Context: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in... Show moreContext: The X-linked immunoglobulin superfamily, member 1 (IGSF1), gene is highly expressed in the hypothalamus and in pituitary cells of the POU1F1 lineage. Human loss-of-function mutations in IGSF1 cause central hypothyroidism, hypoprolactinemia, and macroorchidism. Additionally, most affected adults exhibit higher than average IGF-1 levels and anecdotal reports describe acromegaloid features in older subjects. However, somatotrope function has not yet been formally evaluated in this condition.Objective: We aimed to evaluate the role of IGSF1 in human and murine somatotrope function.Patients, Design, and Setting: We evaluated 21 adult males harboring hemizygous IGSF1 loss-of-function mutations for features of GH excess, in an academic clinical setting.Main Outcome Measures: We compared biochemical and tissue markers of GH excess in patients and controls, including 24-hour GH profile studies in 7 patients. Parallel studies were undertaken in male Igsf1-deficient mice and wild-type littermates.Results: IGSF1-deficient adult male patients demonstrated acromegaloid facial features with increased head circumference as well as increased finger soft-tissue thickness. Median serum IGF-1 concentrations were elevated, and 24-hour GH profile studies confirmed 2- to 3-fold increased median basal, pulsatile, and total GH secretion. Male Igsf1-deficient mice also demonstrated features of GH excess with increased lean mass, organ size, and skeletal dimensions and elevated mean circulating IGF-1 and pituitary GH levels.Conclusions: We demonstrate somatotrope neurosecretory hyperfunction in IGSF1-deficient humans and mice. These observations define a hitherto uncharacterized role for IGSF1 in somatotropes and indicate that patients with IGSF1 mutations should be evaluated for long-term consequences of increased GH exposure. Show less
According to the WHO, mesenchymal tumours of the maxillofacial bones are subdivided in benign and malignant maxillofacial bone and cartilage tumours, fibro-osseous and osteochondromatous lesions as... Show moreAccording to the WHO, mesenchymal tumours of the maxillofacial bones are subdivided in benign and malignant maxillofacial bone and cartilage tumours, fibro-osseous and osteochondromatous lesions as well as giant cell lesions and bone cysts. The histology always needs to be evaluated considering also the clinical and radiological context which remains an important cornerstone in the classification of these lesions. Nevertheless, the diagnosis of maxillofacial bone tumours is often challenging for radiologists as well as pathologists, while an accurate diagnosis is essential for adequate clinical decision-making. The integration of new molecular markers in a multidisciplinary diagnostic approach may not only increase the diagnostic accuracy but potentially also identify new druggable targets for precision medicine. The current review provides an overview of the clinicopathological and molecular findings in maxillofacial bone tumours and discusses the diagnostic value of these genetic aberrations. Show less
Background: In the West, pre-treatment abnormal lateral lymph nodes (LLN+) in patients with a low locally advanced rectal cancer (AJCC Stage III), are treated with neoadjuvant (chemo)radiotherapy ... Show moreBackground: In the West, pre-treatment abnormal lateral lymph nodes (LLN+) in patients with a low locally advanced rectal cancer (AJCC Stage III), are treated with neoadjuvant (chemo)radiotherapy (nCRT), without a lateral lymph node dissection (LLND). It has been suggested, however, that LLN+ patients have higher local recurrence (LR) rates than similarly staged patients with abnormal mesorectal lymph nodes only (LLN-), but no comparative data exist. Therefore, we conducted this international multi-center study in the Netherlands and Australia of Stage III rectal cancer patients with either LLN+ or LLN- to compare oncological outcomes from both groups. Materials and Methods: Patients with Stage III low rectal cancer with (LLN+ group) or without (LLN- group) abnormal lateral lymph nodes on pre-treatment MRI were included. Patients underwent nCRT followed by rectal resection surgery with curative intent between 2009 and 2016 with a minimum follow-up of 2-years. No patient had a LLND. Propensity score matching corrected differences in baseline characteristics. Results: Two hundred twenty-three patients could be included: 125 in the LLN+ group and 98 in the LLN- group. Between groups, there were significant differences in cT-stage and in the rate of adjuvant chemotherapy administered. Propensity score matching resulted in 54 patients in each group, with equal baseline characteristics. The 5-year LR rate in the LLN+ group was 11 vs. 2% in the LLN- group (P = 0.06) and disease-free survival (DFS) was 64 vs. 76%, respectively (P = 0.09). Five-year overall survival was similar between groups (73 vs. 80%, respectively; P = 0.90). Conclusions: In Western patients with Stage III low rectal cancer, there is a trend toward worse LR rate and DFS rates in LLN+ patients compared to similarly staged LLN- patients. These results suggest that LLN+ patients may currently not be treated optimally with nCRT alone, and the addition of LLND requires further consideration. Show less
Radiomics can differentiate an enchondroma (a "don't touch" lesion) from an atypical cartilaginous tumor (which justifies watchful waiting) and a high-grade chondrosarcoma (which necessitates... Show moreRadiomics can differentiate an enchondroma (a "don't touch" lesion) from an atypical cartilaginous tumor (which justifies watchful waiting) and a high-grade chondrosarcoma (which necessitates resection with negative margins), and it will aid in individualized medicine for cartilaginous lesions of the appendicular skeleton. Show less
ObjectiveAneurysmal bone cysts (ABC) rarely present in soft tissue locations (STABC). The 30 cases of STABC reported in the English literature were reviewed. Six new cases retrieved from the files... Show moreObjectiveAneurysmal bone cysts (ABC) rarely present in soft tissue locations (STABC). The 30 cases of STABC reported in the English literature were reviewed. Six new cases retrieved from the files of the Netherlands Committee on Bone Tumors were compared to the six cases described in the radiological literature.Materials and methodsImaging studies and histopathology of six new STABC cases were reviewed. Follow-up was recorded with respect to local recurrence. FISH for USP6 rearrangement and/or anchored multiplex PCR-based targeted NGS using Archer FusionPlex Sarcoma Panel were attempted.ResultsOn imaging, the six STABC cases presented as a solid or multicystic intramuscular soft tissue mass, usually with thin peripheral mineralized bone shell. On MRI, perilesional edema was visualized in nearly all cases. Fluid-fluid levels were observed in one case. All lesions had the distinct histologic features of STABC. In three cases suitable for NGS, the diagnosis of STABC was confirmed by a COL1A1-USP6 fusion gene. In one additional case, USP6 gene rearrangement was detected by FISH. After marginal excision, none of the six STABC recurred after a mean follow-up period of 50months (range, 39-187months).ConclusionsOn imaging, it can be difficult to discriminate between STABC and myositis ossificans. The presence of a thin bony shell and fluid-fluid levels can be helpful in discriminating these two entities. STABC is readily diagnosed after histopathologic examination of the resection specimen. STABC belongs to the spectrum of tumors with USP6 rearrangements, which includes ABC, myositis ossificans, and nodular fasciitis. Show less
Background: Osteoarthritis (OA) severity as demonstrated by preoperative radiographs and preoperative pain play an important role in the indication for total knee arthroplasty (TKA). We... Show moreBackground: Osteoarthritis (OA) severity as demonstrated by preoperative radiographs and preoperative pain play an important role in the indication for total knee arthroplasty (TKA). We investigated whether preoperative radiographic evidence of OA severity modified the effect of preoperative self-reported pain on postoperative pain and function 1 and 2 years after TKA for OA.Methods: Data from the Longitudinal Leiden Orthopaedics Outcomes of Osteoarthritis Study (LOAS), a multicenter cohort study on outcomes after TKA, were used. OA severity was assessed radiographically with the Kellgren and Lawrence (KL) score (range, 0 to 4). Pain and function were evaluated with the Knee injury and Osteoarthritis Outcome Score (KOOS). After adjustment for body mass index (BMI), age, sex, and the Mental Component Summary scores from the Short Form-12, multivariate linear regression analyses with an interaction term between the preoperative KL score and preoperative pain were performed.Results: The study included 559 patients. The preoperative KL score was independently associated with 1-year postoperative pain and function (beta = 5.4, 95% confidence interval [CI] = 1.4 to 9.4, and beta = 7.7, 95% CI = 3.2 to 12.2), while preoperative pain was associated only with postoperative pain (beta = 0.3, 95% CI = 0.1 to 0.6) and not with postoperative function (beta = 0.2, 95% CI = -0.2 to 0.5). Comparable associations were found between 2-year postoperative pain and KL score (beta = 8.0, 95% CI = 3.2 to 12.7) and preoperative pain (beta = 0.5, 95% CI = 0.1 to 0.8) and between 2-year postoperative function and KL score (beta = 7.7, 95% CI = 3.2 to 12.2). The study showed a trend toward the KL score modifying the effect of preoperative pain on 1-year postoperative pain (beta = -0.1, 95% CI = -0.1 to 0.0) and 2-year postoperative pain (beta = -0.1, 95% CI = -0.2 to 0.0) and on 1 and 2-year function (beta = -0.1, 95% CI = -0.2 to 0.0 for both), with the effect of preoperative pain on postoperative pain and function seeming to become less important when there was radiographic evidence of greater preoperative OA severity.Conclusions: Patients with less pain and higher KL grades preoperatively had better function and pain outcomes 1 and 2 years after TKA. However, the effect of preoperative pain on the postoperative outcomes seems to become less important when the patient has radiographic evidence of more severe OA. We believe that analysis of the severity of preoperative pain is an important proxy for optimal postoperative patient outcome. Show less
Purpose: To determine whether patient-specific finite element (FE) computer models are better at assessing fracture risk for femoral bone metastases compared to clinical assessments based on axial... Show morePurpose: To determine whether patient-specific finite element (FE) computer models are better at assessing fracture risk for femoral bone metastases compared to clinical assessments based on axial cortical involvement on conventional radiographs, as described in current clinical guidelines.Methods: Forty-five patients with 50 femoral bone metastases, who were treated with palliative radiotherapy for pain, were included (64% single fraction (8 Gy), 36% multiple fractions (5 or 6 x 4 Gy)) and were followed for six months to determine whether they developed a pathological femoral fracture. All plain radiographs available within a two month period prior to radiotherapy were obtained. Patient-specific FE models were constructed based on the geometry and bone density obtained from the baseline quantitative CT scans used for radiotherapy planning. Femoral failure loads normalized for body weight (BW) were calculated. Patients with a failure load of 7.5 x BW or lower were identified as having high fracture risk, whereas patients with a failure load higher than 7.5 x BW were classified as low fracture risk. Experienced assessors measured axial cortical involvement on conventional radiographs. Following clinical guidelines, patients with lesions larger than 30 mm were identified as having a high fracture risk. FE predictions were compared to clinical assessments by means of diagnostic accuracy values (sensitivity, specificity and positive (PPV) and negative predictive values (NPV)).Results: Seven femurs (14%) fractured during follow-up. Median time to fracture was 8 weeks. FE models were better at assessing fracture risk in comparison to axial cortical involvement (sensitivity 100% vs. 86%, specificity 74% vs. 42%, PPV 39% vs. 19%, and NPV 100% vs. 95%, for the FE computer model vs. axial cortical involvement, respectively).Conclusions: Patient-specific FE computer models improve fracture risk assessments of femoral bone metastases in advanced cancer patients compared to clinical assessments based on axial cortical involvement, which is currently used in clinical guidelines. Show less
Information on the association of self-reported knee instability with clinical outcomes after Total Knee Arthroplasty (TKA) and 1 year follow-up is scarce. The aims were to determine (i) the course... Show moreInformation on the association of self-reported knee instability with clinical outcomes after Total Knee Arthroplasty (TKA) and 1 year follow-up is scarce. The aims were to determine (i) the course and prevalence of self-reported knee instability before and 1 year after TKA and (ii) the associations of preoperative, postoperative, and retained self-reported knee instability with pain, activity limitations, and quality of life (QoL) in patients with knee osteoarthritis. Patients undergoing primary TKA, selected from the Longitudinal Leiden Orthopaedics and Outcomes of OsteoArthritis Study, had their knee instability measured using a questionnaire. The Knee injury and Osteoarthritis Outcome Score pain, activity limitations, and QoL subscales were administered before and 1 year after surgery. Multivariable regression analyses were performed to examine associations between knee instability, pain, activity limitations, and QoL, adjusted for covariates (age, gender, comorbidities, and radiographic severity). Of the 908 included patients, 649 (71%) and 187 (21%) reported knee instability before and following TKA, respectively. Of the patients with preoperative knee instability, this perception was retained in 165 (25%) cases. Knee instability was preoperatively associated with pain (B -9.6; 95%CI: -12.4 to -6.7), activity limitations (B -7.5; 95%CI: -10.2 to -4.8), and QoL (B -4.7; 95%CI: -7.0 to -2.4) and postoperatively with pain (B -15.0; 95%CI: -18.5 to -11.6), activity limitations (B -15.1; 95%CI: -18.4 to -11.8), and QoL (B -18.7; 95%CI: -22.3 to -15.3). Retained knee instability was associated with postoperative pain (B -15.1; 95%CI: -18.9 to -11.2), activity limitations (B -14.1; 95%CI: -17.8 to -10.4), and QoL (B -18.0; 95%CI: -21.7 to -14.3). In conclusion, in clinical care, self-reported knee instability is retained postoperatively in 25% of the patients. Retained knee instability is associated with more pain, activity limitations, and poorer QoL postoperatively. (c) 2018 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:2671-2678, 2018 Show less
Leede, E.M. de; Leersum, N.J. van; Kroon, H.M.; Weel, V. van; Sijp, J.R.M. van der; Bonsing, B.A.; Kauwgomstudie Consortium 2018
Background: Postoperative ileus is a common complication of abdominal surgery, leading to patient discomfort, morbidity and prolonged postoperative length of hospital stay (LOS). Previous studies... Show moreBackground: Postoperative ileus is a common complication of abdominal surgery, leading to patient discomfort, morbidity and prolonged postoperative length of hospital stay (LOS). Previous studies suggested that chewing gum stimulates bowel function after abdominal surgery, but were underpowered to evaluate its effect on LOS and did not include enhanced recovery after surgery (ERAS)-based perioperative care. This study evaluated whether chewing gum after elective abdominal surgery reduces LOS and time to bowel recovery in the setting of ERAS-based perioperative care.Methods: A multicentre RCT was performed of patients over 18 years of age undergoing abdominal surgery in 12 hospitals. Standard postoperative care (control group) was compared with chewing gum three times a day for 30 min in addition to standard postoperative care. Randomization was computer-generated; allocation was concealed. The primary outcome was postoperative LOS. Secondary outcomes were time to bowel recovery and 30-day complications.Results: Between 2011 to 2015, 1000 patients were assigned to chewing gum and 1000 to the control arm. Median LOS did not differ: 7 days in both arms (P = 0.364). Neither was any difference found in time to flatus (24 h in control group versus 23 h with chewing gum; P = 0.873) or time to defaecation (60 versus 52 h respectively; P = 0.562). The rate of 30-day complications was not significantly different either.Conclusion: The addition of chewing gum to an ERAS postoperative care pathway after elective abdominal surgery does not reduce the LOS, time to bowel recovery or the rate of postoperative complications. Registration number: NTR2594 (Netherlands Trial Register). Show less
Beest, S. van; Kroon, F.P.B.; Damman, W.; Liu, R.; Kroon, H.M.; Kloppenburg, M. 2017
