Predicting response to neoadjuvant chemotherapy with liquid biopsies and multiparametric MRI in patients with breast cancer.

Accurate prediction of response to neoadjuvant chemotherapy (NAC) can help tailor treatment to individual patients' needs. Little is known about the combination of liquid biopsies and computer extracted features from multiparametric magnetic resonance imaging (MRI) for the prediction of NAC response in breast cancer. Here, we report on a prospective study with the aim to explore the predictive potential of this combination in adjunct to standard clinical and pathological information before, during and after NAC. The study was performed in four Dutch hospitals. Patients without metastases treated with NAC underwent 3 T multiparametric MRI scans before, during and after NAC. Liquid biopsies were obtained before every chemotherapy cycle and before surgery. Prediction models were developed using penalized linear regression to forecast residual cancer burden after NAC and evaluated for pathologic complete response (pCR) using leave-one-out-cross-validation (LOOCV). Sixty-one patients were included. Twenty-three patients (38%) achieved pCR. Most prediction models yielded the highest estimated LOOCV area under the curve (AUC) at the post-treatment timepoint. A clinical-only model including tumor grade, nodal status and receptor subtype yielded an estimated LOOCV AUC for pCR of 0.76, which increased to 0.82 by incorporating post-treatment radiological MRI assessment (i.e., the "clinical-radiological" model). The estimated LOOCV AUC was 0.84 after incorporation of computer-extracted MRI features, and 0.85 when liquid biopsy information was added instead of the radiological MRI assessment. Adding liquid biopsy information to the clinical-radiological resulted in an estimated LOOCV AUC of 0.86. In conclusion, inclusion of liquid biopsy-derived markers in clinical-radiological prediction models may have potential to improve prediction of pCR after NAC in breast cancer.

Self-reported work ability in breast cancer survivors; a prospective cohort study in the Netherlands.

PURPOSE: To evaluate patient-reported work ability of breast cancer patients, to compare scores with the Dutch general population, and to identify determinants of reduced work ability in breast cancer patients. METHODS: In a prospective cohort study, we identified 939 patients <67 years. Employed patients filled out the Work Ability Index (WAI) questionnaire before the start of radiotherapy treatment (baseline) and at 6, 18, and 30 months. Work ability was compared with a matched Dutch cancer-free population (n=3,641). The association between (clinical) characteristics and work ability over time was assessed using mixed-effects models. RESULTS: At baseline, 68% (n=641) of the respondents were employed and 64% (n=203) were employed at 30 months. Moderate or poor work ability was reported by 71% of patients at baseline, by 24% of the patients at 30 months and by 14% of the general population. Axillary lymph node dissection, (neo)adjuvant chemotherapy and locoregional radiotherapy were associated with reduced work ability. After 30 months, 18% of employed patients reported to have reduced their working hours, made substantial modifications to their work or were unable to work. CONCLUSION: Patient-reported work ability is strongly reduced during breast cancer treatment. Thirty months after treatment the proportion of women reporting poor or moderate work ability remains higher compared to the general population. Even though the proportion of women with paid employment is rather stable over time, substantial amendments in work are needed in 18% of patients. These findings emphasize the importance of informing patients on potential changes in work ability to allow shared decision making.

The effect of chemotherapy on subjective cognitive function in younger early-stage breast cancer survivors treated with chemotherapy compared to older patients.

PURPOSE: To evaluate the impact of chemotherapy on subjective cognitive functioning according to age in a large cohort of breast cancer patients. METHODS: Within the UMBRELLA cohort, 715 patients with early-stage primary invasive breast cancer (T1-3N0-1M0) were selected. Subjective cognitive function was assessed by means of the EORTC QLQ-C30 up to 24 months and compared between patients treated with and without chemotherapy, for three different age strata (355 patients < 55 years, 240 patients aged 55-65 years, and 120 patients > 65 years). Differences between chemotherapy and non-chemotherapy patients by age at different time points were assessed by linear mixed-effect models correcting for age, tumor stage, educational level, endocrine therapy, anxiety, and depression. RESULTS: In total, 979 patients from the UMBRELLA cohort were included, of which 715 (73%) responded to baseline and at least one follow-up questionnaire. Questionnaire response rates ranged between 92 and 70%. The proportion of patients treated with chemotherapy decreased with age: 64% (n = 277) in patients < 55 years, 45% (n = 107) in patients 55-65 years, and 23% (n = 27) in patients > 65 years. Chemotherapy was associated with reduced subjective cognitive functioning. The impact of chemotherapy on subjective cognitive function was most pronounced in patients < 55 years, followed by those between 55 and 65 years. In the youngest age groups, patients treated with chemotherapy had significantly lower cognitive functioning up to 24 months. In women over 65 years, subjective cognitive functioning was comparable between patients treated with and without chemotherapy. CONCLUSION: This study confirms that chemotherapy is associated with impaired subjective self-reported cognitive functioning in breast cancer patients, and the effect persists at least up to 2 years after diagnosis. The impact of chemotherapy on self-reported cognitive functioning in the first 24 months is most pronounced in younger patients, especially those under 55 years of age.

Relative dose intensity as a proxy measure of quality and prognosis in adjuvant chemotherapy for breast cancer in daily clinical practice.

AIM: Adjuvant chemotherapy treatment of women with breast cancer is frequently complicated by toxic side-effects, resulting in dose reduction and delay. In Dutch guidelines, a relative dose intensity (RDI) of at least 85% is recommended for optimal treatment. The aim was to investigate predictors of low RDI and its effect on prognosis. METHODS: All patients treated in the St. Antonius Hospital with adjuvant chemotherapy for breast cancer between 2008 and 2013 were included (N = 605). RDI was calculated for each single chemotherapeutic agent and for chemotherapy regimens in total. Incidence and causes of RDI <85% were studied, as well as the effect of RDI on prognosis. RESULTS: About 10% of 605 patients had RDIs <85%. Predictive factors included age, episodes of febrile neutropenia and grade III or IV hypersensitivity reaction to taxanes. Other adverse events, such as peripheral neuropathy, did not affect RDI. The incidence of febrile neutropenia in the 5-fluorouracil, epirubicin, cyclofosfamide, docetaxel (FEC-D) protocol was 24% and therefore was above the threshold set by the European Organisation for Research and Treatment of Cancer for primary granulocyte colony-stimulating factor (G-CSF) prophylaxis. No relationship between RDI and (disease-free) survival was found with a median follow-up of 38 months. Apart from the stage of disease, obesity is a predictor of poor outcome. CONCLUSIONS: RDI <85% is predicted by patients' age, febrile neutropenia and hypersensitivity reactions to taxanes. The incidence of febrile neutropenia in FEC-D treatment indicates primary prophylaxis with G-CSF following docetaxel treatment. No relationship was found between RDI and (disease-free) survival, but longer follow-up is needed.

No firm association between N-terminal pro-brain natriuretic peptide and percentage of pulmonary vascular obstruction in patients with acute pulmonary embolism.

INTRODUCTION: High concentrations of N-terminal-pro-brain natriuretic peptide (NT-proBNP) are found in patients with right ventricular overload. Right ventricular overload may be the result of large perfusion defects in patients with pulmonary embolism (PE). NT-proBNP levels are associated with poorer outcome in patients with acute PE. Likewise, the percentage of pulmonary vascular obstruction (PVO) has shown to be a prognostic parameter for outcome in PE-patients. We postulated that NT-proBNP is associated with the amount of perfusion defects, expressed as the PVO, on perfusion scintigraphy. METHODS: We included 85 consecutive patients in whom the diagnosis PE was confirmed by ventilation-perfusion scintigraphy. PVO was calculated in all patients. NT-proBNP concentrations were measured at presentation. We plotted the logarithm of NT-proBNP versus the PVO. The strength of the estimated association between NT-proBNP and the PVO was expressed by R2. RESULTS: Eighteen percent of the variation in PVO could be explained by NT-proBNP. A positive association becomes apparent for NT-proBNP values above 200 pg/mL, with an increase in PVO of 6.3% (95% Confidence Interval 2.0 to 10.6), with every doubling of NT-proBNP. CONCLUSION: There is an association between NT-proBNP concentrations and PVO, although this relation is quite weak. Some patients with low NT-proBNP values can have a high PVO, which might be relevant for outcome. Therefore, we advise caution in risk stratification and not to focus on NT-proBNP, without involving the clinical condition.

Out of hospital treatment of acute pulmonary embolism in patients with a low NT-proBNP level.

BACKGROUND: Low NT-proBNP levels are associated with an uncomplicated course in patients with pulmonary embolism (PE). The aim of this multicenter management study was to investigate the safety of home treatment of patients with PE with low (< 500 pg mL(-1)) NT-proBNP. METHODS AND RESULTS: Hemodynamically stable outpatients with acute PE and NT-proBNP level < 500 pg mL(-1) were included. Patients were discharged immediately from the emergency room or within a maximum of 24 h after admission. The primary study objective was the absence of mortality during the first 10 days of treatment. Secondary objectives were the incidence of re-admission due to PE or its treatment and the patient's satisfaction during the first 10 days of treatment as well as the incidence of serious adverse events during the 3-month follow-up period. Of 351 patients, 152 (43%) fulfilled the inclusion criteria and were treated as outpatients. No deaths, major bleedings or recurrent venous thromboembolism occurred in the first 10 days of treatment or in the follow-up period of 3 months in these patients. Seven patients required readmission in the first 10 days: three because of complaints that could be related to PE and four due to an illness unrelated to PE. The HADS-A anxiety score did not change significantly between day 0 and day 10. The PSQ-18 showed a high score for satisfaction with home treatment. CONCLUSION: Out of hospital treatment is safe in hemodynamically stable patients with PE with low (< 500 pg mL(-1)) NT-proBNP levels. Approximately 45% of patients with PE can be treated in an outpatient setting. Patients do not consider out of hospital treatment as inconvenient and have no increase in anxiety scores. CLINICAL TRIAL REGISTRATION INFORMATION: http://clinicaltrials.gov/ct2/show/NCT00455819.

Nocardiosis: a case series and a mini review of clinical and microbiological features.

Infections caused by Nocardia species are uncommon and have a wide variety of clinical manifestations in immunocompetent and immunocompromised patients. The diagnosis of nocardiosis can easily be missed because there are no characteristic symptoms. We present one case of a Nocardia infection in detail and give a brief description of eight other cases, including a relatively unique type of Nocardia veterana, diagnosed in our hospital during a five-year period. The diversity of clinical manifestations, microbiological identification and general principles of treatment of nocardiosis are reviewed.