Changes over time in the impact of gene-expression profiles on the administration of adjuvant chemotherapy in estrogen receptor positive early stage breast cancer patients: A nationwide study.

Ten years ago gene-expression profiles were introduced to aid adjuvant chemotherapy decision making in breast cancer. Since then subsequent national guidelines gradually expanded the indication area for adjuvant chemotherapy. In this nation-wide study the evolution of the proportion of patients with estrogen-receptor positive (ER+) tumors receiving adjuvant chemotherapy in relation to gene-expression profile use in patient groups that became newly eligible for chemotherapy according to national guideline changes over time is assessed. Data on all surgically treated early breast cancer patients diagnosed between 2004-2006 and 2012-2014 were obtained from the Netherlands Cancer Registry. ER+/Her2- patients with tumor-characteristics making them eligible for gene-expression testing in both cohorts and a discordant chemotherapy recommendation over time (2004 guideline not recommending and 2012 guideline recommending chemotherapy) were identified. We identified 3,864 patients eligible for gene-expression profile use during both periods. Gene-expression profiles were deployed in 5% and 35% of the patients in the respective periods. In both periods the majority of patients was assigned to a low genomic risk-profile (67% and 69%, respectively) and high adherence rates to the test result were observed (86% and 91%, respectively). Without deploying a gene-expression profile 8% and 52% (p <0.001) of the respective cohorts received chemotherapy while 21% and 28% of these patients received chemotherapy when a gene-expression profile was used (p 0.191). In conclusion, in ER+/Her2- early stage breast cancer patients gene-expression profile use was associated with a consistent proportion of patients receiving chemotherapy despite an adjusted guideline-based recommendation to administer chemotherapy.

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.

Discordance of intraoperative frozen section analysis with definitive histology of sentinel lymph nodes in breast cancer surgery: complementary axillary lymph node dissection is irrelevant for subsequent systemic therapy.

BACKGROUND: In breast cancer surgery, intraoperative frozen section (FS) analysis of sentinel lymph nodes (SLNs) enables axillary lymph node dissection (ALND) during the same operative procedure. In case of discordance between a "negative" FS analysis and definitive histology, an ALND as a second operation is advocated since additional lymph node metastases may be present. The clinical implications of the subsequent ALND in these patients were evaluated. MATERIALS AND METHODS: Between November 2000 and May 2008, 879 consecutive breast cancer patients underwent surgery including sentinel lymph node biopsy (SLNB) with intraoperative FS analysis of 2 central cuts from axillary SLNs. Following fixation and serial sectioning, SLNs were further examined postoperatively with hematoxylin and eosin (H&E) and immunohistochemical techniques. For patients with a discordant FS examination, the effect of the pathology findings of the subsequent ALND specimen on subsequent nonsurgical therapy were evaluated. RESULTS: FS analysis detected axillary metastases in the SLN(s) in 200 patients (23%), while the definitive pathology examination detected metastases in SLNs in another 151 patients (17%). A complementary ALND was performed in 108 of the 151 patients with discordant FS. Additional tumor positive axillary lymph nodes were found in 17 patients (16%), leading to "upstaging" in 7 (6%). Subsequent nonsurgical treatment was adjusted in 4 patients (4%): all 4 had more extensive locoregional radiotherapy; no patient received additional hormonal and/or chemotherapy. CONCLUSION: Discordance between intraoperative FS analysis and definitive histology of SLNs is common. In this selection of patients, a substantial proportion had additional lymph node metastases, but postsurgical treatment was rarely adjusted based on the findings of the complementary ALND.

[Diagnostic image (376). A man with a tumour in the anal seam]. / Diagnose in beeld (376). Een man met een zwelling in de bilnaad.

A 50-year-old man presented with a sacral tumour due to a sacrococcygeal chordoma.

Long-term prognosis of primary retroperitoneal soft tissue sarcoma.

AIMS: To evaluate the result of treatment and long-term outcome of a population-based cohort of patients with retroperitoneal soft tissue sarcoma (RSTS). METHODS: Between 1 January 1989 and 1 January 1994, 143 patients diagnosed as having primary RSTS were selected from a national pathology database (PALGA) in the Netherlands. In this population-based group of patients, the result of surgery, overall survival (OS) and disease-free survival (DFS) were analysed as well as factors affecting OS and DFS. Median follow-up was 10.2 years. RESULTS: Operative treatment resulted in a complete tumour resection in 55% of the patients (n=78), low- and intermediate-grade tumours were more often completely resected than high-grade tumours (P=0.016). Five- and 10-year cumulative OS was 39% and 21%, respectively, while DFS was 22% and 17%, respectively. In a multivariate analysis low malignancy grade (P=0.017) and a complete tumour resection (P<0.001) were associated with better OS. CONCLUSIONS: Complete tumour resection and low malignancy grade were independent favourable prognosticators. However, these factors were related too, since surgical success was influenced by malignancy grade.

Impact of gene-expression profiling in patients with early breast cancer when applied outside the guideline directed indication area.

PURPOSE: In Dutch guidelines, gene expression profiles (GEP) are indicated in estrogen receptor positive early breast cancer patients in whom benefit of chemotherapy (CT) is uncertain based on traditional prognostic factors alone. Aim of the present study is to assess the use and impact of GEP on administration of adjuvant CT in breast cancer patients who have according to national guidelines a clear indication to either use or withhold adjuvant chemotherapy (clinical high or low risk). METHODS: Clinical low- and high-risk patients, according to Dutch breast cancer guidelines, diagnosed between 2011 and 2014 were selected from the Netherlands Cancer Registry. Influence of GEP use and GEP test result on CT administration was assessed with logistic regression. RESULTS: Overall, 26,425 patients were identified; 4.8% of patients with clinical low risk (444/9354), 7.5% of the patients with a clinical high risk (1281/17,071) received a GEP. GEP use was associated with significantly increased odds of CT administration in clinical low-risk patients (OR = 2.12 95% CI: 1.44-3.11). In clinical high-risk patients, GEP use was associated with a decreased frequency of CT administration (OR = 0.55, 95% CI: 0.48-0.63). Adherence to the GEP result was higher in clinical high-risk patients with a discordant GEP result as compared to clinical low-risk patients with a discordant GEP result: 71.7% vs. 52.2%, respectively. CONCLUSION: GEP is frequently used outside the indicated area and significantly influenced the administration of adjuvant CT, although adherence to the test result was limited.

[The surgical treatment of Graves' disease]. / Chirurgische behandeling van de ziekte van Graves.

A man aged 80 and three women aged 66, 26, and 39 years respectively, underwent surgery for Graves' disease. The first woman had pneumonia and experienced thyrotoxic storm. Euthyroidism was restored with antithyroid drugs (ATD) and thyroidectomy was performed as ablative treatment for hyperthyroidism. The man presented with thyrotoxicosis and had severe Graves' ophthalmopathy. After euthyroidism was restored with ATD, he underwent subtotal thyroidectomy. The second woman presented with severe thyrotoxicosis but was allergic to ATD. She was treated with iodine and beta-blockers after which subtotal thyroidectomy was done as an ablative procedure. Medical treatment for hyperthyroidism failed in the last patient and, as she had experienced severe psychological disturbances during a previous relapse, she too chose surgery as a definitive treatment option. In two patients the postoperative course was complicated by early hypocalcaemia and one of these patients experienced temporary recurrent laryngeal nerve paralysis. Surgery has a limited role in the treatment of Graves' disease. In pregnant women with severe ATD-resistant thyrotoxicosis, surgery is the only treatment option, while in patients with Graves' orbitopathy surgery may be preferable because of its neutral and perhaps even beneficial effects on eye symptoms. Large goitre size and thyroid nodules are concomitant reasons for choosing surgery, as are allergy to ATD and patients' preference. Lastly, in patients who have suffered from severe thyrotoxicosis, surgery provides rapid and definitive treatment. Early morbidity following surgery is common and should be discussed with the patient.

[The 'acute scrotum' in children: the clinical presentation as indicated by a rapid operation]. / Het 'acute scrotum' bij jongens: de klinische presentatie als indicatie voor een spoedoperatie.

Four boys, aged 2 months, 1 month, 16 years and 17 years, presented with an acute painful swelling in the scrotum. Both newborns were considered to have an inguinal hernia, but one of them turned out to have a testicular torsion. Both adolescents, however, were assumed to have a testicular torsion, yet one of them had an incarcerated scrotal hernia. The diagnostic errors resulted in an orchidectomy in the newborn because of delayed operative intervention, while a second (inguinal) incision was required in the adolescent boy for the hernia repair. The other boys were treated appropriately immediately. The post-operative recovery was uncomplicated in all children. Although ultrasound may be valuable in the evaluation of the 'acute scrotum', it should not prevent or postpone prompt surgical exploration in boys with severe symptoms.

[Minimally-invasive parathyroidectomy: a good operative procedure for primary hyperparathyroidism even without the use of intraoperative parathyroid-hormone assessment or a gamma probe]. / Minimaal invasieve parathyreoïdectomie: ook zonder het gebruik van intraoperatieve parathormoonmeting of gammaprobe een goede behandeling voor primaire hyperparathyreoïdie.

OBJECTIVE: To evaluate the results of minimally-invasive parathyroidectomy without the use of intraoperative parathyroid-hormone assessment or a gamma probe. DESIGN: Retrospective. METHODS: In 2 community hospitals in the Netherlands, 49 patients with primary hyperparathyroidism in whom preoperative investigations had shown a solitary adenoma underwent minimally-invasive surgery by the lateral neck approach. In total 9 men and 40 women with an average age of 58 years (limits: 25-84) underwent this procedure. More extensive preoperative investigations were carried out at the Mesos Medisch Centrum (n = 29) including neck CT in 76% of patients as well as ultrasonography, and scintigraphy. At the Diakonessenhuis (n = 20) scintigraphy was the preferred method of adenoma localisation. Intraoperative parathyroidhormone assessment and a gamma probe were not used in the operative procedure. At the Diakonessenhuis intraoperative frozen-section investigations were done. RESULTS: In 44 of the 49 patients (90%) minimally-invasive parathyroidectomy resulted in normocalcaemia. In the remaining 5 patients a second procedure was necessary--a conventional neck exploration and also resulted in normocalcaemia. In 2 of these patients the adenomas had been missed during first procedure by the surgeon, while in 3 other patients preoperative examinations were falsely positive in the sense that the adenoma proved to be present but in an area other than that indicated by preoperative imaging. Permanent recurrent laryngeal-nerve paralysis complicated the postoperative course in 2 patients. The success rate of the minimally-invasive operation was the same for both groups. CONCLUSION: Without the use of intraoperative parathyroid-hormone assessment or a gamma probe minimally-invasive parathyroidectomy was successful in 90% of patients.

ARM: axillary reverse mapping - the need for selection of patients.

BACKGROUND: Axillary reverse mapping (ARM) is a technique that discerns axillary lymphatic drainage of the arm from the breast. This study was performed to evaluate both the feasibility of this technique and the proportion of metastatic involvement of ARM-nodes. PATIENTS AND METHODS: Patients with invasive breast cancer and an indication for axillary lymph node dissection (ALND) were enrolled in the study: patients with a tumor-positive sentinel lymph node (SLN(+)-group) and patients who had axillary metastases proven by preoperative cytology (CP-N(+)-group) were distinguished. ARM was performed in all patients by injecting blue dye. During surgery ARM-nodes were identified and removed first, followed by ALND. RESULTS: Between October 2009 and June 2011 93 patients underwent ARM. There were 43 patients in the SLN(+)-group and 50 patients in the CP-N(+)-group. No significant differences in visualization rate of ARM-nodes between the groups (86 vs 94% respectively, P = 0.196) were identified. In the SLN(+)-group none of the ARM-nodes contained metastases versus 11 patients (22%) in the CP-N(+)-group (P = 0.001). Patients receiving neoadjuvant systemic therapy had a significantly lower risk of additional axillary lymph node metastases (24.6 vs 44.4%, P = 0.046). DISCUSSION: The ARM procedure is technically feasible with a high visualization rate. The proportion of patients with metastases in the ARM-nodes was significantly higher in patients with proven axillary metastases than in patients with a positive SLN. Patients with SLN metastases appear to be good candidates for the ARM technique and possibly also patients with proven axillary metastases receiving neoadjuvant chemotherapy.

The impact on post-surgical treatment of sentinel lymph node biopsy of internal mammary lymph nodes in patients with breast cancer.

BACKGROUND: Since the introduction of the sentinel lymph node (SLN) biopsy in breast cancer patients there is a renewed interest in lymphatic drainage to the internal mammary (IM) chain nodes. We evaluated the frequency of lymphatic drainage to the IM chain, the rate of SLNs that contain metastases and the clinical implications of IM LN metastases. METHODS: Between June 1999 and April 2005 506 consecutive patients underwent SLN biopsy as a staging procedure for clinically T1-2N0 breast cancer. In all patients preoperative lymphoscintigraphy was combined with the intraoperative use of a gammaprobe. In patients with IM SLNs visualized on lymphoscintigraphy, LNs were extirpated through an intercostal parasternal incision. RESULTS: SLNs were visualized by preoperative lymphoscintigraphy in 99% of all patients (502/506): axillary SLNs in 499 patients (99%), ipsilateral IM LNs in 109 patients (22%). In 85 patients with visualized IM SLNs the IM nodes could be removed (78%). In 20 of the latter 85 patients IM SLNs contained metastases (24%). IM metastases were associated with axillary LN metastases (P < 0.001). In 17 patients IM metastases led to extension of the radiotherapy field, while additional (adjuvant) systemic therapy was given in six patients. CONCLUSION: SLNs in the IM chain are common in breast cancer patients and can be extirpated in the majority of these patients. The proportion of patients in whom radiotherapeutic treatment was adjusted due to IM LN metastases was substantial. We advocate retrieval of IM SLNs when visualized by preoperative lymphoscintigraphy.

Mesothelioma of the tunica vaginalis testis: a rare malignancy mimicking more common inguino-scrotal masses.

Malignant pleural mesotheliomas are rare malignancies associated with asbestos exposure and these tumors are infamous for their poor prognosis. Mesotheliomas in other body areas are much rarer. They may occur in the abdominal cavity and also in the inguinal region. In the latter area they are commonly confused with much commoner benign conditions. We present three cases of mesotheliomas in the tunica vaginalis testis.