An Exploration of the Pillars of Leadership in Cancer Education.

Leadership plays a key role in cancer education (CE) and the success of its practices. Leaders in CE must effectively use their leadership skills to be able to communicate, collaborate, and educate their team members. There is a lack of formalized and standardized curriculums for institutions in developing leadership programs, including what themes to focus on in CE. In this article, the authors describe key pillars of leadership in CE that have presented themselves throughout their experience and within the literature. A search was conducted using the Ovid MEDLINE® database and articles were reviewed for eligibility. In this review, thirty articles were selected for their relevance to CE. With this literature search and the authors' reflections, four pillars of leadership in CE were identified: (1) leadership development, (2) collaboration, (3) diversity and equity, and (4) implementation. Within these themes, key areas of importance were discussed further, and barriers to CE leadership were identified. By reflecting upon pillars of leadership in CE, this article may be helpful for developing future leadership programs within CE. It is vital that initiatives continue to be held and barriers are addressed to increase leadership effectiveness within CE.

Longitudinal Serum Protein Analysis of Women with a High Risk of Developing Breast Cancer Reveals Large Interpatient Versus Small Intrapatient Variations: First Results from the TESTBREAST Study.

The prospective, multicenter TESTBREAST study was initiated with the aim of identifying a novel panel of blood-based protein biomarkers to enable early breast cancer detection for moderate-to-high-risk women. Serum samples were collected every (half) year up until diagnosis. Protein levels were longitudinally measured to determine intrapatient and interpatient variabilities. To this end, protein cluster patterns were evaluated to form a conceptual basis for further clinical analyses. Using a mass spectrometry-based bottom-up proteomics strategy, the protein abundance of 30 samples was analyzed: five sequential serum samples from six high-risk women; three who developed a breast malignancy (cases) and three who did not (controls). Serum samples were chromatographically fractionated and an in-depth serum proteome was acquired. Cluster analyses were applied to indicate differences between and within protein levels in serum samples of individuals. Statistical analyses were performed using ANOVA to select proteins with a high level of clustering. Cluster analyses on 30 serum samples revealed unique patterns of protein clustering for each patient, indicating a greater interpatient than intrapatient variability in protein levels of the longitudinally acquired samples. Moreover, the most distinctive proteins in the cluster analysis were identified. Strong clustering patterns within longitudinal intrapatient samples have demonstrated the importance of identifying small changes in protein levels for individuals over time. This underlines the significance of longitudinal serum measurements, that patients can serve as their own controls, and the relevance of the current study set-up for early detection. The TESTBREAST study will continue its pursuit toward establishing a protein panel for early breast cancer detection.

Survival after bilateral risk-reducing mastectomy in healthy BRCA1 and BRCA2 mutation carriers.

BACKGROUND: In healthy BRCA1/2 mutation carriers, bilateral risk-reducing mastectomy (BRRM) strongly reduces the risk of developing breast cancer (BC); however, no clear survival benefit of BRRM over BC surveillance has been reported yet. METHODS: In this Dutch multicenter cohort study, we used multivariable Cox models with BRRM as a time-dependent covariable to estimate the associations between BRRM and the overall and BC-specific mortality rates, separately for BRCA1 and BRCA2 mutation carriers. RESULTS: During a mean follow-up of 10.3 years, 722 out of 1712 BRCA1 (42%) and 406 out of 1145 BRCA2 (35%) mutation carriers underwent BRRM. For BRCA1 mutation carriers, we observed 52 deaths (20 from BC) in the surveillance group, and 10 deaths (one from BC) after BRRM. The hazard ratios were 0.40 (95% CI 0.20-0.90) for overall mortality and 0.06 (95% CI 0.01-0.46) for BC-specific mortality. BC-specific survival at age 65 was 93% for surveillance and 99.7% for BRRM. For BRCA2 mutation carriers, we observed 29 deaths (7 from BC) in the surveillance group, and 4 deaths (no BC) after BRRM. The hazard ratio for overall mortality was 0.45 (95% CI 0.15-1.36). BC-specific survival at age 65 was 98% for surveillance and 100% for BRRM. CONCLUSION: BRRM was associated with lower mortality than surveillance for BRCA1 mutation carriers, but for BRCA2 mutation carriers, BRRM may lead to similar BC-specific survival as surveillance. Our findings support a more individualized counseling based on BRCA mutation type.

The Impact of Massed and Spaced-Out Curriculum in Oncology Knowledge Acquisition.

Starting in 2009, cancer has been the leading cause of death in the Netherlands. Oncology is therefore an important part of the medical curriculum in undergraduate education. It is crucial that medical students know about cancer, since doctors will encounter many cases of oncology. We have compared the influence that teaching oncology has when spread over a 3-year curriculum versus concentrated in one semester. The participants comprised 525 medical students from one medical school with comprehensive integrated curricula. Of those, 436 followed the massed curriculum, with oncology concentrated in one semester. The remaining 89 students followed a spaced-out curriculum, in which oncology was spread out over 3 years. To measure students' knowledge, we used their progress test results from 2009 to 2012. All questions about oncology were categorized and selected. Because of our unbalanced sample and missing data and to reduce the chances for a type II error, we compared the growth of oncology questions using mixed effect models. A cubic growth model with an unstructured covariance matrix fitted our data best. At the start, students in the spaced-out curriculum scored higher on oncology questions. The initial growth was faster for the spaced-out curriculum students, whereas the acceleration over time was slower compared to the massed curriculum students. At the end of the growth curve, the knowledge of the massed curriculum students increased faster. In the last test, the massed curriculum students outperformed those in the spaced-out curriculum. The way students acquired and applied their knowledge was similar in both curricula. It seems, however, that students benefitted more from massed than spaced-out education, which may be due to the comprehensive integrated teaching involved.

The Impact of Curriculum Design in the Acquisition of Knowledge of Oncology: Comparison Among Four Medical Schools.

Over the past 5 years, cancer has replaced coronary heart disease as the leading cause of death in the Netherlands. It is thus paramount that medical doctors acquire a knowledge of cancer, since most of them will face many patients with cancer. Studies, however, have indicated that there is a deficit in knowledge of oncology among medical students, which may be due not only to the content but also to the structure of the curriculum. In this study, we compared students' knowledge acquisition in four different undergraduate medical programs. Further, we investigated possible factors that might influence students' knowledge growth as related to oncology. The participants comprised 1440 medical students distributed over four universities in the Netherlands. To measure students' knowledge of oncology, we used their progress test results from 2007 to 2013. The progress test consists of 200 multiple-choice questions; this test is taken simultaneously four times a year by all students. All questions regarding oncology were selected. We first compared the growth of knowledge of oncology using mixed models. Then, we interviewed the oncology coordinator of each university to arrive at a better insight of each curriculum. Two schools showed similar patterns of knowledge growth, with a slight decrease in the growth rate for one of them in year 6. The third school had a faster initial growth with a faster decrease over time compared to other medical schools. The fourth school showed a steep decrease in knowledge growth during years 5 and 6. The interviews showed that the two higher-scoring schools had a more focused semester on oncology, whereas in the others, oncology was scattered throughout the curriculum. Furthermore, the absence of a pre-internship training program seemed to hinder knowledge growth in one school. Our findings suggest that curricula have an influence on students' knowledge acquisition. A focused semester on oncology and a pre-internship preparatory training program are likely to have a positive impact on students' progress in terms of knowledge of oncology.

Treatment and outcomes in breast cancer patients: A cross section study from the EUSOMA breast centre network.

INTRODUCTION: The present study was designed to describe tumour features and treatments for patients with breast cancer. It also aimed at assessing the risk of distant metastases in relation to biological profiles, disease stages and treatment. METHODS: Data were analysed from 81,882 patients in the EUSOMA database (disease stages at diagnosis 0-IV; median age 61 years; range 20-100 years). All patients were treated between January 2016 and December 2021 in 53 Breast Centres within the EUSOMA certification process in 13 European countries. Cases were classified as HR+ /HER2-, HR+ /HER2 + , HR-/HER2 + or HR-/HER2- and data were analysed accordingly. RESULTS: Univariable and multivariable analyses for distant metastases were conducted on a subset of 38,119 cases with information on whether or not they had developed them. Potential determinants included sub-group type, Ki67 value, disease stage, adjuvant systemic therapies and post-operative radiation therapy. In multivariable analysis, the HR-/HER2 + and HR-/HER2- sub-groups were associated with a higher risk of distant metastases than HR+ /HER2-. Ki67 > 20 % and advanced stage disease also carried a high risk. Radiation therapy emerged as a protective factor against distant metastases. CONCLUSIONS: Present results show a large patient database offers an information stream that can be applied to reduce uncertainties in clinical practice. Database parameters need to be updated dynamically for outcome monitoring. Molecular prognostic factors, gene-expression signatures, tumour-infiltrating lymphocytes and circulating tumoral DNA should be added.

The impact of the SARS-COV-2 pandemic on the quality of breast cancer care in EUSOMA-certified breast centres.

AIMS: We analysed the impact of the SARS-CoV-2 pandemic (COVID-19) on the quality of breast cancer care in certified EUSOMA (European Society of Breast Cancer Specialists) breast centres. MATERIALS AND METHODS: The results of the EUSOMA quality indicators were compared, based on pseudonymised individual records, for the periods 1 March 2020 till 30 June 2020 (first COVID-19 peak in most countries in Europe) and 1 March 2019 till 30 June 2019. In addition, a questionnaire was sent to the participating Centres for investigating the impact of the COVID-19 pandemic on the organisation and the quality of breast cancer care. RESULTS: Forty-five centres provided data and 31 (67%) responded to the questionnaire. The total number of new cases dropped by 19% and there was a small significant higher tumour (p = 0.003) and lymph node (p = 0.011) stage at presentation. Comparing quality indicators (12,736 patients) by multivariable analysis showed mostly non-significant differences. Surgery could be performed in a COVID-free zone in 94% of the centres, COVID testing was performed before surgery in 96% of the centres, and surgical case load was reduced in 55% of the centres. Modifications of the indications for neoadjuvant endocrine therapy, chemotherapy, and targeted therapy were necessary in 23%, 23%, and 10% of the centres; changes in indications for adjuvant endocrine, chemo-, targeted, immune, and radiotherapy in 3%, 19%, 3%, 6%, and 10%, respectively. CONCLUSION: Quality of breast cancer care was well maintained in EUSOMA breast centres during the first wave of the COVID-19 pandemic. A small but significantly higher tumour and lymph node stage at presentation was observed.

Penetrance of breast cancer, ovarian cancer and contralateral breast cancer in BRCA1 and BRCA2 families: high cancer incidence at older age.

Accurate estimations of lifetime risks of breast and ovarian cancer are crucial for counselling women from BRCA1/2 families. We therefore determined breast and ovarian cancer penetrance in BRCA1/2 mutation families in the northern Netherlands and compared them with the incidence of cancers in the general population in this region. We identified 1188 female mutation carriers and first-degree female relatives in 185 families with a pathogenic BRCA1 or BRCA2 mutation. The occurrence of breast cancer, contralateral breast cancer and ovarian cancer was recorded. The cumulative incidence of breast cancer by age 70 was 71.4% (95% CI 67.2-82.4%) in BRCA1 and 87.5% (82.4-92.6%) in BRCA2 mutation carriers. For ovarian cancer at age 70, it was 58.9% (53.5-64.3%) in BRCA1 and 34.5% (25.0-44.0%) in BRCA2 mutation carriers. For breast cancer we saw a rise of 24.2% in the cumulative incidence in the seventh decade for BRCA2 mutation carriers versus 6.3% for BRCA1. For ovarian cancer the rise in the seventh decade was 17.3% for BRCA1 mutation carriers and 15.1% for BRCA2. The 10-year risk for contralateral breast cancer was 34.2% (29.4-39.0%) in BRCA1 families and 29.2% (22.9-35.5%) in BRCA2. We show that the incidence of breast and ovarian cancer in BRCA2 mutation carriers and of ovarian cancer in BRCA1 mutation carriers is still high after 60 years. This may justify intensive breast screening as well as oophorectomy even after age 60. The risk of contralateral breast cancer rises approximately 3% per year, which may affect preventive choices.

Severe hypercortisolism: a medical emergency requiring urgent intervention.

OBJECTIVES: To illustrate the importance of recognizing symptoms of severe hypercortisolism in the intensive care unit and key emergency measures to reduce this extreme hypercortisolism. DESIGN: Case report. SETTING: Intensive care unit in a university hospital. PATIENT: A 55-yr-old woman was admitted to the intensive care unit with multiorgan failure after perforation of the sigmoid. Recent-onset hypertension, spontaneous hypokalemia, and diabetes mellitus suggested severe Cushing's syndrome as the underlying disease. Markedly increased serum cortisol (5900 nmol/L) and adrenocorticotropic hormone (302 ng/L) levels were found, highly suggestive for ectopic adrenocorticotropic hormone secretion. Imaging studies failed to unequivocally establish a solitary source of ectopic adrenocorticotropic hormone secretion. The deteriorating condition of the patient urged rapid intervention. INTERVENTIONS: Etomidate was infused continuously to reduce endogenous adrenal cortisol secretion. Subsequently, a rescue bilateral adrenalectomy was undertaken. MEASUREMENTS AND RESULTS: Etomidate effectively reduced the cortisol level. Serial blood samples were obtained during the bilateral adrenalectomy. Plasma adrenocorticotropic hormone markedly decreased immediately after resection of the right adrenal gland. Histopathological examination revealed a tumor of the right adrenal gland identified as a pheochromocytoma and hyperplasia of the left adrenal gland, but no signs of malignancy. The patient recovered slowly. CONCLUSION: This case illustrates that severe hypercortisolism is a medical emergency and that specific and prompt combined medical and surgical intervention can be life-saving.

A longitudinal comparison of arm morbidity in stage I-II breast cancer patients treated with sentinel lymph node biopsy, sentinel lymph node biopsy followed by completion lymph node dissection, or axillary lymph node dissection.

BACKGROUND: Long-term shoulder and arm function following sentinel lymph node biopsy (SLNB) may surpass that following complete axillary lymph node dissection (CLND) or axillary lymph node dissection (ALND). We objectively examined the morbidity and compared outcomes after SLNB, SLNB + CLND, and ALND in stage I/II breast cancer patients. MATERIALS AND METHODS: Breast cancer patients who had SLNB (n = 51), SLNB + CLND (n = 55), and ALND (n = 65) were physically examined 1 day before surgery (T0), and after 6 (T1), 26 (T2), 52 (T3), and 104 (T4) weeks. Differences in 8 parameters between the affected and unaffected arms were calculated. General linear models were computed to examine time, group, and interaction effects. RESULTS: All outcomes changed significantly, mostly nonlinearly, over time (T0-T4). Between T1 and T4, limitations decreased in abduction (all groups); anteflexion, abduction-exorotation, abduction strength (SLNB + CLND, ALND); flexion strength (SLNB + CLND); and arm volume (SLNB, SLNB + CLND). At T4, limitations in anteflexion (SLNB, ALND), abduction (SLNB + CLND, ALND), exorotation (ALND), abduction-exorotation (all groups), and volume (SLNB + CLND, ALND) increased significantly compared with T0. The SLNB group showed an advantage in anteflexion, abduction, abduction-exorotation, and volume. Groups changed significantly but differently over time in anteflexion, abduction, abduction/exorotation, abduction strength, flexion strength, and volume. Effect sizes varied from 0.19 to 0.00. CONCLUSION: Initial declines in range of motion and strength were followed by recovery, although not always to presurgery levels. Range of motion and volume outcomes were better for SLNB than ALND, but not strength. SLNB surpassed SLNB + CLND in 2 of the range of motion variables. The clinical relevance of these results is negligible.

Personal control over the cure of breast cancer: adaptiveness, underlying beliefs and correlates.

OBJECTIVES: Although cognitive adaptation theory suggests that personal control acts as a stress buffer when facing adversity, maladaptive outcomes might occur when control is disconfirmed. The moderating effect of disappointing news on the adaptiveness of personal control over cure in women with breast cancer was examined and contrasted with the effect on the adaptiveness of general control over life. Additionally, the underlying beliefs and correlates of control over cure were explored. METHODS: Women with newly diagnosed breast cancer were assessed after surgery (n=228). For a sub-sample (n=133) data before surgery and after the end of treatment were available as well. Data were collected through questionnaires and face-to-face interviews. The prescription of chemotherapy after surgery was used as an indicator of disappointing news. RESULTS: A chemotherapy prescription neither enhances nor limits the adaptiveness of disease-specific or general control perceptions. Women reported that maintaining a positive attitude, accepting treatment and adopting a healthy life style gave them a sense of control over cure. Women with a strong sense of control over cure more often had invasive cancer, were younger and were best characterized by high optimism and strong sense of control over life. CONCLUSIONS: The findings add to our understanding of exaggerated control perceptions in cancer patients treated with curative intent and do not give reason to assume that such perceptions should be altered because of potentially maladaptive effects. On the contrary, a strong sense of control over the cure of breast cancer seems to reflect the capacity to adapt.

Vienna international summer school on experimental and clinical oncology for medical students: an Austrian cancer education project.

The "International Summer School on Experimental and Clinical Oncology for Medical Students" is organised at the Medical University of Vienna to teach a multidisciplinary approach to oncology to medical students in the final phase of their studies. The program includes biology, diagnosis, clinical and psycho-oncology. Lectures are given by medical, radiation and surgical oncologists. Teaching includes case reports, poster presentations and role-play. As part of the organising committee, Austrian students organise a social program. Since 1999, six courses have been held (147 students from 19 countries). Students recorded high satisfaction with organisation, scientific content and topic range. Case presentations, poster presentations and role-play were very useful. Early criticism that the program was too intense (long lectures and little interaction) has been answered. The summer school has a high degree of acceptance and is a very useful tool to teach medical students about oncology and approaching a cancer patient.

Obtaining adequate surgical margins in breast-conserving therapy for patients with early-stage breast cancer: current modalities and future directions.

Inadequate surgical margins represent a high risk for adverse clinical outcome in breast-conserving therapy (BCT) for early-stage breast cancer. The majority of studies report positive resection margins in 20% to 40% of the patients who underwent BCT. This may result in an increased local recurrence (LR) rate or additional surgery and, consequently, adverse affects on cosmesis, psychological distress, and health costs. In the literature, various risk factors are reported to be associated with positive margin status after lumpectomy, which may allow the surgeon to distinguish those patients with a higher a priori risk for re-excision. However, most risk factors are related to tumor biology and patient characteristics, which cannot be modified as such. Therefore, efforts to reduce the number of positive margins should focus on optimizing the surgical procedure itself, because the surgeon lacks real-time intraoperative information on the presence of positive resection margins during breast-conserving surgery. This review presents the status of pre- and intraoperative modalities currently used in BCT. Furthermore, innovative intraoperative approaches, such as positron emission tomography, radioguided occult lesion localization, and near-infrared fluorescence optical imaging, are addressed, which have to prove their potential value in improving surgical outcome and reducing the need for re-excision in BCT.

Extra-intestinal manifestations of familial adenomatous polyposis.

Familial adenomatous polyposis (FAP) is an autosomal dominantly inherited disorder, which results from a germ line mutation in the APC (adenomatous polyposis coli) gene. FAP is characterized by the formation of hundreds to thousands of colorectal adenomatous polyps. Although the development of colorectal cancer stands out as the most prevalent complication, FAP is a multisystem disorder of growth. This means, it is comparable to other diseases such as the MEN syndromes, Von Hippel-Lindau disease and neurofibromatosis. However, the incidence of many of its clinical features is much lower. Therefore, a specialized multidisciplinary approach to optimize health care-common for other disorders-is not usually taken for FAP patients. Thus, clinicians that care for and counsel members of high-risk families should have familiarity with all the extra-intestinal manifestations of this syndrome. FAP-related complications, for which medical attention is essential, are not rare and their estimated lifetime risk presumably exceeds 30%. Affected individuals can develop thyroid and pancreatic cancer, hepatoblastomas, CNS tumors (especially medulloblastomas), and various benign tumors such as adrenal adenomas, osteomas, desmoid tumors and dental abnormalities. Due to improved longevity, as a result of better prevention of colorectal cancer, the risk of these clinical problems will further increase. We present a clinical overview of extra-intestinal manifestations, including management and treatment options for the FAP syndrome. Furthermore, we provide recommendations for surveillance of FAP complications based on available literature.

Evolution in sentinel lymph node biopsy in breast cancer.

Sentinel lymph node biopsy (SLNB) is the standard of care for axillary staging in clinically node-negative (cN0) breast cancer patients without neoadjuvant chemotherapy (NAC). The application of SLNB in patients receiving NAC has also been explored. Evidence supports its use after NAC in pretreatment cN0 patients. Nonetheless, its routine use in all the pretreatment node-positive patients who become cN0 after NAC is unjustified due to the unacceptably high false-negative rate, which can be improved in a subset of patients. Axillary surgery omission in selected patients with a low risk of ALN metastasis has gained more and more research interest because the SLNs are tumor-free in more than 70% of all patients. To avoid drawbacks of conventional mapping methods, novel techniques for SLN detection have been developed and shown to be highly accurate in patients with early breast cancer. This article reviews the progress in SLNB in patients with breast cancer.

Micro-computed tomography (micro-CT) for intraoperative surgical margin assessment of breast cancer: A feasibility study in breast conserving surgery.

PURPOSE: Around 15%-30% of patients receiving breast-conserving surgery (BCS) for invasive breast carcinoma or ductal carcinoma in situ (DCIS) need a reoperation due to tumor-positive margins at final histopathology. Currently available intraoperative surgical margin assessment modalities all have specific limitations. Therefore, we aimed to assess the feasibility and accuracy of micro-computed tomography (micro-CT) as a novel method for intraoperative margin assessment in BCS. METHODS: Lumpectomy specimens from 30 consecutive patients diagnosed with invasive breast cancer or DCIS were imaged using a micro-CT. Margin status was assessed on micro-CT images by two investigators who were blinded to the final histopathological margin status. The micro-CT margin status was compared with the histopathological margin status. RESULTS: The margin status could be assessed by micro-CT in 29 out of 30 patients. Of these, nine patients had a positive tumor margin and 20 a negative tumor margin at final histopathology. Margin status evaluation by micro-CT took always less than 15 min. The margin status in 25 patients was correctly predicted by micro-CT. There were four false-negative predictions. The accuracy, sensitivity, specificity, positive predictive value and negative predictive value of micro-CT in margin status prediction were 86%, 56%, 100%, 100% and 83%, respectively. With micro-CT, the positive margin rate could potentially have been reduced from 31% to 14%. CONCLUSIONS: Whole lumpectomy specimen micro-CT scanning is a promising technique for intraoperative margin assessment in BCS. Intraoperative quick feedback on the margin status could potentially lead to a reduction in the number of reoperations.

Implementation and benchmarking of a novel analytical framework to clinically evaluate tumor-specific fluorescent tracers.

During the last decade, the emerging field of molecular fluorescence imaging has led to the development of tumor-specific fluorescent tracers and an increase in early-phase clinical trials without having consensus on a standard methodology for evaluating an optical tracer. By combining multiple complementary state-of-the-art clinical optical imaging techniques, we propose a novel analytical framework for the clinical translation and evaluation of tumor-targeted fluorescent tracers for molecular fluorescence imaging which can be used for a range of tumor types and with different optical tracers. Here we report the implementation of this analytical framework and demonstrate the tumor-specific targeting of escalating doses of the near-infrared fluorescent tracer bevacizumab-800CW on a macroscopic and microscopic level. We subsequently demonstrate an 88% increase in the intraoperative detection rate of tumor-involved margins in primary breast cancer patients, indicating the clinical feasibility and support of future studies to evaluate the definitive clinical impact of fluorescence-guided surgery.

Threshold Analysis and Biodistribution of Fluorescently Labeled Bevacizumab in Human Breast Cancer.

In vivo tumor labeling with fluorescent agents may assist endoscopic and surgical guidance for cancer therapy as well as create opportunities to directly observe cancer biology in patients. However, malignant and nonmalignant tissues are usually distinguished on fluorescence images by applying empirically determined fluorescence intensity thresholds. Here, we report the development of fSTREAM, a set of analytic methods designed to streamline the analysis of surgically excised breast tissues by collecting and statistically processing hybrid multiscale fluorescence, color, and histology readouts toward precision fluorescence imaging. fSTREAM addresses core questions of how to relate fluorescence intensity to tumor tissue and how to quantitatively assign a normalized threshold that sufficiently differentiates tumor tissue from healthy tissue. Using fSTREAM we assessed human breast tumors stained in vivo with fluorescent bevacizumab at microdose levels. Showing that detection of such levels is achievable, we validated fSTREAM for high-resolution mapping of the spatial pattern of labeled antibody and its relation to the underlying cancer pathophysiology and tumor border on a per patient basis. We demonstrated a 98% sensitivity and 79% specificity when using labeled bevacizumab to outline the tumor mass. Overall, our results illustrate a quantitative approach to relate fluorescence signals to malignant tissues and improve the theranostic application of fluorescence molecular imaging. Cancer Res; 77(3); 623-31. ©2016 AACR.

Tumor-Specific Uptake of Fluorescent Bevacizumab-IRDye800CW Microdosing in Patients with Primary Breast Cancer: A Phase I Feasibility Study.

Purpose: To provide proof of principle of safety, breast tumor-specific uptake, and positive tumor margin assessment of the systemically administered near-infrared fluorescent tracer bevacizumab-IRDye800CW targeting VEGF-A in patients with breast cancer.Experimental Design: Twenty patients with primary invasive breast cancer eligible for primary surgery received 4.5 mg bevacizumab-IRDye800CW as intravenous bolus injection. Safety aspects were assessed as well as tracer uptake and tumor delineation during surgery and ex vivo in surgical specimens using an optical imaging system. Ex vivo multiplexed histopathology analyses were performed for evaluation of biodistribution of tracer uptake and coregistration of tumor tissue and healthy tissue.Results: None of the patients experienced adverse events. Tracer levels in primary tumor tissue were higher compared with those in the tumor margin (P < 0.05) and healthy tissue (P < 0.0001). VEGF-A tumor levels also correlated with tracer levels (r = 0.63, P < 0.0002). All but one tumor showed specific tracer uptake. Two of 20 surgically excised lumps contained microscopic positive margins detected ex vivo by fluorescent macro- and microscopy and confirmed at the cellular level.Conclusions: Our study shows that systemic administration of the bevacizumab-IRDye800CW tracer is safe for breast cancer guidance and confirms tumor and tumor margin uptake as evaluated by a systematic validation methodology. The findings are a step toward a phase II dose-finding study aimed at in vivo margin assessment and point to a novel drug assessment tool that provides a detailed picture of drug distribution in the tumor tissue. Clin Cancer Res; 23(11); 2730-41. ©2016 AACR.