. oral administration of postmenopausal hormone therapy (PHT). METHODS: We studied participants in a randomized, controlled trial on the impact of nasal vs. oral administration of PHT (combined 17ß-estradiol plus norethisterone) for 1 year. Two radiologists classified mammographic density at baseline and after 1 year into four categories. Also, the percentage density was calculated by a computer-based method. The main outcome measure was the difference in the proportion of women with an increase in mammographic density category after 1 year between the nasal and oral groups. Also, the change in the percentage density was calculated. RESULTS: The study group comprised 112 healthy postmenopausal women (mean age 56 years), of whom 53 received oral and 59 intranasal PHT. An increase in mammographic density category after 1 year was seen in 20% of the women in the nasal group and in 34% of the oral group. This resulted in a non-significant difference in the proportion of women in whom mammographic breast density had increased by 214% (95% confidence interval (CI) 230% to 2.7%). The mean change in percentage density was 21.2% in the nasal group and + 1.2% in the oral group, yielding a 22.4% differential effect (95% CI 27.3% to 2.5%). CONCLUSIONS: One year of nasal PHT gave a smaller, although not statistically significant, increase in mammographic density than oral PHT. Remaining issues are the relation between the route of administration of PHT and breast complaints and breast cancer risk.