Niels Kroman

Self-reported arm-lymphedema and functional impairment after breast cancer treatment – A nationwide study of prevalence and associated factors

Lymphedema and impairment of function are well-established sequelae to breast cancer treatment and affect an increasing number of women due to continually improved survival. The aim of the present nationwide questionnaire study was to examine the impact of breast cancer treatment on perceived swelling/sensation of heaviness (lymphedema) and on function, reporting prevalence in 12 subgroups of modern treatment and offering estimates for treatment-related associated factors. 3253 Women (87%) returned the study questionnaire. Depending on treatment group prevalence of perceived swelling/heaviness varied from 13 to 65%. Associated factors were young age, axillary lymph node dissection (ALND) and radiotherapy but not type of breast surgery or use of chemotherapy. Depending on treatment group 11-44% had to give up activities. Giving up activities was associated with pain and swelling/heaviness, younger age, ALND, chemotherapy, time elapsed since surgery, and surgery on the dominant side. Radiotherapy and type of breast surgery were of no importance.

Persistent pain and sensory disturbances after treatment for breast cancer: six year nationwide follow-up study

Objective To examine the development of persistent pain after treatment for breast cancer and to examine risk factors associated with continuing pain. Design Repeated cross sectional study in a previously examined nationwide cohort. All eligible women who underwent surgery for primary breast cancer in Denmark in 2005 and 2006 and were examined in 2008 were surveyed again with the same questionnaire. Setting Surgical centres in Denmark. Main outcome measures Prevalence, location, and severity of persistent pain after treatment for breast cancer in well defined treatment groups and changes in pain reporting and sensory disturbances from 2008 to 2012. Participants In 2012, 2828 women were eligible in our database, and 108 were excluded. Exclusion criteria were death; new, recurrent, or other cancer; reconstructive breast surgery; and emigration. Results 2411 (89%) women returned the questionnaire. Prevalence of persistent pain after treatment for breast cancer ranged from 22% to 53% depending on treatment. In 2012, 903 (37%) women reported such pain, a fall from 45% in 2008. Of these, 378 (16%) reported pain of ≥4 on a numerical rating scale (scale 0-10), a fall from 19%. Among women reporting pain in 2008, 36% no longer reported it in 2012. In contrast, 15% of the women who did not report pain in 2008 reported it in 2012. Risk factors for having pain were axillary lymph node dissection rather than sentinel lymph node biopsy (odds ratio 2.04, 95% confidence interval 1.60 to 2.61; P<0.001) and age ≤49 (1.78, 1.25 to 2.54; P<0.001). No particular method of treatment or age was associated with an increase in pain from 2008 to 2012. Conclusions Persistent pain after treatment for breast cancer remains an important problem five to seven years later. The problem is not static as it can either progress or regress with time. Trial registration Clinicaltrials.gov NCT No 01543711.

Preoperative PET/CT in early-stage breast cancer

BACKGROUND The aim of this study was to assess the diagnostic and therapeutic impact of preoperative positron emission tomography and computed tomography (PET/CT) in the initial staging of patients with early-stage breast cancer. PATIENTS AND METHODS A total of 103 consecutive patients with newly diagnosed operable breast cancer with tumors ≥2 cm were independently examined preoperatively with conventional assessment (mammography, breast/axillary ultrasound, chest X-ray and blood samples) and PET/CT with no prior knowledge of the other. RESULTS PET/CT identified a primary tumor in all but three patients (97%). PET/CT solely detected distant metastases (ovary, bones and lung) in 6 patients and new primary cancers (ovary, lung) in another two patients, as well as 12 cases of extra-axillary lymph node involvement. In 15 patients (15%), extra-axillary malignancy was detected by PET/CT only, leading to an upgrade of initial staging in 14% (14/103) and ultimately a modification of planned treatment in 8% (8/103) of patients. CONCLUSIONS PET/CT is a valuable tool to provide information on extra-axillary lymph node involvement, distant metastases and other occult primary cancers. Preoperative (18)F-fluorodeoxyglucose-PET/CT has a substantial impact on initial staging and on clinical management in patients with early-stage breast cancer with tumors ≥2 cm.BACKGROUND The aim of this study was to assess the diagnostic and therapeutic impact of preoperative positron emission tomography and computed tomography (PET/CT) in the initial staging of patients with early-stage breast cancer. PATIENTS AND METHODS A total of 103 consecutive patients with newly diagnosed operable breast cancer with tumors ≥2 cm were independently examined preoperatively with conventional assessment (mammography, breast/axillary ultrasound, chest X-ray and blood samples) and PET/CT with no prior knowledge of the other. RESULTS PET/CT identified a primary tumor in all but three patients (97%). PET/CT solely detected distant metastases (ovary, bones and lung) in 6 patients and new primary cancers (ovary, lung) in another two patients, as well as 12 cases of extra-axillary lymph node involvement. In 15 patients (15%), extra-axillary malignancy was detected by PET/CT only, leading to an upgrade of initial staging in 14% (14/103) and ultimately a modification of planned treatment in 8% (8/103) of patients. CONCLUSIONS PET/CT is a valuable tool to provide information on extra-axillary lymph node involvement, distant metastases and other occult primary cancers. Preoperative 18F-fluorodeoxyglucose-PET/CT has a substantial impact on initial staging and on clinical management in patients with early-stage breast cancer with tumors ≥2 cm.

Use of selective serotonin reuptake inhibitors and risk of re-operation due to post-surgical bleeding in breast cancer patients: a Danish population-based cohort study

BackgroundSelective serotonin reuptake inhibitors (SSRI) decrease platelet-function, which suggests that SSRI use may increase the risk of post-surgical bleeding. Few studies have investigated this potential association.MethodsWe conducted a population-based study of the risk of re-operation due to post-surgical bleeding within two weeks of primary surgery among Danish women with primary breast cancer. Patients were categorised according to their use of SSRI: never users, current users (SSRI prescription within 30 days of initial breast cancer surgery), and former users (SSRI prescription more than 30 days before initial breast cancer surgery). We calculated the risk of re-operation due to post-surgical bleeding within 14 days of initial surgery, and the relative risk (RR) of re-operation comparing SSRI users with never users of SSRI adjusting for potential confounders.Results389 of 14,464 women (2.7%) were re-operated. 1592 (11%) had a history of SSRI use. Risk of re-operation was 2.6% among never users, 7.0% among current SSRI users, and 2.7% among former users. Current users thus had an increased risk of re-operation due to post-operative bleeding (adjusted relative risk = 2.3; 95% confidence interval (CI) = 1.4, 3.9) compared with never users. There was no increased risk of re-operation associated with former use of SSRI (RR = 0.93, 95% CI = 0.66, 1.3).ConclusionsCurrent use of SSRI is associated with an increased risk of re-operation due to bleeding after surgery for breast cancer.

Persistent pain, sensory disturbances and functional impairment after adjuvant chemotherapy for breast cancer: Cyclophosphamide, epirubicin and fluorouracil compared with docetaxel + epirubicin and cyclophosphamide

Abstract Background. Taxanes used in adjuvant therapy for breast cancer are neurotoxic, and thereby being a potential risk factor for persistent pain after breast cancer treatment (PPBCT) and sensory disturbances. The purpose was to compare patients treated with cyclophosphamide, epirubicin and fluorouracil (CEF) and cyclophosphamide and epirubicin + docetaxel (CE + T) in relation to PPBCT, sensory disturbances, peripheral sensory disturbances and functional impairment. Material and methods. A comparative nationwide cross-sectional questionnaire study on two cohorts treated with CEF respectively CE + T, based on the Danish Breast Cancer Cooperative Groups database. Inclusion criteria: women treated with chemotherapy as adjuvant treatment for primary breast cancer, age 18–69 years, without recurrence. Results. One thousand two hundred and forty-one patients allocated to CEF in 2005–2006 and 1652 patients allocated to CE + T in 2007–2008 were included. Six hundred and sixty-four (53%) with CEF and 861 (53%) patients with CE + T reported pain. In the multivariate analysis including available risk factors, CE + T did not confer an increased risk of PPBCT, OR 0.95 (95% CI 0.81–1.11), p = 0.52, compared to CEF. Patients treated with CE + T had a lower risk of sensory disturbances in the area of surgery compared with CEF, OR 0.75 (95% CI 0.62–0.90), p = 0.002. More CE + T patients reported peripheral sensory disturbances in the hands, OR 1.56 (95%CI 1.27–1.92), p < 0.0001, and in the feet, OR 2.0 (95% CI 1.66–2.42) p < 0.0001, compared to CEF. There was no difference in functional impairment (p = 0.62). Conclusion. Docetaxcel as adjuvant treatment for breast cancer does not increase the risk of PPBCT, sensory disturbances in the surgical area or functional impairment, but increase risk for peripheral sensory disturbances.

Pre‐diagnostic alcohol consumption and breast cancer recurrence and mortality: Results from a prospective cohort with a wide range of variation in alcohol intake

The association between pre‐diagnostic alcohol consumption and breast cancer recurrence and breast cancer specific mortality was investigated in 1,052 women diagnosed with early breast cancer in a prospective cohort of 29,875 women. Known clinical, lifestyle and socioeconomic risk factors were evaluated and adjusted for in multivariate analysis. We found a modest but significant association between pre‐diagnostic alcohol consumption and breast cancer recurrence with a median follow‐up of six years after date of diagnosis, both when using baseline measures of alcohol intake (HR, 1.65; 95% CI, 1.02–2.67; >2 units/day vs. ≤1 unit/day) and cumulated alcohol intake (HR, 2.02; 95% CI, 1.06–3.85; >40 drinking years vs. 0

MUC1-derived glycopeptide libraries with improved MHC anchors are strong antigens and prime mouse T cells for proliferative responses to lysates of human breast cancer tissue

Multi‐component glycopeptide libraries and single glycopeptides were used for immunization of mice with the aim of inducing strong T helper cell responses to the repetitive sequence of MUC1 expressed by human tumor cells. The glycopeptides and glycopeptide libraries were modeled upon the native human MUC1 amino acid variable number of tandem repeats sequence by introduction of modifications in the MHC anchor positions to optimally fulfil the binding requirements of the Ad MHC class II molecule in the BALB/c mouse. The immunogenicity of the MUC1 glycopeptides in BALB/c micewas determined by immunization in complete Freunds adjuvant and assaying lymph node T cells for a proliferative response to the glycopeptide used. Strong proliferative responses with stimulation indices over 50 were obtained with anchor‐improved glycopeptide libraries as well as with single glycopeptides. Immunization with one of the glycopeptide libraries primed T cells for a proliferative cross‐response to the native MUC1 glycopeptide, which by itself was nonimmunogenic. In addition, immunization with the same glycopeptide library primed T cells for a strong response to lysate of a MUC1‐expressing human breast cancer, and immunization with the tumor lysate primed T cells for a response to the glycopeptide library. The T cells responding in the assay for proliferation were restricted to the Ad MHC class II molecule. The results indicate that immunization with MHC anchor‐improved MUC1 glycopeptide libraries can effectively prime T helper cells and may induce long‐term memory. The approach may be useful in the design of preventive cancer vaccines for use in humans.

Oestrogen-related cancer risk in mothers of testicular-cancer patients.

The belief that oestrogens are involved in the pathogenesis both of testicular cancer in young men and of cancers of the endometrium and female breast has become widespread. In a search for possible hormonal links between these cancers, we investigated the cancer pattern in a cohort of women who had given birth to sons who developed testicular cancer. Particular focus was given to oestrogen‐related cancers. The present retrospective population‐based cohort study is based on data from the Danish Cancer Registry. Mothers of 2,204 testicular‐cancer patients were followed for the occurrence of cancer over a total of 70,063 person years. The ratio of observed cancers in the cohort over the expected numbers based on cancer incidence in the underlying female population served as measure of the relative risk (RR). The RR of developing breast cancer among mothers of testicular‐cancer patients was 0.8 (95% confidence interval 0.6–1.1), the relative risk of endometrial cancer 0.6 (0.3–1.0) and of ovarian cancer 1.0 (0.6–1.6). Mothers of testicular‐cancer patients are not at increased risk of developing oestrogen‐related cancers.

First-in-human uPAR PET: Imaging of Cancer Aggressiveness

A first-in-human clinical trial with Positron Emission Tomography (PET) imaging of the urokinase-type plasminogen activator receptor (uPAR) in patients with breast, prostate and bladder cancer, is described. uPAR is expressed in many types of human cancers and the expression is predictive of invasion, metastasis and indicates poor prognosis. uPAR PET imaging therefore holds promise to be a new and innovative method for improved cancer diagnosis, staging and individual risk stratification. The uPAR specific peptide AE105 was conjugated to the macrocyclic chelator DOTA and labeled with 64Cu for targeted molecular imaging with PET. The safety, pharmacokinetic, biodistribution profile and radiation dosimetry after a single intravenous dose of 64Cu-DOTA-AE105 were assessed by serial PET and computed tomography (CT) in 4 prostate, 3 breast and 3 bladder cancer patients. Safety assessment with laboratory blood screening tests was performed before and after PET ligand injection. In a subgroup of the patients, the in vivo stability of our targeted PET ligand was determined in collected blood and urine. No adverse or clinically detectable side effects in any of the 10 patients were found. The ligand exhibited good in vivo stability and fast clearance from plasma and tissue compartments by renal excretion. In addition, high uptake in both primary tumor lesions and lymph node metastases was seen and paralleled high uPAR expression in excised tumor tissue. Overall, this first-in-human study therefore provides promising evidence for safe use of 64Cu-DOTA-AE105 for uPAR PET imaging in cancer patients.

Intercostobrachial nerve handling and pain after axillary lymph node dissection for breast cancer.

Moderate to severe pain in the first week after axillary lymph node dissection (ALND) for breast cancer is experienced by approximately 50% of the patients. Damage to the intercostobrachial nerve (ICBN) has been proposed as a risk factor for the development of persistent pain following breast cancer surgery but with limited information on acute post‐operative pain. The aim of the present study was to examine the influence of ICBN handling on pain during the first week after ALND.