Pregnancy-associated desmoid fibromatosis: A Dutch multi-centre retrospective study.

INTRODUCTION: The development of desmoid fibromatosis (DF) is associated with pregnancy. The current treatment consensus recommends active surveillance (AS). However, data in pregnancy-associated DF is scarce and it is uncertain whether AS is the best management strategy for this DF-subgroup. The aim of this study was to describe demographic, tumor, obstetric, treatment characteristics and treatment outcome in pregnancy-associated DF. METHODS: Female DF patients who were 18-50 years old at time of diagnosis (2000-2020) and had a history (≤5 years) of pregnancy at time of diagnosis were included. RESULTS: Overall, 62 patients were included. The most common locations were abdominal wall (74%), pelvis (10%) and extremities (10%). Mutational analysis was conducted in 31 patients of which 94% had CTNNB1-mutations. Ten patients (16%) were diagnosed during pregnancy, while the remainder were diagnosed after pregnancy with a median time from delivery to diagnosis of 19 months (1-60). The frontline management was AS in 38 patients (61%) of whom 12 (33%) developed progressive disease and surgery in 23 patients (37%). In total, 30 patients underwent surgery and five had local recurrence (17%). Positive resection margins were no prognostic factor. Nine patients received systemic treatment in second- or third-line. CONCLUSIONS: Pregnancy-associated DF generally has an indolent behavior, where our results underscore the difficulty of establishing a clear definition of this entity. This study shows that AS should be the frontline management strategy for pregnancy-associated DF. When active treatment is indicated, surgery is a good option with low recurrence rates, even with positive (R1) resection margins.

The oncological outcomes of isolated limb perfusion and neo-adjuvant radiotherapy in soft tissue sarcoma patients - A nationwide multicenter study.

INTRODUCTION: Patients with locally extensive high-grade extremity soft tissue sarcomas (eSTS) are often presented in multidisciplinary teams to decide between ablative surgery (amputation) or limb-salvage surgery supplemented with either neo-adjuvant radiotherapy (RT) or induction isolated limb perfusion (ILP). In The Netherlands, ILP typically aims to reduce the size of tumors that would otherwise be considered irresectable, whereas neo-adjuvant RT aims mainly at improving local control and reducing morbidity of required marginal margins. This study presents a 15-year nationwide cohort to describe the oncological outcomes of both pre-operative treatment strategies. METHODS: All consecutive patients with locally extensive primary high-grade eSTS surgically treated between 2000 and 2015 at five tertiary sarcoma centers that received neo-adjuvant ILP or RT were included. 169 patients met the inclusion criteria (89 ILP, 80 RT). Median follow-up was 7.3 years. RESULTS: Limb salvage was achieved in 84% of cases in the ILP group (80% for patients with amputation indication) and 96% of cases in the RT group. 5-Year overall survival was 47% in the ILP group, 69% in the RT group. 5-Year local recurrence rate was 14% in the ILP group, 10% in the RT group. Distant metastasis rate was 55% in the ILP group, 36% in the RT group. CONCLUSION: We find oncological outcomes and limb salvage rates in line with existing literature for both treatment modalities. Whether the tumor was locally advanced with an indication for induction therapy to prevent amputation or morbid surgery appeared to be the main determinant in choosing between neo-adjuvant ILP or RT.

Health-related quality of life analysis in stage III melanoma patients treated with adjuvant dendritic cell therapy.

BACKGROUND: Health-related quality of life (HRQoL) is an important issue in the rapidly evolving field of adjuvant treatment for stage III melanoma. Dendritic cell vaccination is one of the adjuvant forms of therapy currently investigated. METHODS: We enrolled adults with stage III melanoma to receive adjuvant dendritic cell vaccination after a complete radical lymph node dissection. HRQoL assessment was one of the secondary endpoints of this trial and investigated with the EORTC-QLQ-C30 questionnaire at baseline and week 26. RESULTS: Fifteen patients with a median age of 50 years were included in the study, with twelve evaluable patients on study at time of the second questionnaire. Global health status and role functioning improved clinically relevant with a mean difference of 15 (p = 0.010) and 26 points (p = 0.005), respectively. DISCUSSION: Despite the small number of patients, we found a clinically relevant improved global health status. Besides, compared to the other investigated therapies, toxicity of dendritic cell vaccination is low, which supports our finding. CONCLUSION: This is the first description of HRQoL in melanoma patients receiving dendritic cell vaccination. We show the expected improvement in global health status after surgical treatment of stage III melanoma. Thus, adjuvant dendritic cell vaccination does not seem to hamper this improvement, as shown in our small explorative study.

Surgical and medical management of small bowel gastrointestinal stromal tumors: A report of the Dutch GIST registry.

BACKGROUND: A cohort of 201 patients with small bowel gastrointestinal stromal tumors (GIST) treated between January 1st, 2009 and December 31st, 2016 in five GIST expertise centers in the Netherlands was analyzed. Goal of this study was to describe the clinical, surgical and pathological characteristics of this rare subpopulation of GIST patients, registered in the Dutch GIST registry. METHODS: Clinical outcomes and risk factors of patients with small bowel GIST who underwent surgery or treated with systemic therapy were analyzed. A classification was made based on disease status at diagnosis (localized vs. metastasized). RESULTS: 201 patients with small bowel GIST were registered of which 138 patients (69%) were diagnosed with localized disease and 63 patients (31%) with metastatic disease. Approximately 19% of the patients had emergency surgery, and in 22% GIST was an accidental finding. In patients with high risk localized disease, recurrence occurred less often in patients who received adjuvant treatment (4/32) compared to patients who did not (20/31, p < 0.01). Disease progression during palliative imatinib treatment occurred in 23 patients (28%) after a median of 20.7 (range 1.8-47.1) months. Ongoing response was established in 52/82 patients on first line palliative treatment with imatinib after a median treatment time of 30.6 (range 2.5-155.3) months. CONCLUSION: Patients with small-bowel GIST more frequently present with metastatic disease when compared to patients with gastric GIST in literature. We advocate for Prospective registration of these patients and investigate the use of surgery in patients with limited metastatic disease.

Nationwide trends in the incidence and outcome of patients with gastrointestinal stromal tumour in the imatinib era.

BACKGROUND: The incidence, treatment and outcome of patients with newly diagnosed gastrointestinal stromal tumour (GIST) were studied in an era known for advances in diagnosis and treatment. METHODS: Nationwide population-based data were retrieved from the Netherlands Cancer Registry. All patients with GIST diagnosed between 2001 and 2012 were included. Primary treatment, defined as any treatment within the first 6-9 months after diagnosis, was studied. Age-standardized incidence was calculated according to the European standard population. Changes in incidence were evaluated by calculating the estimated annual percentage change (EAPC). Relative survival was used for survival calculations with follow-up available to January 2017. RESULTS: A total of 1749 patients (54·0 per cent male and median age 66 years) were diagnosed with a GIST. The incidence of non-metastatic GIST increased from 3·1 per million person-years in 2001 to 7·0 per million person-years in 2012; the EAPC was 7·1 (95 per cent c.i. 4·1 to 10·2) per cent (P < 0·001). The incidence of primary metastatic GIST was 1·3 per million person-years, in both 2001 and 2012. The 5-year relative survival rate increased from 71·0 per cent in 2001-2004 to 81·4 per cent in 2009-2012. Women had a better outcome than men. Overall, patients with primary metastatic GIST had a 5-year relative survival rate of 48·2 (95 per cent c.i. 42·0 to 54·2) per cent compared with 88·8 (86·0 to 91·4) per cent in those with non-metastatic GIST. CONCLUSION: This population-based nationwide study found an incidence of GIST in the Netherlands of approximately 8 per million person-years. One in five patients presented with metastatic disease, but relative survival improved significantly over time for all patients with GIST in the imatinib era.

Impact of neoadjuvant chemoradiotherapy on health-related quality of life in long-term survivors of esophageal or junctional cancer: results from the randomized CROSS trial.

Background: Neoadjuvant chemoradiotherapy (nCRT) plus surgery is a standard of care for patients with esophageal or junctional cancer, but the long-term impact of nCRT on health-related quality of life (HRQOL) is unknown. The purpose of this study is to compare very long-term HRQOL in long-term survivors of esophageal cancer who received nCRT plus surgery or surgery alone. Patients and methods: Patients were randomly assigned to receive nCRT (carboplatin/paclitaxel with 41.4-Gy radiotherapy) plus surgery or surgery alone. HRQOL was measured using EORTC-QLQ-C30, EORTC-QLQ-OES24 and K-BILD questionnaires after a minimum follow-up of 6 years. To allow for examination over time, EORTC-QLQ-C30 and QLQ-OES24 questionnaire scores were compared with pretreatment and 12 months postoperative questionnaire scores. Physical functioning (QLQ-C30), eating problems (QLQ-OES24) and respiratory problems (K-BILD) were predefined primary end points. Predefined secondary end points were global quality of life and fatigue (both QLQ-C30). Results: After a median follow-up of 105 months, 123/368 included patients (33%) were still alive (70 nCRT plus surgery, 53 surgery alone). No statistically significant or clinically relevant differential effects in HRQOL end points were found between both groups. Compared with 1-year postoperative levels, eating problems, physical functioning, global quality of life and fatigue remained at the same level in both groups. Compared with pretreatment levels, eating problems had improved (Cohen's d -0.37, P = 0.011) during long-term follow-up, whereas physical functioning and fatigue were not restored to pretreatment levels in both groups (Cohen's d -0.56 and 0.51, respectively, both P < 0.001). Conclusions: Although physical functioning and fatigue remain reduced after long-term follow-up, no adverse impact of nCRT is apparent on long-term HRQOL compared with patients who were treated with surgery alone. In addition to the earlier reported improvement in survival and the absence of impact on short-term HRQOL, these results support the view that nCRT according to CROSS can be considered as a standard of care. Trial registration number: Netherlands Trial Register NTR487.

Optimal extent of completion lymphadenectomy for patients with melanoma and a positive sentinel node in the groin.

BACKGROUND: The optimal extent of groin completion lymph node dissection (CLND) (inguinal or ilioinguinal dissection) in patients with melanoma is controversial. The aim of this study was to evaluate whether the extent of groin CLND after a positive sentinel node biopsy (SNB) is associated with improved outcome. METHODS: Data from all sentinel node-positive patients who underwent groin CLND at four tertiary melanoma referral centres were retrieved retrospectively. Baseline patient and tumour characteristics were collected for descriptive statistics, survival analyses and Cox proportional hazards regression analyses. RESULTS: In total, 255 patients were included, of whom 137 (53·7 per cent) underwent inguinal dissection and 118 (46·3 per cent) ilioinguinal dissection. The overall CLND positivity rate was 18·8 per cent; the inguinal positivity rate was 15·5 per cent and the pelvic positivity rate was 9·3 per cent. The pattern of recurrence, and 5-year melanoma-specific survival, disease-free survival and distant-metastasis free survival rates were similar for both dissection types, even for patients with a positive CLND result. Cox regression analysis showed that type of CLND was not associated with disease-free or melanoma-specific survival. CONCLUSION: There was no significant difference in recurrence pattern and survival rates between patients undergoing inguinal or ilioinguinal dissection after a positive SNB, even after stratification for a positive CLND result. An inguinal dissection is a safe first approach as CLND in patients with a positive SNB.

Impact of Centralizing Gastric Cancer Surgery on Treatment, Morbidity, and Mortality.

INTRODUCTION: Centralization of gastric cancer surgery is thought to improve outcome and has been imposed in the Netherlands since 2012. This study analyzes the effect of centralization in terms of treatment outcome and survival in the Eastern part of the Netherlands. METHODS: All gastric cancer patients without distant metastases who underwent a gastrectomy in six hospitals in the Eastern part of the Netherlands between 2008 and 2011 (pre-centralization) and 2013-2016 (post-centralization) were selected from the Netherlands Cancer Registry. Patient and tumor characteristics and treatment outcomes (duration of surgery, blood loss, resection margin, lymphadenectomy, chemotherapy, postoperative complications and hospital stay, and overall and disease-free survival) were analyzed and compared between pre- and post-centralization. RESULTS: One hundred forty-four patients were included pre-centralization and 106 patients post-centralization. Patient and tumor characteristics were almost similar in the two periods. After centralization, more patients were treated with perioperative chemotherapy (25 vs. 42% p < 0.01). The proportion of patients treated with an adequate lymphadenectomy (21 vs. 93% p < 0.01) and laparoscopic surgery (6 vs. 40% p < 0.01) increased significantly (p < 0.01). The amount of cardiac complications (16 vs. 7.5% p < 0.05) decreased; however, complications needing a re-intervention were comparable (42 vs. 40% p = 0.79). Median hospital stay decreased from 10 to 8 days (p < 0.01). A 30-day mortality did not differ significantly (4.2 vs. 1.9%). A 1-year overall (78 vs. 80% p = 0.17) and disease-free survival (73 vs. 74% p = 0.66) remained stable. DISCUSSION: Centralizing gastric cancer treatment in the Eastern part of the Netherlands resulted in improved lymph node harvesting and a successful introduction of laparoscopic gastrectomies. Centralization has not translated into improved mortality, and other variables may also have led to these improved outcomes. Further research using a nationwide population-based study will be needed to confirm these data.

Esophageal and Gastric Cancer Pearl: a nationwide clinical biobanking project in the Netherlands.

Esophageal and gastric cancer is associated with a poor prognosis since many patients develop recurrent disease. Treatment requires specific expertise and a structured multidisciplinary approach. In the Netherlands, this type of expertise is mainly found at the University Medical Centers (UMCs) and a few specialized nonacademic centers. Aim of this study is to implement a national infrastructure for research to gain more insight in the etiology and prognosis of esophageal and gastric cancer and to evaluate and improve the response on (neoadjuvant) treatment. Clinical data are collected in a prospective database, which is linked to the patients' biomaterial. The collection and storage of biomaterial is performed according to standard operating procedures in all participating UMCs as established within the Parelsnoer Institute. The collected biomaterial consists of tumor biopsies, blood samples, samples of malignant and healthy tissue of the resected specimen and biopsies of recurrence. The collected material is stored in the local biobanks and is encoded to respect the privacy of the donors. After approval of the study was obtained from the Institutional Review Board, the first patient was included in October 2014. The target aim is to include 300 patients annually. In conclusion, the eight UMCs of the Netherlands collaborated to establish a nationwide database of clinical information and biomaterial of patients with esophageal and gastric cancer. Due to the national coverage, a high number of patients are expected to be included. This will provide opportunity for future studies to gain more insight in the etiology, treatment and prognosis of esophageal and gastric cancer.

Health-related quality of life and hospital costs following esophageal resection: a prospective cohort study.

BACKGROUND: The incidence rates for adenocarcinoma of the esophagus are increasing while the prognosis has only improved slightly. There is no apparent benefit in short- and long-term survival after different surgical strategies, but surgery is associated with significant morbidity. The goal of this study is to prospectively assess the quality of life and hospital costs after esophageal resections depending on the development of complications. METHODS: Prospective data was collected from 47 patients undergoing an esophageal resection for esophageal cancer participating in the prospective LAParotomy or LAParoscopy and Adhesions (LAPAD) study (clinicaltrials.gov registration number: NCT01236625). A comparison was made between patients who developed major complications and minor or no complications regarding quality of life and hospital costs. RESULTS: Thirteen patients developed major complications while 34 patients developed only minor or no complications. Patients with major complications had a mean hospital cost of $16,369 vs $12,409 for patients without or with minor complications. We found no difference in quality of life between the two groups 6 months after surgery. CONCLUSIONS: In our cohort, major complications did not seem to have a detrimental effect on postoperative quality of life 6 months after surgery but they increased costs associated with esophageal resection.

Risk Factors for Positive Deep Pelvic Nodal Involvement in Patients with Palpable Groin Melanoma Metastases: Can the Extent of Surgery be Safely Minimized? : A Retrospective, Multicenter Cohort Study.

BACKGROUND: Patients with palpable melanoma groin metastases have a poor prognosis. There is debate whether a combined superficial and deep groin dissection (CGD) is necessary or if superficial groin dissection (SGD) alone is sufficient. AIM: The aim of this study was to analyze risk factors for deep pelvic nodal involvement in a retrospective, multicenter cohort of palpable groin melanoma metastases. This could aid in the development of an algorithm for selective surgery in the future. METHODS: This study related to 209 therapeutic CGDs from four tertiary centers in The Netherlands (1992-2013), selected based on complete preoperative imaging and pathology reports. Analyzed risk factors included baseline and primary tumor characteristics, total and positive number of inguinal nodes, inguinal lymph node ratio (LNR) and positive deep pelvic nodes on imaging (computed tomography [CT] ± positron emission tomography [PET], or PET - low-dose CT). RESULTS: Median age was 57 years, 54 % of patients were female, and median follow-up was 21 months (interquartile range [IQR] 11-46 months). Median Breslow thickness was 2.10 mm (IQR 1.40-3.40 mm), and 26 % of all primary melanomas were ulcerated. Positive deep pelvic nodes occurred in 35 % of CGDs. Significantly fewer inguinal nodes were positive in case of negative deep pelvic nodes (median 1 [IQR 1-2] vs. 3 [IQR 1-4] for positive deep pelvic nodes; p < 0.001), and LNR was significantly lower for negative versus positive deep pelvic nodes [median 0.15 (IQR 0.10-0.25) vs. 0.33 (IQR 0.14-0.54); p < 0.001]. A combination of negative imaging, low LNR, low number of positive inguinal nodes, and no extracapsular extension (ECE) could accurately predict the absence of pelvic nodal involvement in 84 % of patients. CONCLUSIONS: Patients with negative imaging, few positive inguinal nodes, no ECE, and low LNR have a low risk of positive deep pelvic nodes and may safely undergo SGD alone.

Outcome of clinical stage III melanoma patients with FDG-PET and whole-body CT added to the diagnostic workup.

BACKGROUND: Combined whole-body FDG-PET and CT provide the most comprehensive staging of melanoma patients with palpable lymph node metastases (LNM). The aim of this study is to analyze survival of FDG-PET and CT negative or positive melanoma patients and to assess which factors have independent prognostic impact on survival of these patients. METHODS: Patients with palpable and histologically or cytologically proven LNM of melanoma, referred to participating hospitals for examination with FDG-PET and CT, were selected from a previous study. Melanoma-specific survival (MSS) and disease-free period (DFP) were analyzed for FDG-PET and CT positive and negative patients using the Kaplan-Meier method. Cox-regression analysis was performed to analyze which patient or melanoma characteristics had significant impact on MSS or DFP. RESULTS: For all 252 patients 5-year MSS was 38.2%. For FDG-PET and CT negative and positive patients 5-year MSS was 47.6 and 16.9%, respectively. Disease-free period for FDG-PET and CT negative patients was 46.0% after 5 years. Gender, a positive FDG-PET and CT, LNM in axilla compared to head or neck, and presence of extranodal growth were independent factors for worse MSS in all patients. Positive FDG-PET and CT was the most important prognostic factor for MSS with a hazard ratio of 2.54 (95% CI, 1.55-4.17, P<0.001). CONCLUSIONS: Staging melanoma patients with palpable LNM is more accurate when whole-body FDG-PET and CT is added to the diagnostic workup. Hence, FDG-PET and CT, preferably combined, are indicated in the staging of clinical stage III melanoma patients.

Surgical treatment of locally advanced, non-metastatic, gastrointestinal stromal tumours after treatment with imatinib.

AIMS: Patients with locally advanced gastrointestinal stromal tumours (GISTs) have a high risk of tumour perforation, incomplete tumour resections and often require multivisceral resections. Long-term disease-free and overall survival is usually impaired in this group of patients. Induction therapy with imatinib followed by surgery seems to be beneficial in terms of improved surgical results and long-term outcome. We report on a large cohort of locally advanced GIST patients who have been treated in four centres in the Netherlands specialized in the treatment of sarcomas. METHODS: Between August 2001 and June 2011, 57 patients underwent surgery for locally advanced GISTs after imatinib treatment. Data of all patients were retrospectively collected. Endpoints were progression-free and overall survival. RESULTS: The patients underwent surgery after a median of 8 (range 1-55) months of imatinib treatment. Median tumour size before treatment was 12.2 (range 5.2-30) cm and reduced to 6.2 (range 1-20) cm before surgery. No tumour perforation occurred and a surgical complete (R0) resection was achieved in 48 (84%) patients. Five-year PFS and OS were 77% and 88%. Eight patients had recurrent/metastatic disease. CONCLUSIONS: Imatinib in locally advanced GIST is feasible and enables a high complete resection rate without tumour rupture. The combination of imatinib and surgery in patients with locally advanced GIST seems to improve PFS and OS.

Preoperative chemoradiotherapy for esophageal or junctional cancer.

BACKGROUND: The role of neoadjuvant chemoradiotherapy in the treatment of patients with esophageal or esophagogastric-junction cancer is not well established. We compared chemoradiotherapy followed by surgery with surgery alone in this patient population. METHODS: We randomly assigned patients with resectable tumors to receive surgery alone or weekly administration of carboplatin (doses titrated to achieve an area under the curve of 2 mg per milliliter per minute) and paclitaxel (50 mg per square meter of body-surface area) for 5 weeks and concurrent radiotherapy (41.4 Gy in 23 fractions, 5 days per week), followed by surgery. RESULTS: From March 2004 through December 2008, we enrolled 368 patients, 366 of whom were included in the analysis: 275 (75%) had adenocarcinoma, 84 (23%) had squamous-cell carcinoma, and 7 (2%) had large-cell undifferentiated carcinoma. Of the 366 patients, 178 were randomly assigned to chemoradiotherapy followed by surgery, and 188 to surgery alone. The most common major hematologic toxic effects in the chemoradiotherapy-surgery group were leukopenia (6%) and neutropenia (2%); the most common major nonhematologic toxic effects were anorexia (5%) and fatigue (3%). Complete resection with no tumor within 1 mm of the resection margins (R0) was achieved in 92% of patients in the chemoradiotherapy-surgery group versus 69% in the surgery group (P<0.001). A pathological complete response was achieved in 47 of 161 patients (29%) who underwent resection after chemoradiotherapy. Postoperative complications were similar in the two treatment groups, and in-hospital mortality was 4% in both. Median overall survival was 49.4 months in the chemoradiotherapy-surgery group versus 24.0 months in the surgery group. Overall survival was significantly better in the chemoradiotherapy-surgery group (hazard ratio, 0.657; 95% confidence interval, 0.495 to 0.871; P=0.003). CONCLUSIONS: Preoperative chemoradiotherapy improved survival among patients with potentially curable esophageal or esophagogastric-junction cancer. The regimen was associated with acceptable adverse-event rates. (Funded by the Dutch Cancer Foundation [KWF Kankerbestrijding]; Netherlands Trial Register number, NTR487.).

Primary hyperparathyroidism in MEN1 patients: a cohort study with longterm follow-up on preferred surgical procedure and the relation with genotype.

OBJECTIVE: To identify the optimal surgical strategy for multiple endocrine neoplasia type 1 (MEN1)-related primary hyperparathyroidism (pHPT). To describe the course of postoperative hypoparathyroidism and to assess whether genotype is associated with persistent/recurrent pHPT. BACKGROUND: Surgery is the preferred treatment in MEN1-related pHPT, but the surgical procedure of choice is still uncertain. METHODS: This retrospective cohort study was performed at the Departments of Endocrinology of the University Medical Centers of Utrecht and Nijmegen, the Netherlands. Patients were selected from the Dutch MEN1 database, including all patients 16 years or older treated for MEN1 from 1990 to 2009. Data were collected by medical record review. RESULTS: Seventy-three patients underwent parathyroid surgery. Persistent/recurrent pHPT occurred in 53% after less than 3 parathyroids resected (

Results of surgery for perforated gastroduodenal ulcers in a Dutch population.

OBJECTIVE: Despite improvements in anesthesiology and intensive care medicine, mortality for perforated gastroduodenal ulcer disease remains high. This study was designed to evaluate the results of surgery for perforated ulcer disease and to identify prognostic factors for mortality in order to optimize treatment. PATIENTS AND METHODS: The medical records of 272 patients undergoing emergency surgery for perforated ulcer disease from 2000 to 2005 in two large teaching hospitals and one university hospital in the Netherlands were retrospectively analyzed. Information on 89 pre-, peri- and postoperative data were recorded. Statistical analysis was performed using multiple logistic regression analysis. The primary endpoint was 30-day mortality. RESULTS: The 30-day mortality rate was 16%. Variables associated with 30-day mortality were age, shock, tachycardia, anemia and ASA class. CONCLUSIONS: A relatively low 30-day mortality rate was achieved. Age, shock, tachycardia and anemia were significantly associated with 30-day mortality. Finding that shock, tachycardia and anemia are independently associated with 30-day mortality could indicate that patients are septic upon admission. Improvements in survival might be achieved by early sepsis treatment.