The Dilemma After an Unforeseen Positive Sentinel Node in Primary Breast Cancer: Is Completion Axillary Dissection Necessary?

BACKGROUND: In the majority of cases, the sentinel node is the only positive node in the axilla and completion ALND (cALND) is a futile procedure. However, refraining from cALND will lead to less accurate staging and, possibly, undertreatment. To help resolve this dilemma, we examined the clinical value of cALND in staging and determining adjuvant treatment. METHODS: In a retrospective cohort, all consecutive patients over a five-year period with primary breast cancer who received ALND were identified and grouped based on timing of ALND. Total nodal yield and positive lymph nodes were defined and factors with possible impact identified. In the case of cALND, N-status upstaging and possible impact on adjuvant treatment were studied in detail. RESULTS: A total of 280 patients were selected of whom 204 underwent primary ALND (pALND) and 76 cALND. pALND resulted in a significantly higher total nodal yield and more positive nodes when compared to cALND (p = 0.003, and p < 0.001, respectively). Neoadjuvant chemotherapy (NAC) had no effect on total nodal yield (p = 0.413), but resulted in fewer positive nodes (p < 0.001). Due to the results of cALND, only 11 patients (14%) had upstaging of N-status. All these patients were advised more extensive adjuvant radiotherapy. CONCLUSION: In the majority of patients, cALND does not lead to upstaging. cALND should be performed only after a careful discussion with the patient about the pros and cons of this procedure, and most probably only in the presence of multiple risk factors for axillary disease in the absence of systemic therapy.

Using a gene expression signature when controversy exists regarding the indication for adjuvant systemic treatment reduces the proportion of patients receiving adjuvant chemotherapy: a nationwide study.

PURPOSE: The Dutch national guideline advises use of gene-expression signatures, such as the 70-gene signature (70-GS), in case of ambivalence regarding the benefit of adjuvant chemotherapy (CT). In this nationwide study, the impact of 70-GS use on the administration of CT in early breast cancer patients with a dubious indication for CT is assessed. METHODS: Patients within a national guideline directed indication area for 70-GS use who were surgically treated between November 2011 and April 2013 were selected from the Netherlands Cancer Registry database. The effect of 70-GS use on the administration of CT was evaluated in guideline- and age-delineated subgroups addressing potential effect of bias by linear mixed-effect modeling and instrumental variable (IV) analyses. RESULTS: A total of 2,043 patients within the indicated area for 70-GS use were included, of whom 298 received a 70-GS. Without use of the 70-GS, 45% of patients received CT. The 70-GS use was associated with a 9.5% decrease in CT administration (95% confidence interval (CI): -15.7 to -3.3%) in linear mixed-effect model analyses and IV analyses showed similar results (-9.9%; 95% CI: -19.3 to -0.4). CONCLUSION: In patients in whom the Dutch national guidelines suggest the use of a gene-expression profile, 70-GS use is associated with a 10% decrease in the administration of adjuvant CT.Genet Med 18 7, 720-726.Genetics in Medicine (2016); 18 7, 720-726. doi:10.1038/gim.2015.152.

Magnetic resonance imaging in patients with unilateral bloody nipple discharge; useful when conventional diagnostics are negative?

BACKGROUND: Unilateral bloody nipple discharge (UBND) is mostly caused by benign conditions such as papilloma or ductal ectasia. However, in 7-33 % of all nipple discharge, it is caused by breast cancer. Conventional diagnostic imaging like mammography (MMG) and ultrasonography (US) is performed to exclude malignancy. Preliminary investigations of breast magnetic resonance imaging (MRI) assume that it has additional value. With an increasing availability of MRI, it is of clinical importance to evaluate this. We evaluated the additional diagnostic value of MRI in patients with UBND in the absence of a palpable mass, with normal conventional imaging. METHODS: All women with UBND in the period November 2007-July 2012 were included. In addition to the standard work-up (patient's history, physical examination, MMG, and US), MRI was performed. Data from these examinations and treatment were collected retrospectively. RESULTS: A total of 111 women (mean age 52 years; range 23-80) were included. In nine (8 %) patients, malignancy was suspected on MRI while conventional imaging was normal. In eight (89 %) of these patients, histology was obtained, two by core biopsy and six by terminal duct excision. Benign conditions were found in six patients (86 %) and a (pre-) malignant lesion in two patients. In both cases, it concerned a ductal carcinoma in situ, which was treated with breast-conserving therapy. Moreover, in two cases of (pre)malignancy, the MRI was interpreted as negative. CONCLUSION: In patients with UBND who show no signs of a malignancy on conventional diagnostic examinations, the added value of a breast MRI is limited, since a malignancy can be demonstrated in <2 %.

Metastatic oligodendroglioma: a case report and incidence in The Netherlands.

Oligodendroglioma is a tumor of the central nervous system which rarely metastasizes. The diagnosis of oligodendroglioma is based on histomorphology with limited use of immunohistochemistry. However, recently a specific 1p/19q codeletion has been found which can be demonstrated by in situ hybridization. We report a case of a 58-years-old man with a 31-months history of oligodendroglioma presenting with fatigue and anemia. A bone marrow biopsy demonstrated massive localization of oligodendroglioma which was confirmed by in situ hybridization for the 1p/19q deletion. In addition we studied data from PALGA, the nationwide network and registry of histo- and cytopathology in the Netherlands and found an incidence of approximately 2 in 1,000 for metastasis of oligodendroglioma outside the central nervous system.

[Splenectomy in a large general hospital: often caused by iatrogenic injury, often causing multiple complications; poor adherence to post-operative guidelines for vaccination and prophylaxis]. / Splenectomie in een groot algemeen ziekenhuis: vaak iatrogeen letsel als oorzaak, veel complicaties tot gevolg; naleving postoperatieve richtlijnen voor vaccinatie en profylaxe gebrekkig.

OBJECTIVE: To assess the indications, complications and mortality associated with splenectomy in a large general hospital, and to evaluate adherence to guidelines for postoperative vaccination and prophylactic antibiotics. DESIGN: Retrospective, descriptive. METHOD: Data were collected on 106 patients who underwent splenectomy between 1999 and 2004. Indications for surgery, complications, duration of hospitalisation, and vaccination status were investigated retrospectively. Patients were contacted by telephone for a structured interview regarding vaccination and antibiotic prophylaxis. RESULTS: Of the 95 patients with sufficient data for analysis, 41 underwent elective surgery and 54 underwent non-elective surgery, including 37 who required splenectomy due to iatrogenic injury. Posteroperative complications arose in 45 patients, including 23 who developed serious complications. 10 patients died due to complications, including 7 who died within one month after the procedure. Vaccination coverage for the entire group was 58%. CONCLUSION: In this large general hospital, splenectomy was often performed due to iatrogenic injury and was associated with a relatively high complication rate. Adherence to guidelines on vaccination and prophylactic antibiotics could be improved.

[Revised practice guideline 'Screening and diagnosis of breast cancer']. / Richtlijn 'screening en diagnostiek van het mammacarcinoom' (herziening).

Revised practice guideline 'Screening and diagnosis of breast cancer' The evidence-based revision of the practice guideline 'Screening and diagnosis of breast cancer' was necessitated by new insights, for instance on the cost-effectiveness of screening modalities other than mammography. Mammography is the only screening modality that is recommended for the general population. In the Netherlands, women from 50-75 years of age are invited for screening. However, in view of the ongoing increase in the incidence of breast cancer and of the image quality advantages of radiological digitalization, a study on the decrease of the lower age limit--preferably 45 years--is recommended. Screening with MRI is indicated for carriers of breast cancer gene mutations. Evaluation of risk factors has resulted in a rearrangement of screening recommendations, based on relative risks (RRs): screening apart from the population screening is only recommended in case the RRis 4 or more and in patients with a positive family history in case of a RR of 2 or more. Additional risks require further genetic evaluation. The 'Breast imaging reporting and data system' (BI-RADS) is now recommended for both screening and diagnostic imaging. Its application has had an impact on the triple diagnostic approach, which has now evolved into a consensus between surgeon, radiologist and pathologist. Axillary ultrasound should be carried out ifa sentinel node procedure is being considered. MRI should be included if the cancer cannot be reliably delineated on mammography or ultrasound. The increased complexity of the diagnostic work-up often means that the final diagnosis is not arrived within one day. Every effort should be made to achieve this goal within 5 working days. Ned Tijdschr Geneeskd. 2008;I52:2336-9

Elevated serum IgG4 levels in diagnosis and treatment response in patients with idiopathic retroperitoneal fibrosis.

Idiopathic retroperitoneal fibrosis (iRPF) may be a manifestation of IgG4-related disease. Measuring serum IgG4 (sIgG4) may be of value in monitoring iRPF, but this has scarcely been evaluated. It is unknown if tamoxifen (TMX) affects sIgG4 levels. We performed a prospective inception cohort study of 59 patients with untreated (re)active iRPF stratified by elevated (>1.4 g/L) or normal sIgG4 level. Changes in sIgG4 levels following TMX initiation and, if treatment failed, during subsequent corticosteroid (CS) treatment were analyzed. The median sIgG4 level was 1.1 g/L (interquartile range (IQR) 0.4-2.2); 24 patients (40%) had elevated sIgG4 level. Patients with elevated sIgG4 tended to present with higher ESR (46 vs. 34 mm/h; P = 0.08) and more frequent locoregional lymphadenopathy adjacent to the mass (41.7 vs. 20.0%; P = 0.08). sIgG4 also correlated with ESR (ρ = 0.26; P = 0.05) and serum creatinine (SC) (ρ = 0.26; P = 0.04). Following TMX initiation, sIgG4 level decreased, particularly when achieving treatment success (P < 0.01). Odds ratio for TMX treatment success in patients with elevated sIgG4 level was 0.77 (95% CI 0.53-1.14; P = 0.19). After adjusting for age, sex, and SC, the odds ratio was 0.78 (95% CI 0.51-1.18; P = 0.24). ROC curve analyses of sIgG4 on a continuous scale and treatment success showed an AUC of 0.62. Treatment success and concurrent sIgG4 decrease (P < 0.01) were achieved in 78% of patients who converted to CS therapy. Patients with elevated sIgG4 level may be more inflammatory than patients with normal sIgG4 level, but this needs further study. TMX affects sIgG4 levels, but to a lesser extent than CSs. sIgG4 cannot be used as an outcome prediction tool, irrespective of which cutoff value was chosen.

Preoperative indication for systemic therapy extended to patients with early-stage breast cancer using multiparametric 7-tesla breast MRI.

PURPOSE: To establish a preoperative decision model for accurate indication of systemic therapy in early-stage breast cancer using multiparametric MRI at 7-tesla field strength. MATERIALS AND METHODS: Patients eligible for breast-conserving therapy were consecutively included. Patients underwent conventional diagnostic workup and one preoperative multiparametric 7-tesla breast MRI. The postoperative (gold standard) indication for systemic therapy was established from resected tumor and lymph-node tissue, based on 10-year risk-estimates of breast cancer mortality and relapse using Adjuvant! Online. Preoperative indication was estimated using similar guidelines, but from conventional diagnostic workup. Agreement was established between preoperative and postoperative indication, and MRI-characteristics used to improve agreement. MRI-characteristics included phospomonoester/phosphodiester (PME/PDE) ratio on 31-phosphorus spectroscopy (31P-MRS), apparent diffusion coefficients on diffusion-weighted imaging, and tumor size on dynamic contrast-enhanced (DCE)-MRI. A decision model was built to estimate the postoperative indication from preoperatively available data. RESULTS: We included 46 women (age: 43-74yrs) with 48 invasive carcinomas. Postoperatively, 20 patients (43%) had positive, and 26 patients (57%) negative indication for systemic therapy. Using conventional workup, positive preoperative indication agreed excellently with positive postoperative indication (N = 8/8; 100%). Negative preoperative indication was correct in only 26/38 (68%) patients. However, 31P-MRS score (p = 0.030) and tumor size (p = 0.002) were associated with the postoperative indication. The decision model shows that negative indication is correct in 21/22 (96%) patients when exempting tumors larger than 2.0cm on DCE-MRI or with PME>PDE ratios at 31P-MRS. CONCLUSIONS: Preoperatively, positive indication for systemic therapy is highly accurate. Negative indication is highly accurate (96%) for tumors sized ≤2,0cm on DCE-MRI and with PME≤PDE ratios on 31P-MRS.

Tumour size and vascular invasion predict distant metastasis in stage I breast cancer. Grade distinguishes early and late metastasis.

BACKGROUND: Recent Dutch guidelines recommend adjuvant systemic treatment (AST) for women with high grade stage I breast carcinoma > or =1 cm. High grade is defined as Bloom and Richardson grade 3 (B&R3), Nottingham modification, or mitotic activity (MAI) > or =10/1.59 mm2. AIMS: To investigate the validity of these histological prognostic factors as the exclusive defining criteria. MATERIALS/METHODS: Fifty patients with stage I breast carcinoma who developed distant metastases and 50 matched controls without metastasis were studied; none had received AST. RESULTS: Cases more often had tumours > or =1 cm (p = 0,019), B&R3 tumours (p = 0.059), grade 3 nuclei (p = 0.005), and vascular invasion (p = 0.007). No differences were found for MAI > or =10 (p = 0.46). In multivariate analysis, the only significant variables were vascular invasion and tumour size (odds ratios: 8.21 and 5.35, respectively). In a separate analysis, the 50 cases were divided into 25 patients with early and 25 with late metastasis. Those with early metastasis more often had B&R3 tumours (p = 0.009) and grade 3 nuclei (p = 0.006). No differences were found for tumours > or =1 cm, vessel invasion, or MAI > or =10. Using the present Dutch guidelines for AST, based on B&R3, 20 cases and 11 controls would have received AST. Based on MAI > or =10, 14 cases and 11 controls would have received AST. CONCLUSIONS: Tumour size and vessel invasion are the best prognostic factors for disease free survival in patients with stage I breast cancer. Dutch selection criteria for AST for these patients need to be improved. Some prognostic factors are time dependent, making their use as selection criteria for AST more complicated.

A 4-year-old boy with neurofibromatosis and severe renovascular hypertension due to renal arterial dysplasia.

A 4-year-old boy had severe hypertension, cardiac failure, and signs of neurofibromatosis. Arteriography disclosed renal artery stenosis in both kidneys with signs of ischemia, particularly in the right kidney. Because of insufficient response to antihypertensive therapy, a right-sided nephrectomy was performed. Histological examination of this kidney showed segmental stenosis in all branches of the renal artery. The vascular lesions were characterized by an intimal proliferation of spindle cells in a mucoid matrix with destruction of the internal elastic membrane frequently accompanied by loss or attenuation of the media and fibrosis of the adventitia. Occasionally, a nodular arrangement of the spindle cells at the interface between intima and media was observed. Immunohistochemical studies demonstrate a smooth-muscle cell origin for these cells.

The effect of a converting enzyme inhibitor upon renal damage in spontaneously hypertensive Fawn Hooded rats.

OBJECTIVE: To determine the effect of angiotensin converting enzyme inhibition (CEI) upon renal function and the incidence of glomerulosclerosis in spontaneously hypertensive Fawn Hooded rats (FHR). DESIGN: Male FHR were treated with captopril from the age of 5 months when mild hypertension, proteinuria and glomerulosclerosis are present, and sacrificed at 12 months of age. Renal function was determined in separate groups of FHR at 6 months of age. METHODS: Proteinuria, body weight and systolic blood pressure were determined at regular intervals. Blood pressure was measured by the tail-cuff method. Kidneys were prepared for histological examination by standard methods. Renal function was determined by inulin clearance and urinary kallikrein by an amydolitic assay. RESULTS: In untreated FHR blood pressure, proteinuria and glomerulosclerosis increased with time. Captopril normalized blood pressure and stabilized proteinuria at pretreatment levels. At the end of the study, the incidence of glomerulosclerosis was significantly lower and comparable with the incidence at 5 months. Glomerular volume did not show a correlation with the incidence of glomerulosclerosis. Hemodynamic studies showed a significant increase of glomerular filtration rate in captopril-treated rats. No statistically significant effect was seen on renal plasma flow or filtration fraction. Urinary excretion of kallikrein was increased in captopril-treated rats. CONCLUSIONS: CEI is effective in protecting the kidney from structural damage in hypertensive FHR even when treatment is started under conditions of established glomerular injury. The protection given by captopril is probably related to intrarenal effects.

Gene expression in derivatives of embryonic foregut during prenatal development of the rat.

Proteins characteristic for the adult cellular phenotype, i.e., carbamoylphosphate synthetase (CPS) for liver and small intestine, arginase for liver, glutamate dehydrogenase (GLDH) for pancreas, liver, and small intestine, and amylase for pancreas were studied immunohistochemically in rat embryos and fetuses. At distinct developmental stages, subsets of enzymes appear synchronously in the foregut derivatives, suggesting that gene expression in the different organs is regulated by common factors. In contrast to the long-held opinion that fetal hepatocytes are a homogeneous cell population, it is shown that arginase and CPS are heterogeneously distributed between ED 16 and ED 20. This heterogeneity is related to the vascular architecture of the liver and disappears perinatally as the result of strong stimulation of enzyme synthesis. In addition, an intercellular heterogeneity in CPS content that is not related to the vasculature is observed between ED 14 and ED 20. This "random" heterogeneity reflects temporal differences in the onset of CPS accumulation in individual cells.

Core needle biopsy in male breast lesions.

AIMS: To describe results of needle core biopsies of the male breast. METHODS: Needle core biopsies from male breasts and corresponding histological follow up data were retrieved from pathology computer files. For those biopsies with no histological follow up data, the nationwide pathology computer files were consulted. RESULTS: Twenty six core biopsies of male breasts were performed from 1993 until the end of 2002. All patients had unilateral lesions and were between 20 and 88 years old. In seven patients, core biopsy results were confirmed in the excision specimen. In one patient, the core biopsy diagnosis of cancer was confirmed in another hospital. In 17 patients with a benign core biopsy that was not excised in one of the hospitals served by this laboratory, the nationwide pathology computer files did not retrieve a missed malignancy. One patient with cancer in a core biopsy did not receive surgery because of old age. Core biopsy or aspiration cytology was not used in six of 19 men with cancer. CONCLUSIONS: Core biopsy of the male breast is a reliable preoperative diagnostic procedure, which should be used more often because it can help to avoid unnecessary surgery and in planning surgery for cancer.

[Fatal varicella-zoster encephalitis; a rare complication of herpes zoster]. / Fatale varicella-zosterencefalitis; een zeldzame complicatie van herpes zoster.

In a 82-year-old woman varicella zoster encephalitis was diagnosed, a rare complication of shingles. The case was remarkable for its rapid and fatal course in a patient without an underlying disease. At autopsy, the histological picture of an acute haemorrhagic encephalitis was seen, also a rare finding.

Re-resection rates after breast-conserving surgery as a performance indicator: introduction of a case-mix model to allow comparison between Dutch hospitals.

AIM: Re-resection rate after breast-conserving surgery (BCS) has been introduced as an indicator of quality of surgical treatment in international literature. The present study aims to develop a case-mix model for re-resection rates and to evaluate its performance in comparing results between hospitals. METHODS: Electronic records of eligible patients diagnosed with in-situ and invasive breast cancer in 2006 and 2007 were derived from 16 hospitals in the Rotterdam Cancer Registry (RCR) (n = 961). A model was built in which prognostic factors for re-resections after BCS were identified and expected re-resection rate could be assessed for hospitals based on their case mix. To illustrate the opportunities of monitoring re-resections over time, after risk adjustment for patient profile, a VLAD chart was drawn for patients in one hospital. RESULTS: In general three out of every ten women had re-surgery; in about 50% this meant an additive mastectomy. Independent prognostic factors of re-resection after multivariate analysis were histological type, sublocalisation, tumour size, lymph node involvement and multifocal disease. After correction for case mix, one hospital was performing significantly less re-resections compared to the reference hospital. On the other hand, two were performing significantly more re-resections than was expected based on their patient mix. CONCLUSIONS: Our population-based study confirms earlier reports that re-resection is frequently required after an initial breast-conserving operation. Case-mix models such as the one we constructed can be used to correct for variation between hospitals performances. VLAD charts are valuable tools to monitor quality of care within individual hospitals.

Preoperative MRI and surgical management in patients with nonpalpable breast cancer: the MONET - randomised controlled trial.

BACKGROUND: We evaluated whether performing contrast-enhanced breast MRI in addition to mammography and/or ultrasound in patients with nonpalpable suspicious breast lesions improves breast cancer management. METHODS: The MONET - study (MR mammography of nonpalpable breast tumours) is a randomised controlled trial in patients with a nonpalpable BIRADS 3-5 lesion. Patients were randomly assigned to receive routine medical care, including mammography, ultrasound and lesion sampling by large core needle biopsy or additional MRI preceding biopsy. Patients with cancer were referred for surgery. Primary end-point was the rate of additional surgical procedures (re-excisions and conversion to mastectomy) in patients with a nonpalpable breast cancer. FINDINGS: Four hundred and eighteen patients were randomised, 207 patients were allocated to MRI, and 211 patients to the control group. In the MRI group 74 patients had 83 malignant lesions, compared to 75 patients with 80 malignant lesions in the control group. The primary breast conserving surgery (BCS) rate was similar in both groups; 68% in the MRI group versus 66% in the control group. The number of re-excisions performed because of positive resection margins after primary BCS was increased in the MRI group; 18/53 (34%) patients in the MRI group versus 6/50 (12%) in the control group (p=0.008). The number of conversions to mastectomy did not differ significantly between groups. Overall, the rate of an additional surgical intervention (BCS and mastectomy combined) after initial breast conserving surgery was 24/53 (45%) in the MRI group versus 14/50 (28%) in the control group (p=0.069). INTERPRETATION: Addition of MRI to routine clinical care in patients with nonpalpable breast cancer was paradoxically associated with an increased re-excision rate. Breast MRI should not be used routinely for preoperative work-up of patients with nonpalpable breast cancer.

Completeness of notification of tuberculosis in The Netherlands: how reliable is record-linkage and capture-recapture analysis?

The aim of this study was to describe a systematic process of record-linkage, cross-validation, case-ascertainment and capture-recapture analysis to assess the quality of tuberculosis registers and to estimate the completeness of notification of incident tuberculosis cases in The Netherlands in 1998. After record-linkage and cross-validation 1499 tuberculosis patients were identified, of whom 1298 were notified, resulting in an observed under-notification of 13.4%. After adjustment for possible imperfect record-linkage and remaining false-positive hospital cases observed under-notification was 7.3%. Log-linear capture-recapture analysis initially estimated a total number of 2053 (95% CI 1871-2443) tuberculosis cases, resulting in an estimated under-notification of 36.8%. After adjustment for possible imperfect record-linkage and remaining false-positive hospital cases various capture-recapture models estimated under-notification at 13.6%. One of the reasons for the higher than expected estimated under-notification in a country with a well-organized system of tuberculosis control might be that some tuberculosis cases, e.g. extrapulmonary tuberculosis, are managed by clinicians less familiar with notification of infectious diseases. This study demonstrates the possible impact of violation of assumptions underlying capture-recapture analysis, especially the perfect record-linkage, perfect positive predictive value and absent three-way interaction assumptions.