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PubMed | Karolinska Institutet, Dana-Farber Cancer Institute, National Hospital for Neurology and Neurosurgery, Pole dImagerie Neuroradiologie and 8 more.
Type: Journal Article | Journal: Haematologica | Year: 2016

Bing Neel syndrome is a rare disease manifestation of Waldenstrms macroglobulinemia that results from infiltration of the central nervous system by malignant lymphoplasmacytic cells. In this guideline we describe the clinical symptoms, as well as the appropriate laboratory and radiological studies, that can aid in the diagnosis. The presentation of Bing Neel syndrome may be very diverse, and includes headaches, cognitive deficits, paresis, and psychiatric symptoms. The syndrome can present in patients with known Waldenstrms macroglobulinemia, even in the absence of systemic progression, but also in previously undiagnosed patients. Diagnostic work-up should include cerebral spinal fluid analysis with multiparameter flow cytometry to establish B-cell clonality, protein electrophoresis and immunofixation for the detection and classification of a monoclonal protein as well as molecular diagnostic testing for immunoglobulin gene rearrangement and mutated MYD88. MRI of the brain and spinal cord is also essential. The second challenge is to expand our knowledge of prognosis and treatment outcome. Prospective clinical trials on Bing Neel syndrome patients that employ uniform treatment along with appropriate laboratory cerebral spinal fluid assessments and standardized MRI protocols will be invaluable, constituting a significant step forward in delineating treatment outcome for this intriguing disease manifestation.


PubMed | Erasmus MC Cancer Clinic, Netherlands Cancer Institute, Leiden University, University of Groningen and 6 more.
Type: | Journal: BMC cancer | Year: 2015

Risk-reducing salpingo-oophorectomy (RRSO) around the age of 40 is currently recommended to BRCA1/2 mutation carriers. This procedure decreases the elevated ovarian cancer risk by 80-96% but it initiates premature menopause as well. The latter is associated with short-term and long-term morbidity, potentially affecting quality of life (QoL). Based on recent insights into the Fallopian tube as possible site of origin of serous ovarian carcinomas, an alternative preventive strategy has been put forward: early risk-reducing salpingectomy (RRS) and delayed oophorectomy (RRO). However, efficacy and safety of this alternative strategy have to be investigated.A multicentre non-randomised trial in 11 Dutch centres for hereditary cancer will be conducted. Eligible patients are premenopausal BRCA1/2 mutation carriers after completing childbearing without (a history of) ovarian carcinoma. Participants choose between standard RRSO at age 35-40 (BRCA1) or 40-45 (BRCA2) and the alternative strategy (RRS upon completion of childbearing and RRO at age 40-45 (BRCA1) or 45-50 (BRCA2)). Women who opt for RRS but do not want to postpone RRO beyond the currently recommended age are included as well. Primary outcome measure is menopause-related QoL. Secondary outcome measures are ovarian/breast cancer incidence, surgery-related morbidity, histopathology, cardiovascular risk factors and diseases, and cost-effectiveness. Mixed model data analysis will be performed.The exact role of the Fallopian tube in ovarian carcinogenesis is still unclear. It is not expected that further fundamental research will elucidate this role in the near future. Therefore, this clinical trial is essential to investigate RRS with delayed RRO as alternative risk-reducing strategy in order to improve QoL.ClinicalTrials.gov ( NCT02321228 ).


PubMed | Leeds Teaching Hospitals NHS Trust, Dana-Farber Cancer Institute, Mayo Medical School, University of Pavia and 10 more.
Type: Journal Article | Journal: British journal of haematology | Year: 2016

The diagnosis of Waldenstrm macroglobulinaemia (WM) can be challenging given the variety of signs and symptoms patients can present. Furthermore, once the diagnosis of WM is established, the initial evaluation should be thorough as well as appropriately directed. During the 8th International Workshop for WM in London, United Kingdom, a multi-institutional task force was formed to develop consensus recommendations for the diagnosis and initial evaluation of patients with WM. In this document, we present the results of the deliberations that took place to address these issues. We provide recommendations for history-taking and physical examination, laboratory studies, bone marrow aspiration and biopsy analysis and imaging studies. We also provide guidance on the initial evaluation of special situations, such as anaemia, hyperviscosity, neuropathy, Bing-Neel syndrome and amyloidosis. We hope these recommendations serve as a practical guidance to clinicians taking care of patients with a suspected or an established diagnosis of WM.


PubMed | Erasmus Medical Center, University Utrecht, Image science Institute, Utrecht Cancer Center and Netherlands Cancer Institute
Type: Journal Article | Journal: Annals of oncology : official journal of the European Society for Medical Oncology | Year: 2016

Early signs of efficacy are critical in drug development. Response Evaluation Criteria in Solid Tumors (RECIST) are commonly used to determine the efficacy of anti-cancer therapy in clinical trials. RECIST, however, emphasizes the value of tumor shrinkage, while many targeted agents induce prolonged tumor growth arrest. This limits its use for the detection of treatment efficacy for these more cytostatic regimens. Therefore, we designed an individualized variant of a time to progression (TTP) end point based on prospective volumetric measurements and an intra-patient control, the TTP ratio.Patients with any metastatic malignancy, without regular treatment options, were treated with the mTOR inhibitor everolimus. Treatment response was determined using both RECIST and the TTP ratio. The TTP ratio was defined as the volumetric pretreatment TTP divided by the volumetric on-treatment TTP. A patient was classified as a responder if the TTP ratio was <0.7. Consistency and reproducibility of volumetric measurements were determined.Seventy-three patients were included of whom 59 started treatment. A TTP ratio could be established in 73% (n = 43) of the treated patients. The inter-observer agreement for volumetric progression was 0.78 (95% confidence interval 0.70-0.87) (Krippendorffs -coefficient). According to RECIST, 35 patients (59%) had stable disease (SD) and 1 patient demonstrated a partial response (PR), whereas only 21 patients (36%) met the prespecified criteria for treatment efficacy according to the TTP ratio. Treatment response according to both the TTP ratio and RECIST (SD + PR) correlated with overall survival (OS) [P(log-rank) < 0.001]. The TTP ratio, however, was also able to differentiate which patients had a better OS within the RECIST SD group [P(log-rank) = 0.0496].The TTP ratio had a high inter-observer agreement, correlated with OS and identified which patients within the RECIST SD group had a longer OS.NCT01566279.


PubMed | Sint Antonius Hospital, Flevo Hospital, Utrecht Cancer Center, Erasmus Medical Center and 4 more.
Type: Journal Article | Journal: Modern pathology : an official journal of the United States and Canadian Academy of Pathology, Inc | Year: 2016

Women who test positive for a high-risk type of the human papillomavirus (HPV) require triage testing to identify those women with cervical intraepithelial neoplasia grade 3 or cancer (CIN3). Although Pap cytology is considered an attractive triage test, its applicability is hampered by its subjective nature. This study prospectively compared the clinical performance of p16/Ki-67 dual-stained cytology to that of Pap cytology, with or without HPV16/18 genotyping, in high-risk HPV-positive women visiting gynecologic outpatient clinics (n=446 and age 18-66 years). From all women, cervical scrapes (for Pap cytology, HPV16/18 genotyping, and p16/Ki-67 dual-stained cytology) and colposcopy-directed biopsies were obtained. The sensitivity of p16/Ki-67 dual-stained cytology for CIN3 (93.8%) did neither differ significantly from that of Pap cytology (87.7%; ratio 1.07 and 95% confidence interval (CI): 0.97-1.18) nor from that of Pap cytology combined with HPV16/18 genotyping (95.1%; ratio 0.99 and 95% CI: 0.91-1.07). However, the specificity of p16/Ki-67 dual-stained cytology for CIN3 (51.2%) was significantly higher than that of Pap cytology (44.9%; ratio 1.14 and 95% CI: 1.01-1.29) and Pap cytology combined with HPV16/18 genotyping (25.8%; ratio 1.99 and 95% CI: 1.68-2.35). After exclusion of women who had been referred because of abnormal Pap cytology, the specificity of p16/Ki-67 dual-stained cytology for CIN3 (56.7%) remained the same, whereas that of Pap cytology (60.3%) increased substantially, resulting in a similar specificity of both assays (ratio 0.94 and 95% CI: 0.83-1.07) in this sub-cohort. In summary, p16/Ki-67 dual-stained cytology has a good clinical performance and is an interesting objective microscopy-based triage tool for high-risk HPV-positive women.


PubMed | VU University Amsterdam, Spaarne Hospital, Netherlands Comprehensive Cancer Organisation IKNL, Maxima Medical Center and Utrecht Cancer Center
Type: Journal Article | Journal: Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer | Year: 2016

Chemotherapy-induced peripheral neuropathy (CIPN) may negatively influence multiple myeloma (MM) patients health-related quality of life (HRQOL). Dose modification is the only way to minimize CIPN. To measure CIPN in daily practice, the Indication for Common Toxicity Criteria (CTC) Grading of Peripheral Neuropathy Questionnaire (ICPNQ) was developed which can be completed within five minutes by the patient. The aims of this study were to (1) perform a psychometric evaluation of the ICPNQ and (2) examine the prevalence of CIPN and its influence on HRQOL in population-based MM patients.One hundred fifty-six MM patients, diagnosed between 2000 and 2014, completed the ICPNQ, European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Chemotherapy-Induced Peripheral Neuropathy 20 (EORTC QLQ-CIPN20), and EORTC QLQ-C30 (65% response).The psychometric analyses showed a Cronbachs alpha of 0.84, 0.74, and 0.61 for, respectively, the sensory, motoric, and autonomic subscales of the ICPNQ. Test-retest reliability and construct validity were good for all subscales. Overall, 65% of patients reported grade 2-3 neuropathy according to the ICPNQ. Patients with the highest CTC grades (grade 2 with neuropathic pain and grade 3 (38%)) according to the ICPNQ reported significantly worse scores on all EORTC QLQ-CIPN20 subscales compared to patients with lower CTC grades (p0.002). In addition, they reported statistically significant and clinically relevant worse HRQOL scores on almost all EORTC QLQ-C30 subscales.CIPN is a common side effect in MM patients, which has a negative impact on HRQOL. The ICPNQ is a valid instrument to distinguish the highest CIPN CTC grades from the lower CTC grades necessary to decide on dose modifications of chemotherapy in daily clinical practice.


PubMed | Spaarne Hospital, Netherlands Comprehensive Cancer Organisation IKNL, Maxima Medical Center and Utrecht Cancer Center
Type: | Journal: Annals of hematology | Year: 2017

The aim of this analysis is to assess (1) self-reported chemotherapy-induced peripheral neuropathy (CIPN) symptoms; (2) its association with sociodemographic and clinical characteristics; and (3) treatment dose modifications and its influence on the magnitude of neurotoxicity in a population-based cohort of patients with multiple myeloma (MM). MM patients (n=156), diagnosed between 2000 and 2014, filled out the EORTC QLQ-CIPN20 (65% response). Data on treatment, outcomes, and dose modifications were extracted from the medical files. Fifty-three percent of patients reported at least one and on average three neuropathy symptoms that bothered them the most during the past week, with tingling toes/feet as most reported. In multivariate analysis, thalidomide, especially higher cumulative dose, was associated with neuropathy (=0.26, CI 95% 0.27-15.34, p=0.04) and CIPN was not associated with age, sex, time since last course of therapy, number of prior therapies, osteoarthritis, or diabetes. Dose modifications were often applied (65%). Although not statistically significant, a trend towards higher sensory (22 vs. 15 vs. 12, p=0.22) and motor neuropathy scores (21 vs. 15 vs. 11, p=0.36) was observed among patients receiving dose modification because of CIPN (31%) compared to those receiving a dose modification for another reason or no dose modification, without altering treatment response. CIPN is a common dose limiting side effect in patients with MM. Severity of CIPN was mainly affected by treatment with thalidomide. In spite of dose modifications, patients still reported somewhat higher neuropathy scores without altered response rates. Early dose modification based on a more reliable tool for CIPN measurements may prove value.


De Boer H.C.J.,Utrecht Cancer Center | Van Den Bongard D.J.G.,Utrecht Cancer Center | Van Asselen B.,Utrecht Cancer Center
Radiotherapy and Oncology | Year: 2016

Background and purpose Breath hold is increasingly used for cardiac sparing in left-sided breast cancer irradiation. We have developed a fast automated method to verify breath hold stability in each treatment fraction. Material and methods We evaluated 504 patients treated with breath hold. Moderate deep inspiration breath hold was audio-guided. Medial and lateral large tangential field segments were delivered in a single breath hold and movieloops of these fields were acquired with an EPID. The thoracic wall position was automatically detected in each frame and the full range of thoracic wall motion (RTWM) was determined. If the RTWM >4 mm more than 3 times, the patient was excluded from breath hold treatment if further coaching did not yield improvement. Results Unstable breath hold was observed in 2.8% of the patients. However, this frequency dropped from 9.5% in the first 6 months to 1.6% in the subsequent 16 months. The 97% of patients with proper breath hold showed excellent stability: the average RTWM was 0.9 ± 0.5 mm. The reproducibility of the breath hold depth was confirmed by (1) the small difference between the thoracic wall positions in the medial and lateral fields within one fraction and (2) the setup errors of breath hold patients showed no significant differences with those of right-sided breast patients. Conclusions We have developed and clinically applied an imaging tool to automatically determine stability of breath holds in each treatment fraction during beam delivery. © 2016 Elsevier Ireland Ltd. All rights reserved.


PubMed | Utrecht Cancer Center
Type: Journal Article | Journal: BJOG : an international journal of obstetrics and gynaecology | Year: 2016

The proportion of women with mucinous ovarian carcinoma in whom nodal metastases are identified during staging remains unclear.To review the literature on surgical lymph node assessment during staging of women diagnosed with mucinous ovarian carcinoma.A systematic search using synonyms of mucinous ovarian carcinoma and lymph node assessment was conducted in PubMed, Scopus, Embase and the Cochrane Library.When they covered ten or more mucinous ovarian carcinoma cases, staging surgery and minimally one of the following outcomes: prevalence of metastases, stage shift or survival data.Studies were quality evaluated with the Cochrane risk-of-bias assessment tool for non-randomised studies of interventions. Outcomes were pooled using an inverse variance weighted random effects model.Sixteen studies were included. In 278 women with mucinous ovarian cancer suspected to be stage I-II, a pooled proportion of 0.8% (95% CI <0.1-2.9%) had lymph node metastases and were upstaged. In those suspected of stage I (n = 184), this proportion was 0.7% (95% CI <0.1-3.8%). No difference (P = 0.287) was found in metastases between sampling at 0.0% (95% CI 0.0-3.3%) and complete pelvic and/or para-aortic lymph node dissection at 1.2% (95% CI <0.1-4.2%). One study directly compared the survival of patients staged with and without lymph node dissection and reported no significant difference.Surgical lymph node assessment in women suspected of stage I-II mucinous ovarian carcinoma rarely identifies nodal metastases and consequently has no significant impact on staging.Surgical lymph node assessment in women with stage I-II mucinous ovarian cancer rarely has staging consequences.


PubMed | Sint Antonius Hospital, Flevo Hospital, Utrecht Cancer Center, Onze Lieve Vrouwe Gasthuis West and 4 more.
Type: Journal Article | Journal: British journal of cancer | Year: 2016

High-risk human papillomavirus (hrHPV)-positive women require triage to identify those with cervical high-grade intraepithelial neoplasia and cancer (CIN3 (cervical intraepithelial neoplasia grade 3)). FAM19A4 methylation analysis, which detects advanced CIN and cancer, is applicable to different sample types. However, studies comparing the performance of FAM19A4 methylation analysis in hrHPV-positive self-samples and paired physician-taken scrapes are lacking.We compared the performance of FAM19A4 methylation analysis (and/or HPV16/18 genotyping) in self-samples and paired physician-taken scrapes for CIN3 detection in hrHPV-positive women (n=450,18-66 years).Overall FAM19A4 methylation levels between sample types were significantly correlated, with strongest correlation in women with CIN3 (Spearmans 0.697, P<0.001). The performance of FAM19A4 methylation analysis and/or HPV16/18 genotyping did not differ significantly between sample types. In women 30 years, CIN3 sensitivity of FAM19A4 methylation analysis was 78.4% in self-samples and 88.2% in scrapes (ratio 0.89; CI: 0.75-1.05). In women <30 years, CIN3 sensitivities were 37.5% and 45.8%, respectively (ratio 0.82; CI: 0.55-1.21). In both groups, CIN3 specificity of FAM19A4 methylation analysis was significantly higher in self-samples compared with scrapes.FAM19A4 methylation analysis in hrHPV-positive self-samples had a slightly lower sensitivity and a higher specificity for CIN3 compared with paired physician-taken scrapes. With a similarly good clinical performance in both sample types, combined FAM19A4 methylation analysis and HPV16/18 genotyping provides a feasible triage strategy for hrHPV-positive women, with direct applicability on self-samples.

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