Pre-Transplant Hyperparathyroidism and Graft or Patient Outcomes After Kidney Transplantation.

The impact of pre-transplant parathyroid hormone (PTH) levels on early or long-term kidney function after kidney transplantation is subject of debate. We assessed whether severe hyperparathyroidism is associated with delayed graft function (DGF), death-censored graft failure (DCGF), or all-cause mortality. In this single-center cohort study, we studied the relationship between PTH and other parameters related to bone and mineral metabolism, including serum alkaline phosphatase (ALP) at time of transplantation with the subsequent risk of DGF, DCGF and all-cause mortality using multivariable logistic and Cox regression analyses. In 1,576 kidney transplant recipients (51.6 ± 14.0 years, 57.3% male), severe hyperparathyroidism characterized by pre-transplant PTH ≥771 pg/mL (>9 times the upper limit) was present in 121 patients. During 5.2 [0.2-30.0] years follow-up, 278 (15.7%) patients developed DGF, 150 (9.9%) DCGF and 432 (28.6%) died. A higher pre-transplant PTH was not associated with DGF (HR 1.06 [0.90-1.25]), DCGF (HR 0.98 [0.87-1.13]), or all-cause mortality (HR 1.02 [0.93-1.11]). Results were consistent in sensitivity analyses. The same applied to other parameters related to bone and mineral metabolism, including ALP. Severe pre-transplant hyperparathyroidism was not associated with an increased risk of DGF, DCGF or all-cause mortality, not supporting the need of correction before kidney transplantation to improve graft or patient survival.

Empowering Tomorrow's Cancer Specialists: Evaluating the Co-creation and Impact of Malawi's First Surgical Oncology Summerschool.

Annually more than 1 million newly diagnosed cancer cases and 500,000 cancer-related deaths occur in Sub Saharan Africa (SSA). By 2030, the cancer burden in Africa is expected to double accompanied by low survival rates. Surgery remains the primary treatment for solid tumours especially where other treatment modalities are lacking. However, in SSA, surgical residents lack sufficient training in cancer treatment. In 2022, Malawian and Dutch specialists co-designed a training course focusing on oncologic diseases and potential treatment options tailored to the Malawian context. The aim of this study was to describe the co-creation process of a surgical oncology education activity in a low resource setting, at the same time attempting to evaluate the effectiveness of this training program. The course design was guided and evaluated conform Kirkpatrick's requirements for an effective training program. Pre-and post-course questionnaires were conducted to evaluate the effectiveness. Thirty-five surgical and gynaecological residents from Malawi participated in the course. Eighty-six percent of respondents (n = 24/28) were highly satisfied at the end of the course. After a 2-month follow-up, 84% (n = 16/19) frequently applied the newly acquired knowledge, and 74% (n = 14/19) reported to have changed their patient care. The course costs were approximately 119 EUR per attendee per day. This course generally received generally positively feedback, had high satisfaction rates, and enhanced knowledge and confidence in the surgical treatment of cancer. Its effectiveness should be further evaluated using the same co-creation model in different settings. Integrating oncology into the regular curriculum of surgical residents is recommended.

Immunogenicity phase II study evaluating booster capacity of nonadjuvanted AKS-452 SARS-Cov-2 RBD Fc vaccine.

AKS-452, a subunit vaccine comprising an Fc fusion of the ancestral wild-type (WT) SARS-CoV-2 virus spike protein receptor binding domain (SP/RBD), was evaluated without adjuvant in a single cohort, non-randomized, open-labelled phase II study (NCT05124483) at a single site in The Netherlands for safety and immunogenicity. A single 90 µg subcutaneous booster dose of AKS-452 was administered to 71 adults previously primed with a registered mRNA- or adenovirus-based vaccine and evaluated for 273 days. All AEs were mild and no SAEs were attributable to AKS-452. While all subjects showed pre-existing SP/RBD binding and ACE2-inhibitory IgG titers, 60-68% responded to AKS-452 via ≥2-fold increase from days 28 to 90 and progressively decreased back to baseline by day 180 (days 28 and 90 mean fold-increases, 14.7 ± 6.3 and 8.0 ± 2.2). Similar response kinetics against RBD mutant proteins (including omicrons) were observed but with slightly reduced titers relative to WT. There was an expected strong inverse correlation between day-0 titers and the fold-increase in titers at day 28. AKS-452 enhanced neutralization potency against live virus, consistent with IgG titers. Nucleocapsid protein (Np) titers suggested infection occurred in 66% (46 of 70) of subjects, in which only 20 reported mild symptomatic COVID-19. These favorable safety and immunogenicity profiles support booster evaluation in a planned phase III universal booster study of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Actual physical activity after major abdominal cancer surgery: Far from optimal.

BACKGROUND: Enhanced recovery after surgery protocols emphasize the importance of early postoperative mobilization. However, literature quantifying actual physical activity after major abdominal cancer surgery is scarce and inconclusive. MATERIAL AND METHODS: A single-center prospective cohort study was conducted at the University Medical Center Groningen from 2019 to 2021. Patients' postoperative physical activity was measured using an accelerometer, with the primary aim of assessing daily physical activity. Secondary aims were identifying patient-related factors associated with low physical activity and studying the consequences of low physical activity in terms of complication rate and length of hospital stay. RESULTS: 143 patients included (48 % male; mean age 65 years), 38.5 %, 24.5 %, 19.6 %, and 14 % underwent pancreatic, hepatic, colorectal, or cytoreductive surgery with hyperthermic intraperitoneal chemotherapy, respectively. Median daily step count was low; from median 71 steps on the first to 918 steps on the seventh postoperative day. An association between physical activity and age (OR 3.597, p = 0.013), preoperative weight loss ≥10 % (OR 4.984, p = 0.004), Eastern Cooperative Oncology Group performance status ≥2 (OR 4.016, p = 0.001), midline laparotomy (OR 2.851, p = 0.025), and operation duration (OR 1.003, p = 0.044) was found. An association was observed between physical activity and the occurrence of complications (OR 3.197, p = 0.039) and prolonged hospital stay (ß 4.068, p = 0.013). CONCLUSION: Postoperative physical activity is low in patients undergoing major abdominal cancer surgery and is linked to postoperative outcomes. Although physical activity should be encouraged in all patients, patient-specific risk factors were identified that can aid early recognition of patients at risk of low physical activity.

Head-to-head comparison of [11C]methionine PET, [11C]choline PET, and 4-dimensional CT as second-line scans for detection of parathyroid adenomas in primary hyperparathyroidism.

PURPOSE: Accurate preoperative localization is imperative to guide surgery in primary hyperparathyroidism (pHPT). It remains unclear which second-line imaging technique is most effective after negative first-line imaging. In this study, we compare the diagnostic effectiveness of [11C]methionine PET/CT, [11C]choline PET/CT, and four dimensional (4D)-CT head-to-head in patients with pHPT, to explore which of these imaging techniques to use as a second-line scan. METHODS: We conducted a powered, prospective, blinded cohort study in patients with biochemically proven pHPT and prior negative or discordant first-line imaging consisting of ultrasonography and 99mTc-sestamibi. All patients underwent [11C]methionine PET/CT, [11C]choline PET/CT, and 4D-CT. At first, all scans were interpreted by a nuclear medicine physician, and a radiologist who were blinded from patient data and all imaging results. Next, a non-blinded scan reading was performed. The scan results were correlated with surgical and histopathological findings. Serum calcium values at least 6 months after surgery were used as gold standard for curation of HPT. RESULTS: A total of 32 patients were included in the study. With blinded evaluation, [11C]choline PET/CT was positive in 28 patients (88%), [11C]methionine PET/CT in 23 (72%), and 4D-CT in 15 patients (47%), respectively. In total, 30 patients have undergone surgery and 32 parathyroid lesions were histologically confirmed as parathyroid adenomas. Based on the blinded evaluation, lesion-based sensitivity of [11C]choline PET/CT, [11C]methionine PET/CT, and 4D-CT was respectively 85%, 67%, and 39%. The sensitivity of [11C]choline PET/CT differed significantly from that of [11C]methionine PET/CT and 4D-CT (p = 0.031 and p < 0.0005, respectively). CONCLUSION: In the setting of pHPT with negative first-line imaging, [11C]choline PET/CT is superior to [11C]methionine PET/CT and 4D-CT in localizing parathyroid adenomas, allowing correct localization in 85% of adenomas. Further studies are needed to determine cost-benefit and efficacy of these scans, including the timing of these scans as first- or second-line imaging techniques.

MET-receptor targeted fluorescent imaging and spectroscopy to detect multifocal papillary thyroid cancer.

PURPOSE: Multifocal disease in PTC is associated with an increased recurrence rate. Multifocal disease (MD) is underdiagnosed with the current gold standard of pre-operative ultrasound staging. Here, we evaluate the use of EMI-137 targeted molecular fluorescence-guided imaging (MFGI) and spectroscopy as a tool for the intra-operative detection of uni- and multifocal papillary thyroid cancer (PTC) aiming to improve disease staging and treatment selection. METHODS: A phase-1 study (NCT03470259) with EMI-137 was conducted to evaluate the possibility of detecting PTC using MFGI and quantitative fiber-optic spectroscopy. RESULTS: Fourteen patients underwent hemi- or total thyroidectomy (TTX) after administration of 0.09 mg/kg (n = 1), 0.13 mg/kg (n = 8), or 0.18 mg/kg (n = 5) EMI-137. Both MFGI and spectroscopy could differentiate PTC from healthy thyroid tissue after administration of EMI-137, which binds selectively to MET in PTC. 0.13 mg/kg was the lowest dosage EMI-137 that allowed for differentiation between PTC and healthy thyroid tissue. The smallest PTC focus detected by MFGI was 1.4 mm. MFGI restaged 80% of patients from unifocal to multifocal PTC compared to ultrasound. CONCLUSION: EMI-137-guided MFGI and spectroscopy can be used to detect multifocal PTC. This may improve disease staging and treatment selection between hemi- and total thyroidectomy by better differentiation between unifocal and multifocal disease. TRIAL REGISTRATION: NCT03470259.

Bilaterality, not multifocality, is an independent risk factor for recurrence in low-risk papillary thyroid cancer.

BACKGROUND: The impact of multifocality and bilaterality on recurrence in patients with low-risk papillary thyroid cancer (PTC) is relevant when considering patients for a de-escalated treatment strategy: hemithyroidectomy instead of total thyroidectomy followed with or without radioactive iodine. This study aims to analyze contralateral tumor probability in patients treated for low-risk PTC and assess multifocality and bilaterality as possible predictors for recurrence. METHODS: Patients with low-risk PTC treated with total thyroidectomy followed with or without radioactive iodine in the Netherlands between 2005 and 2015 were included in this study. Patients were identified from the Netherlands Comprehensive Cancer Organization (IKNL) and linked with the nationwide network and registry of Pathology in the Netherlands (PALGA). Contralateral tumor probability and recurrence were assessed. RESULTS: Of 791 included patients, 41.8% (331 of 791) had multifocal disease, with 68.9% (228 of 331) of those patients having bilateral disease. The contralateral tumor probability after hemithyroidectomy was 24.6% (150 of 610) for patients with unifocal disease and 43.1% (78 of 181) for patients with multifocal disease. We found a higher trend of recurrence in patients with bilateral disease, regardless of multifocality: in patients with contralateral disease after precompletion diagnosed unifocal disease 7.3% (11 of 150) had recurrent disease, and patients without contralateral disease after precompletion diagnosed multifocal disease 1.9% (2 per 103) had recurrence. Cox regression analysis showed that bilaterality (hazard ratio = 3.621, 95% confidence interval = 1.548 to 8.471) was the sole statistically significant risk factor for recurrence. CONCLUSION: Low recurrence rates are found in patients with either multifocal or bilateral disease with low-risk PTC. Bilaterality should be taken into account when considering these patients for de-escalated treatment strategy.

Towards in vivo characterization of thyroid nodules suspicious for malignancy using multispectral optoacoustic tomography.

PURPOSE: Patient-tailored management of thyroid nodules requires improved risk of malignancy stratification by accurate preoperative nodule assessment, aiming to personalize decisions concerning diagnostics and treatment. Here, we perform an exploratory pilot study to identify possible patterns on multispectral optoacoustic tomography (MSOT) for thyroid malignancy stratification. For the first time, we directly correlate MSOT images with histopathology data on a detailed level. METHODS: We use recently enhanced data processing and image reconstruction methods for MSOT to provide next-level image quality by means of improved spatial resolution and spectral contrast. We examine optoacoustic features in thyroid nodules associated with vascular patterns and correlate these directly with reference histopathology. RESULTS: Our methods show the ability to resolve blood vessels with diameters of 250 µm at depths of up to 2 cm. The vessel diameters derived on MSOT showed an excellent correlation (R2-score of 0.9426) with the vessel diameters on histopathology. Subsequently, we identify features of malignancy observable in MSOT, such as intranodular microvascularity and extrathyroidal extension verified by histopathology. Despite these promising features in selected patients, we could not determine statistically relevant differences between benign and malignant thyroid nodules based on mean oxygen saturation in thyroid nodules. Thus, we illustrate general imaging artifacts of the whole field of optoacoustic imaging that reduce image fidelity and distort spectral contrast, which impedes quantification of chromophore presence based on mean concentrations. CONCLUSION: We recommend examining optoacoustic features in addition to chromophore quantification to rank malignancy risk. We present optoacoustic images of thyroid nodules with the highest spatial resolution and spectral contrast to date, directly correlated to histopathology, pushing the clinical translation of MSOT.

Surgery-Related Muscle Loss after Pancreatic Resection and Its Association with Postoperative Nutritional Intake.

To study the occurrence of surgery-related muscle loss (SRML) and its association with in-hospital nutritional intake, we conducted a prospective observational cohort study including patients who underwent pancreatic surgery because of (suspected) malignant diseases. Muscle diameter was measured by using bedside ultrasound 1 day prior to surgery and 7 days postoperatively. Clinically relevant SRML was defined as ≥10% muscle diameter loss in minimally one arm and leg muscle within 1 week after surgery. Protein and caloric intake was measured by nutritional diaries. The primary endpoint included the number of patients with SRML. Secondary endpoints included the association between SRML and postoperative nutritional intake. Of the 63 included patients (60.3% men; age 67.1 ± 10.2 years), a total of 24 patients (38.1%) showed SRML. No differences were observed in severe complication rate or length of hospital stay between patients with and without SRML. During the first postoperative week, patients with clinically relevant SRML experienced more days without any nutritional intake compared with the non-SRML group (1 [0-4] versus 0 [0-1] days, p = 0.007). Significantly lower nutritional intake was found in the SRML group at postoperative days 2, 3 and 5 (p < 0.05). Since this study shows that SRML occurred in 38.1% of the patients and most of the patients failed to reach internationally set nutritional goals, it is suggested that more awareness concerning direct postoperative nutritional intake is needed in our surgical community.

A randomized phase I/II safety and immunogenicity study of the Montanide-adjuvanted SARS-CoV-2 spike protein-RBD-Fc vaccine, AKS-452.

BACKGROUND: Previous interim data from a phase I study of AKS-452, a subunit vaccine comprising an Fc fusion of the respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein receptor binding domain (SP/RBD) emulsified in the water-in-oil adjuvant, Montanide™ ISA 720, suggested a good safety and immunogenicity profile in healthy adults. This phase I study was completed and two dosing regimens were further evaluated in this phase II study. METHODS: This phase II randomized, open-labelled, parallel group study was conducted at a single site in The Netherlands with 52 healthy adults (18 - 72 years) receiving AKS-452 subcutaneously at one 90 µg dose (cohort 1, 26 subjects) or two 45 µg doses 28 days apart (cohort 2, 26 subjects). Serum samples were collected at the first dose (day 0) and at days 28, 56, 90, and 180. Safety and immunogenicity endpoints were assessed, along with induction of IgG isotypes, cross-reactive immunity against viral variants, and IFN-γ T cell responses. RESULTS: All AEs were mild/moderate (grades 1 or 2), and no SAEs were attributable to AKS-452. Seroconversion rates reached 100% in both cohorts, although cohort 2 showed greater geometric mean IgG titers that were stable through day 180 and associated with enhanced potencies of SP/RBD-ACE2 binding inhibition and live virus neutralization. AKS-452-induced IgG titers strongly bound mutant SP/RBD from several SARS-CoV-2 variants (including Omicrons) that were predominantly of the favorable IgG1/3 isotype and IFN-γ-producing T cell phenotype. CONCLUSION: These favorable safety and immunogenicity profiles of the candidate vaccine as demonstrated in this phase II study are consistent with those of the phase I study (ClinicalTrials.gov: NCT04681092) and suggest that a total of 90 µg received in 2 doses may offer a greater duration of cross-reactive neutralizing titers than when given in a single dose.

International Center-Level Variation in Utilization of Completion Lymph Node Dissection and Adjuvant Systemic Therapy for Sentinel Lymph Node-Positive Melanoma at Major Referral Centers.

OBJECTIVE: The aim of this study was to determine overall trends and center-level variation in utilization of completion lymph node dissection (CLND) and adjuvant systemic therapy for sentinel lymph node (SLN)-positive melanoma. SUMMARY BACKGROUND DATA: Based on recent clinical trials, management options for SLN-positive melanoma now include effective adjuvant systemic therapy and nodal observation instead of CLND. It is unknown how these findings have shaped practice or how these contemporaneous developments have influenced their respective utilization. METHODS: We performed an international cohort study at 21 melanoma referral centers in Australia, Europe, and the United States that treated adults with SLN-positive melanoma and negative distant staging from July 2017 to June 2019. We used generalized linear and multinomial logistic regression models with random intercepts for each center to assess center-level variation in CLND and adjuvant systemic treatment, adjusting for patient and disease-specific characteristics. RESULTS: Among 1109 patients, performance of CLND decreased from 28% to 8% and adjuvant systemic therapy use increased from 29 to 60%. For both CLND and adjuvant systemic treatment, the most influential factors were nodal tumor size, stage, and location of treating center. There was notable variation among treating centers in management of stage IIIA patients and use of CLND with adjuvant systemic therapy versus nodal observation alone for similar risk patients. CONCLUSIONS: There has been an overall decline in CLND and simultaneous adoption of adjuvant systemic therapy for patients with SLN-positive melanoma though wide variation in practice remains. Accounting for differences in patient mix, location of care contributed significantly to the observed variation.

Postoperative muscle loss, protein intake, physical activity and outcome associations.

BACKGROUND: Skeletal muscle loss is often observed in intensive care patients. However, little is known about postoperative muscle loss, its associated risk factors, and its long-term consequences. The aim of this prospective observational study is to identify the incidence of and risk factors for surgery-related muscle loss (SRML) after major abdominal surgery, and to study the impact of SRML on fatigue and survival. METHODS: Patients undergoing major abdominal cancer surgery were included in the MUSCLE POWER STUDY. Muscle thickness was measured by ultrasound in three muscles bilaterally (biceps brachii, rectus femoris, and vastus intermedius). SRML was defined as a decline of 10 per cent or more in diameter in at least one arm and leg muscle within 1 week postoperatively. Postoperative physical activity and nutritional intake were assessed using motility devices and nutritional diaries. Fatigue was measured with questionnaires and 1-year survival was assessed with Cox regression analysis. RESULTS: A total of 173 patients (55 per cent male; mean (s.d.) age 64.3 (11.9) years) were included, 68 of whom patients (39 per cent) showed SRML. Preoperative weight loss and postoperative nutritional intake were statistically significantly associated with SRML in multivariable logistic regression analysis (P < 0.050). The combination of insufficient postoperative physical activity and nutritional intake had an odds ratio of 4.00 (95 per cent c.i. 1.03 to 15.47) of developing SRML (P = 0.045). No association with fatigue was observed. SRML was associated with decreased 1-year survival (hazard ratio 4.54, 95 per cent c.i. 1.42 to 14.58; P = 0.011). CONCLUSION: SRML occurred in 39 per cent of patients after major abdominal cancer surgery, and was associated with a decreased 1-year survival.

Deescalating Follow-up After Hemithyroidectomy for Patients With Low-risk Papillary Thyroid Microcarcinoma.

Importance: Structural recurrent disease (RD) after surgical treatment of papillary thyroid microcarcinoma (mPTC) is rare. We hypothesized that the RD rate after hemithyroidectomy in low-risk patients with mPTC is low. Objective: To assess the occurrence of RD in Dutch patients with mPTC who received surgical treatment according to the Dutch guidelines. Design, Setting, and Participants: This nationwide retrospective cohort study included all patients who had undergone surgery with a diagnosis of cN0/cNx mPTC in the Netherlands between January 2000 and December 2020 were identified from the Netherlands Cancer Registry database. Patients with preoperative lymph node metastases were excluded. Two groups were defined: group 1 (incidental), mPTC in pathology report after thyroid surgery for another indication; and group 2 (nonincidental), patients with a preoperative highly suspect thyroid nodule (Bethesda 5) or proven mPTC (Bethesda 6). Dutch guidelines state that a hemithyroidectomy is sufficient in patients with unifocal, intrathyroidal mPTC. Main Outcomes and Measures: The occurrence of RD in patients with low-risk mPTC after hemithyroidectomy. Results: In total, 1636 patients with mPTC were included. Patients had a median (IQR) follow-up time of 71 (32-118) months. Median (IQR) age at time of diagnosis was 51 (41-61) years and 1292 (79.0%) were women. Overall, RD after initial treatment was seen in 25 patients (1.5%). The median (IQR) time to RD was 8.2 (3.6-16.5) months and 22 of the 25 (88%) patients developed RD within 2 years. Recurrent disease was not significantly different between both groups (group 1, n = 15 [1.3%]; group 2, n = 10 [2.1%]; difference, 0.8%; 95% CI, -0.5% to 2.5%). Of the 484 patients with nonincidental mPTC (group 2), 246 (50.8%) patients were treated with a hemithyroidectomy and follow-up in accordance with Dutch guidelines. Lymph node metastases were found in 1 of 246 (0.4%) patients after hemithyreoidectomy, and new mPTC in the contralateral thyroid was detected in 3 of 246 (1.2%) patients. Median (IQR) follow-up of this patient group was 37 (18-71) months. The 10-year probability of RD was 1.3% for patients without vascular invasion and 24.4% for patients with vascular invasion. Conclusions and Relevance: This nationwide cohort study found that overall, RD after hemithyroidectomy for patients with low-risk mPTC was rare (<2%). Based on these results, it seems reasonable to deescalate follow-up of patients with low-risk mPTC without vascular invasion after hemithyroidectomy. From a health care perspective, deescalation of follow-up may contribute to increased sustainability and accessibility to health care, both large challenges for the future.

Feasibility of bevacizumab-IRDye800CW as a tracer for fluorescence-guided meningioma surgery.

OBJECTIVE: Meningiomas are frequently occurring, often benign intracranial tumors. Molecular fluorescence can be used to intraoperatively identify residual meningioma tissue and optimize safe resection; however, currently no clinically approved agent is available for this specific tumor type. In meningiomas, vascular endothelial growth factor α (VEGFα) is upregulated, and this biomarker could be targeted with bevacizumab-IRDye800CW, a fluorescent agent that is already clinically applied for the resection of other tumors and neoplasms. Here, the authors investigated the feasibility of using bevacizumab-IRDye800CW to target VEGFα in a CH-157MN xenografted mouse model. METHODS: Five mice with CH-157MN xenografts with volumes of 500 mm3 were administered intravenous bevacizumab-IRDye800CW. Mice were imaged in vivo at 24 hours, 48 hours, and 72 hours after injection with the FMT2500 fluorescence imaging system. Biodistribution was determined ex vivo using the Pearl fluorescent imager at 72 hours after injection. To mimic a clinical scenario, 2 animals underwent postmortem xenograft resection using both white-light and fluorescence guidance. Lastly, fresh and frozen human meningioma specimens were incubated ex vivo with bevacizumab-IRDye800CW, stained with anti-VEGFα, and microscopically examined. RESULTS: In vivo, tumors fluoresced at all time points after tracer administration and background fluorescence decreased with time. Ex vivo analyses of tracer biodistribution showed the highest fluorescence in resected tumor tissue. Brain, skull, and muscle tissue showed very low fluorescence. Microscopically, fluorescence was observed in the cytoplasm and was correlated with VEGFα expression patterns. During postmortem surgery, both the tumor bulk and a small tumor remnant were detected. Bevacizumab-IRDye800CW bound specifically to all tested human meningioma samples, as indicated by a high fluorescent signal in the tumor bulk compared with the surrounding healthy dura mater. CONCLUSIONS: Bevacizumab-IRDye800CW showed meningioma specificity, as illustrated by high VEGFα-mediated uptake in the meningioma xenograft mouse model. Small tumor lesions were detected using fluorescence guidance. Thus, the next step will be to assess the feasibility of using already available clinical grade bevacizumab-IRDye800CW to optimize meningioma resection in a human trial.

Thickness of Biceps and Quadriceps Femoris Muscle Measured Using Point-of-Care Ultrasound as a Representation of Total Skeletal Muscle Mass.

Generalized loss of muscle mass is associated with increased morbidity and mortality in patients with cancer. The gold standard to measure muscle mass is by using computed tomography (CT). However, the aim of this prospective observational cohort study was to determine whether point-of-care ultrasound (POCUS) could be an easy-to-use, bedside measurement alternative to evaluate muscle status. Patients scheduled for major abdominal cancer surgery with a recent preoperative CT scan available were included. POCUS was used to measure the muscle thickness of mm. biceps brachii, mm. recti femoris, and mm. vasti intermedius 1 day prior to surgery. The total skeletal muscle index (SMI) was derived from patients' abdominal CT scan at the third lumbar level. Muscle force of the upper and lower extremities was measured using a handheld dynamometer. A total of 165 patients were included (55% male; 65 ± 12 years). All POCUS measurements of muscle thickness had a statistically significant correlation with CT-derived SMI (r ≥ 0.48; p < 0.001). The strongest correlation between POCUS muscle measurements and SMI was observed when all POCUS muscle groups were added together (r = 0.73; p < 0.001). Muscle strength had a stronger correlation with POCUS-measured muscle thickness than with CT-derived SMI. To conclude, this study indicated a strong correlation between combined muscle thickness measurements performed by POCUS- and CT-derived SMI and measurements of muscle strength. These results suggest that handheld ultrasound is a valid tool for the assessment of skeletal muscle status.

Impact of cumulative complications on 1-year treatment-related healthcare costs in patients with colorectal peritoneal metastases undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy.

BACKGROUND: The aim of this study was to evaluate the impact of all minor and major complications on treatment-related healthcare costs in patients who undergo cytoreductive surgery (CRS) with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of colorectal peritoneal metastases (PMs). METHOD: Patients with histologically proven colorectal PMs who underwent CRS + HIPEC from March 2006 to October 2019 in a tertiary referral centre were retrospectively identified from a prospectively maintained database. Patients were divided into six subgroups according to the severity of the complications, which were scored using the comprehensive complication index (CCI) (CCI 0-9.9, CCI 10-19.9, CCI 20-29.9, CCI 30-39.9, CCI 40-49.9, and CCI 50 or higher). Treatment-related healthcare costs up to 1 year after CRS + HIPEC were obtained from the financial department. Differences in costs and survival outcomes were compared using the chi-squared test and Kruskal-Wallis H test. RESULTS: A total of 142 patients were included (CCI 0-9.9, 53 patients; CCI 10-19.9, 0 patients; CCI 20-29.9, 45 patients; CCI 30-39.9, 14 patients; CCI 40-49, 9 patients; and CCI 50 or higher, 21 patients). Median (interquartile range) treatment-related healthcare costs increased significantly and exponentially for the CCI 30-39, CCI 40-49, and CCI 50 or higher groups (€48 993 (€44 262-€84 805); €57 167 (€43 047-€67 591); and €82 219 (€55 487-€145 314) respectively) compared with those for the CCI 0-9.9 and CCI 20-29.9 groups (€33 856 (€24 433-€40 779) and €40 621 (€31 501-€58 761) respectively, P < 0.010). CONCLUSION: Treatment-related healthcare costs increase exponentially as more complications develop among patients who undergo CRS + HIPEC for the treatment of colorectal PMs. Anastomotic leakages after CRS + HIPEC lead to an increase of 295 per cent of treatment-related healthcare costs.

Patient-derived parathyroid organoids as a tracer and drug-screening application model.

Parathyroid diseases are characterized by dysregulation of calcium homeostasis and alterations in parathyroid hormone (PTH) excretion. The development of parathyroid-targeted treatment and imaging tracers could benefit from in vitro models. Therefore, we aim to establish a patient-derived parathyroid organoid model representing human parathyroid tissue. Hyperplastic parathyroid tissue was dispersed, and parathyroid organoids (PTOs) were cultured and characterized. PTO-derived cells exhibited self-renewal over several passages, indicative of the presence of putative stem cells. Immunofluorescence and RNA sequencing confirmed that PTOs phenocopy hyperplastic parathyroid tissue. Exposure of PTOs to increasing calcium concentrations and PTH-lowering drugs resulted in significantly reduced PTH excretion. PTOs showed specific binding of the imaging tracers 11C-methionine and 99mTc-sestamibi. These data show the functionality of PTOs resembling the parathyroid. This PTO model recapitulates the originating tissue on gene and protein expression and functionality, paving the way for future physiology studies and therapeutic target and tracer discovery.

Correction: Lebbink et al. Opposite Incidence Trends for Differentiated and Medullary Thyroid Cancer in Young Dutch Patients over a 30-Year Time Span. Cancers 2021, 13, 5104.

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Impact of parathyroidectomy on quality of life in multiple endocrine neoplasia type 1.

Background: Potential influences of parathyroidectomy (PTx) on the quality of life (QoL) in multiple endocrine neoplasia type 1-related primary hyperparathyroidism (HPT/MEN1) are unknown. Method: Short Form 36 Health Survey Questionnaire was prospectively applied to 30 HPT/MEN1 patients submitted to PTx (20, subtotal; 10, total with autograft) before, 6 and 12 months after surgery. Parameters that were analyzed included QoL, age, HPT-related symptoms, general pain, comorbidities, biochemical/hormonal response, PTx type and parathyroid volume. Results: Asymptomatic patients were younger (30 vs 38 years; P = 0.04) and presented higher QoL scores than symptomatic ones: Physical Component Summary score (PCS) 92.5 vs 61.2, P = 0.0051; Mental Component Summary score (MCS) 82.0 vs 56.0, P = 0.04. In both groups, QoL remained stable 1 year after PTx, independently of the number of comorbidities. Preoperative general pain was negatively correlated with PCS (r = -0.60, P = 0.0004) and MCS (r = -0.57, P = 0.0009). Also, moderate/intense pain was progressively (6/12 months) more frequent in cases developing hypoparathyroidism. The PTx type and hypoparathyroidism did not affect the QoL at 12 months although remnant parathyroid tissue volume did have a positive correlation (P = 0.0490; r = 0.3625) to PCS 12 months after surgery. Patients with one to two comorbidities had as pre-PTx PCS (P = 0.0015) as 12 months and post-PTx PCS (P = 0.0031) and MCS (P = 0.0365) better than patients with three to four comorbidities. Conclusion: A variable QoL profile was underscored in HPT/MEN1 reflecting multiple factors associated with this complex disorder as comorbidities, advanced age at PTx and presence of preoperative symptoms or of general pain perception. Our data encourage the early indication of PTx in HPT/MEN1 by providing known metabolic benefits to target organs and avoiding potential negative impact on QoL.

Intraoperative MET-receptor targeted fluorescent imaging and spectroscopy for lymph node detection in papillary thyroid cancer: novel diagnostic tools for more selective central lymph node compartment dissection.

PURPOSE: Patients undergoing prophylactic central compartment dissection (PCLND) for papillary thyroid cancer (PTC) are often overtreated. This study aimed to determine if molecular fluorescence-guided imaging (MFGI) and spectroscopy can be useful for detecting PTC nodal metastases (NM) and to identify negative central compartments intraoperatively. METHODS: We used a data-driven prioritization strategy based on transcriptomic profiles of 97 primary PTCs and 80 normal thyroid tissues (NTT) to identify tumor-specific antigens for a clinically available near-infrared fluorescent tracer. Protein expression of the top prioritized antigen was immunohistochemically validated with a tissue microarray containing primary PTC (n = 741) and NTT (n = 108). Staining intensity was correlated with 10-year locoregional recurrence-free survival (LRFS). A phase 1 study (NCT03470259) with EMI-137, targeting MET, was conducted to evaluate safety, optimal dosage for detecting PTC NM with MFGI, feasibility of NM detection with quantitative fiber-optic spectroscopy, and selective binding of EMI-137 for MET. RESULTS: MET was selected as the most promising antigen. A worse LRFS was observed in patients with positive versus negative MET staining (81.9% versus 93.2%; p = 0.02). In 19 patients, no adverse events related to EMI-137 occurred. 0.13 mg/kg EMI-137 was selected as optimal dosage for differentiating NM from normal lymph nodes using MFGI (p < 0.0001) and spectroscopy (p < 0.0001). MFGI identified 5/19 levels (26.3%) without NM. EMI-137 binds selectively to MET. CONCLUSION: MET is overexpressed in PTC and associated with increased locoregional recurrence rates. Perioperative administration of EMI-137 is safe and facilitates NM detection using MFGI and spectroscopy, potentially reducing the number of negative PCLNDs with more than 25%. CLINICAL TRIAL REGISTRATION: NCT03470259.