Calculating Tumor Volume Using Three-Dimensional Models in Preoperative Soft-Tissue Sarcoma Surgical Planning: Does Size Matter?

This feasibility study aims to explore the use of three-dimensional virtual surgical planning to preoperatively determine the need for reconstructive surgery following resection of an extremity soft-tissue sarcoma. As flap reconstruction is performed more often in advanced disease, we hypothesized that tumor volume would be larger in the group of patients that had undergone flap reconstruction. All patients that were treated by surgical resection for an extremity soft-tissue sarcoma between 1 January 2016 and 1 October 2019 in the University Medical Center Groningen were included retrospectively. Three-dimensional models were created using the diagnostic magnetic resonance scan. Tumor volume was calculated for all patients. Three-dimensional tumor volume was 107.8 (349.1) mL in the group of patients that had undergone primary closure and 29.4 (47.4) mL in the group of patients in which a flap reconstruction was performed, p = 0.004. Three-dimensional tumor volume was 76.1 (295.3) mL in the group of patients with a complication following ESTS treatment, versus 57.0 (132.4) mL in patients with an uncomplicated course following ESTS treatment, p = 0.311. Patients who had undergone flap reconstruction had smaller tumor volumes compared to those in the group of patients treated by primary closure. Furthermore, a larger tumor volume did not result in complications for patients undergoing ESTS treatment. Therefore, tumor volume does not seem to influence the need for reconstruction. Despite the capability of three-dimensional virtual surgical planning to measure tumor volume, we do not recommend its utilization in the multidisciplinary extremity soft-tissue sarcoma treatment, considering the findings of the study.

Three-Dimensional Evaluation of Isodose Radiation Volumes in Cases of Severe Mandibular Osteoradionecrosis for the Prediction of Recurrence after Segmental Resection.

BACKGROUND: Pre-operative margin planning for the segmental resection of affected bone in mandibular osteoradionecrosis (ORN) is difficult. The aim of this study was to identify a possible relation between the received RT dose, exposed bone volume and the progression of ORN after segmental mandibular resection. METHOD: Patients diagnosed with grade 3-4 ORN for which a segmental resection was performed were included in the study. Three-dimensional reconstructions of RT isodose volumes were fused with postoperative imaging. The primary outcome was the recurrence of ORN after segmental resection. Subsequently, RT exposed mandibular bone volumes were calculated and the location of the bone cuts relative to the isodose volumes were assessed. RESULTS: Five out of thirty-three patients developed recurrent ORN after segmental mandibular resection. All cases with recurrent ORN were resected inside an isodose volume of ≥56 Gy. The absolute mandibular volume radiated with 56 Gy was significantly smaller in the recurrent group (10.9 mL vs. 30.7 mL, p = 0.006), as was the proportion of the mandible radiated with 56 Gy (23% vs. 45%, p = 0.013). CONCLUSION: The volume of radiated bone was not predictive for risk of progression. The finding that recurrent ORN occurred with bone resection margins within the 56 Gy isodose volume suggests that this could serve as a starting point for the pre-operative planning of reducing the risk of ORN recurrence.

Three-Dimensional Guided Zygomatic Implant Placement after Maxillectomy.

Zygomatic implants are used in patients with maxillary defects to improve the retention and stability of obturator prostheses, thereby securing good oral function. Prosthetic-driven placement of zygomatic implants is even difficult for experienced surgeons, and with a free-hand approach, deviation from the preplanned implant positions is inevitable, thereby impeding immediate implant-retained obturation. A novel, digitalized workflow of surgical planning was used in 10 patients. Maxillectomy was performed with 3D-printed cutting, and drill guides were used for subsequent placement of zygomatic implants with immediate placement of implant-retained obturator prosthesis. The outcome parameters were the accuracy of implant positioning and the prosthetic fit of the obturator prosthesis in this one-stage procedure. Zygomatic implants (n = 28) were placed with good accuracy (mean deviation 1.73 ± 0.57 mm and 2.97 ± 1.38° 3D angle deviation), and in all cases, the obturator prosthesis fitted as pre-operatively planned. The 3D accuracy of the abutment positions was 1.58 ± 1.66 mm. The accuracy of the abutment position in the occlusal plane was 2.21 ± 1.33 mm, with a height accuracy of 1.32 ± 1.57 mm. This feasibility study shows that the application of these novel designed 3D-printed surgical guides results in predictable zygomatic implant placement and provides the possibility of immediate prosthetic rehabilitation in head and neck oncology patients after maxillectomy.

Additional burden of iron deficiency in heart failure patients beyond the cardio-renal anaemia syndrome: findings from the BIOSTAT-CHF study.

AIMS: Whereas the combination of anaemia and chronic kidney disease (CKD) has been extensively studied in patients with heart failure (HF), the contribution of iron deficiency (ID) to this dysfunctional interplay is unknown. We aimed to assess clinical associates and pathophysiological pathways related to ID in this multimorbid syndrome. METHODS AND RESULTS: We studied 2151 patients with HF from the BIOSTAT-CHF cohort. Patients were stratified based on ID (transferrin saturation <20%), anaemia (World Health Organization definition) and/or CKD (estimated glomerular filtration rate <60 ml/min/1.73 m2 ). Patients were mainly men (73.3%), with a median age of 70.5 (interquartile range 61.4-78.1). ID was more prevalent than CKD and anaemia (63.3%, 47.2% and 35.6% respectively), with highest prevalence in those with concomitant CKD and anaemia (77.5% vs. 59.3%; p < 0.001). There was a considerable overlap in biomarkers and pathways between patients with isolated ID, anaemia or CKD, or in combination, with processes related to immunity, inflammation, cell survival and cancer amongst the common pathways. Key biomarkers shared between syndromes with ID included transferrin receptor, interleukin-6, fibroblast growth factor-23, and bone morphogenetic protein 6. Having ID, either alone or on top of anaemia and/or CKD, was associated with a lower overall summary Kansas City Cardiomyopathy Questionnaire score, an impaired 6-min walk test and increased incidence of hospitalizations and/or mortality in multivariable analyses (all p < 0.05). CONCLUSION: Iron deficiency, CKD and/or anaemia in patients with HF have great overlap in biomarker profiles, suggesting common pathways associated with these syndromes. ID either alone or on top of CKD and anaemia is associated with worse quality of life, exercise capacity and prognosis of patients with worsening HF.

Three-dimensional virtual surgical planning in the oncologic treatment of the mandible.

OBJECTIVES: In case of surgical removal of oral squamous cell carcinomas, a resection of mandibular bone is frequently part of the treatment. Nowadays, such resections frequently include the application of 3D virtual surgical planning (VSP) and guided surgery techniques. In this paper, current methods for 3D VSP leads for optimisation of the workflow, and patient-specific application of guides and implants are reviewed. RECENT FINDINGS: Current methods for 3D VSP enable multi-modality fusion of images. This fusion of images is not restricted to a specific software package or workflow. New strategies for 3D VSP in Oral and Maxillofacial Surgery include finite element analysis, deep learning and advanced augmented reality techniques. These strategies aim to improve the treatment in terms of accuracy, predictability and safety. CONCLUSIONS: Application of the discussed novel technologies and strategies will improve the accuracy and safety of mandibular resection and reconstruction planning. Accurate, easy-to-use, safe and efficient three-dimensional VSP can be applied for every patient with malignancies needing resection of the mandible.

Patient-specific finite element models of the human mandible: Lack of consensus on current set-ups.

The use of finite element analysis (FEA) has increased rapidly over the last decennia and has become a popular tool to design implants, osteosynthesis plates and prostheses. With increasing computer capacity and the availability of software applications, it has become easier to employ the FEA. However, there seems to be no consensus on the input variables that should be applied to representative FEA models of the human mandible. This review aims to find a consensus on how to define the representative input factors for a FEA model of the human mandible. A literature search carried out in the PubMed and Embase database resulted in 137 matches. Seven papers were included in this current study. Within the search results, only a few FEA models had been validated. The material properties and FEA approaches varied considerably, and the available validations are not strong enough for a general consensus. Further validations are required, preferably using the same measuring workflow to obtain insight into the broad array of mandibular variations. A lot of work is still required to establish validated FEA settings and to prevent assumptions when it comes to FEA applications.

The use of 3D virtual surgical planning and computer aided design in reconstruction of maxillary surgical defects.

PURPOSE OF REVIEW: The present review describes the latest development of 3D virtual surgical planning (VSP) and computer aided design (CAD) for reconstruction of maxillary defects with an aim of fully prosthetic rehabilitation. The purpose is to give an overview of different methods that use CAD in maxillary reconstruction in patients with head and neck cancer. RECENT FINDINGS: 3D VSP enables preoperative planning of resection margins and osteotomies. The current 3D VSP workflow is expanded with multimodal imaging, merging decision supportive information. Development of more personalized implants is possible using CAD, individualized virtual muscle modelling and topology optimization. Meanwhile the translation of the 3D VSP towards surgery is improved by techniques like intraoperative imaging and augmented reality. Recent improvements of preoperative 3D VSP enables surgical reconstruction and/or prosthetic rehabilitation of the surgical defect in one combined procedure. SUMMARY: With the use of 3D VSP and CAD, ablation surgery, reconstructive surgery, and prosthetic rehabilitation can be planned preoperatively. Many reconstruction possibilities exist and a choice depends on patient characteristics, tumour location and experience of the surgeon. The overall objective in patients with maxillary defects is to follow a prosthetic-driven reconstruction with the aim to restore facial form, oral function, and do so in accordance with the individual needs of the patient.

The influence of atrial fibrillation on the levels of NT-proBNP versus GDF-15 in patients with heart failure.

BACKGROUND: In heart failure (HF), levels of NT-proBNP are influenced by the presence of concomitant atrial fibrillation (AF), making it difficult to distinguish between HF versus AF in patients with raised NT-proBNP. It is unknown whether levels of GDF-15 are also influenced by AF in patients with HF. In this study we compared the plasma levels of NT-proBNP versus GDF-15 in patients with HF in AF versus sinus rhythm (SR). METHODS: In a post hoc analysis of the index cohort of BIOSTAT-CHF (n = 2516), we studied patients with HF categorized into three groups: (1) AF at baseline (n = 733), (2) SR at baseline with a history of AF (n = 183), and (3) SR at baseline and no history of AF (n = 1025). The findings were validated in the validation cohort of BIOSTAT-CHF (n = 1738). RESULTS: Plasma NT-proBNP levels of patients who had AF at baseline were higher than those of patients in SR (both with and without a history of AF), even after multivariable adjustment (3417 [25th-75th percentile 1897-6486] versus 1788 [682-3870], adjusted p < 0.001, versus 2231 pg/mL [902-5270], adjusted p < 0.001). In contrast, after adjusting for clinical confounders, the levels of GDF-15 were comparable between the three groups (3179 [2062-5253] versus 2545 [1686-4337], adjusted p = 0.36, versus 2294 [1471-3855] pg/mL, adjusted p = 0.08). Similar patterns of both NT-proBNP and GDF-15 were found in the validation cohort. CONCLUSION: These data show that in patients with HF, NT-proBNP is significantly influenced by underlying AF at time of measurement and not by previous episodes of AF, whereas the levels of GDF-15 are not influenced by the presence of AF. Therefore, GDF-15 might have additive value combined with NT-proBNP in the assessment of patients with HF and concomitant AF.

Iron deficiency in worsening heart failure is associated with reduced estimated protein intake, fluid retention, inflammation, and antiplatelet use.

AIMS: Iron deficiency (ID) is common in heart failure (HF) patients and negatively impacts symptoms and prognosis. The aetiology of ID in HF is largely unknown. We studied determinants and the biomarker profile of ID in a large international HF cohort. METHODS AND RESULTS: We studied 2357 worsening HF patients from the BIOSTAT-CHF cohort. ID was defined as transferrin saturation <20%. Univariable and multivariable logistic regression models were constructed to identify determinants for ID. We measured 92 cardiovascular markers (Olink Cardiovascular III) to establish a biomarker profile of ID. The primary endpoint was the composite of all-cause mortality and first HF rehospitalization. Mean age (±standard deviation) of all patients was 69 ± 12.0 years, 26.1% were female and median N-terminal pro B-type natriuretic peptide levels (+interquartile range) were 4305 (2360-8329) ng/L. Iron deficiency was present in 1453 patients (61.6%), with highest prevalence in females (71.1% vs. 58.3%; P < 0.001). Independent determinants of ID were female sex, lower estimated protein intake, higher heart rate, presence of peripheral oedema and orthopnoea, chronic kidney disease, lower haemoglobin, higher C-reactive protein levels, lower serum albumin levels, and P2Y12 inhibitor use (all P < 0.05). None of these determinants were sex-specific. The biomarker profile of ID largely consisted of pro-inflammatory markers, including paraoxonase 3 (PON3) and tartrate-resistant acid phosphatase type 5. In multivariable Cox proportional hazard regression analyses, ID was associated to worse outcome, independently of predictors of ID (hazard ratio 1.25, 95% confidence interval 1.06-1.46; P = 0.007). CONCLUSION: Our data suggest that the aetiology of ID in worsening HF is complex, multifactorial and seems to consist of a combination of reduced iron uptake (malnutrition, fluid overload), impaired iron storage (inflammation, chronic kidney disease), and iron loss (antiplatelets).

Automatic segmentation of the mandible from computed tomography scans for 3D virtual surgical planning using the convolutional neural network.

Segmentation of mandibular bone in CT scans is crucial for 3D virtual surgical planning of craniofacial tumor resection and free flap reconstruction of the resection defect, in order to obtain a detailed surface representation of the bones. A major drawback of most existing mandibular segmentation methods is that they require a large amount of expert knowledge for manual or partially automatic segmentation. In fact, due to the lack of experienced doctors and experts, high quality expert knowledge is hard to achieve in practice. Furthermore, segmentation of mandibles in CT scans is influenced seriously by metal artifacts and large variations in their shape and size among individuals. In order to address these challenges we propose an automatic mandible segmentation approach in CT scans, which considers the continuum of anatomical structures through different planes. The approach adopts the architecture of the U-Net and then combines the resulting 2D segmentations from three orthogonal planes into a 3D segmentation. We implement such a segmentation approach on two head and neck datasets and then evaluate the performance. Experimental results show that our proposed approach for mandible segmentation in CT scans exhibits high accuracy.

Differences in Clinical Profile and Outcomes of Low Iron Storage vs Defective Iron Utilization in Patients With Heart Failure: Results From the DEFINE-HF and BIOSTAT-CHF Studies.

Importance: Iron deficiency is present in half of patients with heart failure (HF) and is associated with increased morbidity and an impaired prognosis. Iron deficiency due to low iron storage (LIS) and defective iron utilization (DIU) are not entirely the same clinical problem, although they generally receive the same treatment. Objective: To define and describe similarities and differences between LIS and DIU in patients with HF. Design, Setting, and Participants: This analysis included data from 2 prospective observational studies: the Definition of Iron Deficiency in Chronic Heart Failure (DEFINE-HF) study, a single-center study conducted from 2013 to 2015 including 42 patients with a reduced left ventricular ejection fraction of 45% or less scheduled for coronary artery bypass graft surgery, and the A Systems Biology Study to Tailored Treatment in Chronic Heart Failure (BIOSTAT-CHF) study, a multinational study conducted from 2010 to 2014 including 2357 patients with worsening HF from 69 centers in 11 countries. The median (interquartile range) follow-up time was 1.8 (1.3-2.3) years. Data were analyzed from January 2018 to January 2019. Main Outcomes and Measures: The DEFINE-HF cohort was set up to derive a definition for different etiologies of iron deficiency using bone marrow iron staining as the criterion standard. This definition was applied to the BIOSTAT-CHF cohort to assess its association with clinical profile, biomarkers, and the primary composite end point of all-cause mortality or HF hospitalizations. Results: Among the 42 patients in the DEFINE-HF study, 10 (24%) were women, and the mean (SD) age was 68.0 (9.5) years. Low iron storage was defined as a bone marrow-validated combination of transferrin saturation less than 20% and a serum ferritin concentration of 128 ng/mL or less; DIU was defined as transferrin saturation less than 20% and a serum ferritin concentration greater than 128 ng/mL. These criteria were applied to 2356 patients with worsening HF in the BIOSTAT-CHF study; 1074 (45.6%) were women, and the mean (SD) age was 68.9 (12.0) years. A total of 1453 patients with worsening HF (61.6%) had iron deficiency, of whom 960 (66.1%) had LIS and 493 (33.9%) had DIU. Low iron storage was characterized by a higher proportion of anemia and a poorer quality of life, while DIU was characterized by higher levels of various inflammatory markers. Both LIS and DIU were associated with an impaired 6-minute walking test. Low iron storage was independently associated with the composite end point of all-cause mortality or HF hospitalizations (hazard ratio, 1.47; 95% CI, 1.26-1.71; P < .001), while DIU was not (hazard ratio, 1.05; 95% CI, 0.87-1.26; P = .64). Conclusions and Relevance: In this study, both LIS and DIU were prevalent in patients with HF and had a distinct clinical profile. Only LIS was independently associated with increased rates of morality and HF hospitalizations, while DIU was not.

Definition of Iron Deficiency Based on the Gold Standard of Bone Marrow Iron Staining in Heart Failure Patients.

BACKGROUND: The most commonly used definition of iron deficiency (ID; ferritin <100 ng/mL or ferritin 100-300 ng/mL and transferrin saturation [TSAT] <20%) has not been validated in patients with heart failure (HF). We aimed to define and validate the biomarker-based definition of ID in HF, using bone marrow iron staining as the gold standard. Second, we aimed to assess the prognostic value of the optimized definition. METHODS AND RESULTS: Bone marrow aspiration with iron staining was performed in 42 patients with HF and a reduced left ventricular ejection fraction (≤45%) undergoing median sternotomy for coronary artery bypass grafting. Patients were mostly male (76%) with mild-to-moderate HF and a mean age of 68±10 years. Bone marrow ID was found in 17 (40%) of the HF patients. The most commonly used definition of ID had a sensitivity of 82% and a specificity of 72%. A definition solely based on TSAT ≤19.8% or serum iron ≤13 µmol/L had a sensitivity of 94% and specificity of 84% and 88%, respectively (P<0.05 compared with the former definition). Subsequently, we assessed the incidence of all-cause mortality in 387 consecutive outpatient HF patients (left ventricular ejection fraction ≤45%). In these patients, TSAT ≤19.8% and serum iron ≤13 µmol/L, and not ferritin, were independently associated with mortality. CONCLUSIONS: A TSAT ≤19.8% or a serum iron ≤13 µmol/L shows the best performance in selecting patients with ID and identifies HF patients at the highest risk of death. Our findings validate the currently used TSAT cutoff of <20% for the identification of ID in HF patients, but question the diagnostic value of ferritin.

Potassium and the use of renin-angiotensin-aldosterone system inhibitors in heart failure with reduced ejection fraction: data from BIOSTAT-CHF.

BACKGROUND: Hyperkalaemia is a common co-morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Whether it affects the use of renin-angiotensin-aldosterone system inhibitors and thereby negatively impacts outcome is unknown. Therefore, we investigated the association between potassium and uptitration of angiotensin-converting enzyme inhibitors (ACEi)/angiotensin receptor blockers (ARB) and its association with outcome. METHODS AND RESULTS: Out of 2516 patients from the BIOSTAT-CHF study, potassium levels were available in 1666 patients with HFrEF. These patients were sub-optimally treated with ACEi/ARB or beta-blockers and were anticipated and encouraged to be uptitrated. Potassium levels were available at inclusion and at 9 months. Outcome was a composite of all-cause mortality and heart failure hospitalization at 2 years. Patients' mean age was 67 ± 12 years and 77% were male. At baseline, median serum potassium was 4.3 (interquartile range 3.9-4.6) mEq/L. After 9 months, 401 (24.1%) patients were successfully uptitrated with ACEi/ARB. During this period, mean serum potassium increased by 0.16 ± 0.66 mEq/L (P < 0.001). Baseline potassium was an independent predictor of lower ACEi/ARB dosage achieved [odds ratio 0.70; 95% confidence interval (CI) 0.51-0.98]. An increase in potassium was not associated with adverse outcomes (hazard ratio 1.15; 95% CI 0.86-1.53). No interaction on outcome was found between baseline potassium, potassium increase during uptitration, or potassium at 9 months and increased dosage of ACEi/ARB (Pinteraction > 0.5 for all). CONCLUSION: Higher potassium levels are an independent predictor of enduring lower dosages of ACEi/ARB. Higher potassium levels do not attenuate the beneficial effects of ACEi/ARB uptitration.

Comorbidities in Heart Failure.

Comorbidities frequently accompany chronic heart failure (HF), contributing to increased morbidity and mortality, and an impaired quality of life. We describe the prevalence of several high-impact comorbidities in chronic HF patients and their impact on morbidity and mortality. Furthermore, we try to explain the underlying pathophysiological processes and the complex interaction between chronic HF and specific comorbidities. Although common risk factors are likely to contribute, it is reasonable to believe that factors associated with HF might cause other comorbidities and vice versa. Potential factors are inflammation, neurohormonal activation, and hemodynamic changes.

Dynamics of cerebral blood flow in patients with mild non-ischaemic heart failure.

AIMS: Heart failure (HF) is associated with tissue hypoperfusion and congestion leading to organ dysfunction. Although cerebral blood flow (CBF) is preserved over a wide range of perfusion pressures in healthy subjects, it is impaired in end-stage HF. We aimed to compare CBF, autoregulation, and cognitive function in patients with mild non-ischaemic HF with healthy controls. METHODS AND RESULTS: Fifteen patients with mild idiopathic dilated cardiomyopathy and 15 matched healthy controls were studied. Co-existing cerebrovascular disease was excluded. All subjects, except five patients with an implantable cardioverter defibrillator, underwent magnetic resonance imaging for measurements of both CBF by arterial spin labelling and quantitative volume flow entering the brain. Cardiocerebral vascular function was assessed with Doppler techniques testing cerebral dynamic autoregulation and vasomotor reactivity. Cognitive analysis was performed by neuropsychological testing. Global and regional CBF did not differ between HF patients (44.3 mL/100 g.min) and controls (42.1 mL/100 g.min). Basilar but not carotid artery inflow was reduced in patients (1.95 mL/s vs. 2.51 mL/s, P = 0.009). Testing autoregulation revealed fewer dampened blood flow fluctuations in HF patients vs. controls (0.96% vs. 0.67%, P < 0.001). Vasomotor reactivity in HF patients showed a reduced CBF velocity (48.4% vs. 61.0%, P = 0.05) and regional cerebral oxygen saturation (18.3% vs. 23.8%, P = 0.02). Cognitive function overall was not affected. CONCLUSION: Although global CBF was unaffected in patients with mild HF, significant changes in basilar inflow volume, cerebral autoregulation and vasomotor reactivity were observed. We describe a model of dynamic cerebral mechanisms required to compensate for the impaired haemodynamics in early-stage HF.

Pharmacotherapy for comorbidities in chronic heart failure: a focus on hematinic deficiencies, diabetes mellitus and hyperkalemia.

INTRODUCTION: Chronic heart failure (HF) is frequently accompanied by one or more comorbidities. The presence of comorbidities in chronic HF is strongly correlated to HF severity and impaired outcome. AREAS COVERED: This review will address several comorbidities with high prevalence and/or high impact in patients with chronic HF, including diabetes, anemia, hematinic deficiencies, and hyperkalemia. The background and subsequent pharmacotherapeutic options of these comorbidities will be discussed. For this review, a MEDLINE search was performed. EXPERT OPINION: Heart failure is increasingly considered a multimorbid syndrome, including metabolic derangements and chronic inflammation. Persistent metabolic derangements and low-grade inflammation might lead to progression of HF and the development of comorbidities. Although several comorbidity-specific drugs became available in the past decade, most of these therapies are studied in relatively small cohorts using surrogate end-points. Therefore, larger studies are needed to address whether treating these comorbidities will improve patient outcome in chronic HF.