Genetics-guided therapy in neuroendocrine carcinoma: response to BRAF- and MEK-inhibitors.

Background: Metastatic neuroendocrine carcinoma (NEC) is associated with short survival. Other than platinum-based chemotherapy, there is no clear standard regimen. Current guidelines suggest that combination treatment with BRAF-inhibitors should be considered for patients with BRAF V600E-mutated NEC. However, since only eight such patients have been reported in the literature, our object was to confirm the validity of this recommendation. Methods: This was a single-center retrospective cohort study conducted at Uppsala University Hospital. The included patients 1) had a histopathologically confirmed diagnosis of NEC, 2) were diagnosed between January 1st, 2018 and December 31st, 2023, 3) had tumor tissue genetically screened by a broad next-generation sequencing (NGS) panel, and 4) showed a tumor mutation for which there is a currently available targeted therapy. Results: We screened 48 patients diagnosed with NEC between January 1st, 2018 and December 31st, 2023. Twelve had been analyzed with a broad NGS-panel, and two had a targetable mutation. Both these patients harbored a BRAF V600E-mutated colon-NEC and were treated with BRAF- and MEK-inhibitors dabrafenib and trametinib in second-line. At first radiological evaluation (RECIST 1.1), both patients had a reduction of tumor size, which decreased by 31 and 40%. Both had short response periods, and their overall survival was 12 and 9 months. Conclusions: BRAF-mutated NEC is sensitive to treatment with BRAF- and MEK-inhibitor combination. These results further support that DNA sequencing should be considered as standard of care in NECs to screen for potential treatment targets.

[Treatment of Graves' disease is moving towards precision medicine]. / Behandling av Graves sjukdom.

This is the first national guideline in hyperthyroidism to harmonise and update clinical practice according to what is evidence based and direct care from patients' needs. We present 4 articles in Läkartidningen of different views of the guideline, including family care perspectives, patient care perspectives and perspectives on ophthalmology. This article concerns treatment of Graves' disease and includes endocrinological, surgical and oncological perspectives on what is established practice, but also news in the national guideline that remain to be fully implemented in Sweden in the years to come. News are precision medicine using the GREAT score, preoperative calcium/D vitamin treatment, individualized levothyroxine treatment after thyroid surgery, uniformed levothyroxine replacement strategy, access to national patient information and national guidelines on radiation protection and treatment schemes for radioactive iodine. A national guideline is the creation of many persons' views, including patient representatives, and the recommendations have undergone a thorough national review process from stakeholders. It is a guideline with future perspectives for an improved care.

Prevalence of metastases outside the liver and abdominal lymph nodes on 68Ga-DOTATOC-PET/CT in patients with small intestinal and pancreatic neuroendocrine tumours.

Metastases outside the liver and abdominal/retroperitoneal lymph nodes are nowadays detected frequently in patients with neuroendocrine tumours (NETs), owing to the high sensitivity of positron emission tomography (PET) with Gallium-68-DOTA-somatostatin analogues (68Ga-SSA) and concomitant diagnostic computed tomography (CT). Our aim was to determine the prevalence of extra-abdominal metastases on 68Ga-DOTATOC-PET/CT in a cohort of patients with small intestinal (Si-NET) and pancreatic NET (Pan-NET), as well as that of pancreatic metastasis in patients with Si-NET. Among 2090 patients examined by 68Ga-DOTATOC-PET/CT at two tertiary referral centres, a total of 1177 patients with a history of Si- or Pan-NET, were identified. The most recent 68Ga-DOTATOC-PET/CT report for each patient was reviewed, and the location and number of metastases of interest were recorded. Lesions outside the liver and abdominal nodes were found in 26% of patients (n = 310/1177), of whom 21.5% (255/1177) were diagnosed with Si-NET and 4.5% (55/1177) Pan-NET. Bone metastases were found in 18.4% (215/1177), metastases to Virchow's lymph node in 7.1% (83/1177), and lung/pleura in 4.8% (56/1177). In the subset of 255 Si-NET patients, 5.4% (41/255) manifested lesions in the pancreas, 1.5% in the breast (18/255), 1.3% in the heart (15/255) and 1% in the orbita (12/255). In Si-NET patients, the Ki-67 proliferation index was higher in those with ≥2 metastatic sites of interest, than with 1 metastatic site, (p <0.001). Overall, extra-abdominal or pancreatic metastases were more often found in patients with Si-NET (34%) than in those with Pan-NET (13%) (p <0.001). Bone metastases were 2.6 times more frequent in patients with Si-NET compared to Pan-NET patients (p <0.001). Lesions to the breast and orbita were encountered in almost only Si-NET patients. In conclusion, lesions outside the liver and abdominal nodes were detected in as many as 26% of the patients, with different prevalence and metastatic patterns in patients with Si-NET compared to Pan-NET. The impact of such metastases on overall survival and clinical decision-making needs further evaluation.

Modified Histopathological Grading Optimizes Prediction of Survival Outcomes in Small Intestinal Neuroendocrine Tumours.

CONTEXT: One of the major prognostic indices in neuroendocrine tumours (NETs) is Ki67 proliferation index. OBJECTIVE: To identify optimal grading Ki-67 cut-offs to delineate differences in prognosis of patients with small intestinal NETs (SI-NETs). DESIGN, SETTING, PARTICIPANTS: Multicentre retrospective cohort analysis of 551 SI-NET patients diagnosed from 1993 through 2021 at five European referral centres with a mean(±SD) follow-up time of 51.5(±52.9) months. MAIN OUTCOME MEASURES: Overall- and event-free survival (OS and EFS) rates. RESULTS: Median age at baseline was 62.3(range:17-90) years; 252(45.7%) patients were female. All SI-NETs were well-differentiated with 326 being grade 1(G1; 59.2%), 169G2(30.7%), and only 8G3(1.5), while 48 tumours were of unspecified grade (8.7%). The median Ki67 was 2%(range:1-70%). Two-hundred forty-seven patients (44.8%) had distant metastases at baseline (stage IV), 217 locoregional disease (41.1%; stage III), whereas 29(7.1%) and 25(4.5%) presented at stages II and I, respectively. The median OS was 214.7(95%CI:152.7-276.6) months and the median EFS was 79.8(95%CI:68.2-91.5) months, respectively. In multivariable Cox-regression OS analysis, the proposed modified histopathological Ki67 grading system (K67:5-10% group: HR=2.2, 95%CI:1.15-4.31; p=0.018 and K67≥10% group: HR=5.11, 95%CI:2.87-9.09; p<0.001), age (HR=1.07, 95%CI:1.04-1.09; p<0.001), Charlson Comorbidity Index (HR=1.08, 95%CI:1-1.16; p=0.028) and TNM stage (HR=1.79, 95%CI:1.05-3.06; p=0.034) were independent predictors for death. Pertinent EFS analysis, confirmed the proposed modified histopathological Ki67 grading system (K67≥10% group: HR=4.01, 95%CI:2.6-6.37; p<0.001) and age (HR=1.04, 95%CI:1.02-1.05; p<0.001) as independent predictors for recurrence, progression and/or death. CONCLUSIONS: Ki-67 proliferation index was a strong and independent predictor of OS and EFS. A modified histopathological grading system applying Ki-67 cut-offs of 5 and 10% could be superior to predict differences in SI-NET patient survival outcomes.

Impact of fine-needle aspiration cytology in thyroidectomy extent and associated surgical morbidity in thyroid cancer.

PURPOSE: To assess the impact of fine-needle aspiration cytology (FNAC) in the extent of surgery in patients with thyroid cancer (TC) and the associated surgical morbidity in primary and completion setting. METHODS: A Swedish nationwide cohort of patients having surgery for TC (n = 2519) from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal surgery between 2004 and 2013 was obtained. Data was validated through scrutinizing FNAC and histology reports. RESULTS: Among the 2519 cases operated for TC, the diagnosis was substantiated and validated through the histology report in 2332 cases (92.6%). Among these, 1679 patients (72%) were female, and the median age at TC diagnosis was 52.3 years (range 18-94.6). Less than total thyroidectomy (LTT) was undertaken in 944 whereas total thyroidectomy (TT) in 1388 cases. The intermediate FNAC categories of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/ FLUS), as well as suspicion for follicular neoplasm (SFN) lesions were more often encountered in LTT (n = 314, 33.3%) than TT (n = 63, 4.6%), whereas FNACs suspicion for malignancy and/or malignancy were overrepresented in TT (n = 963, 69.4%). Completion thyroidectomies were undertaken in 553 patients out of 944 that initially had LTT. In 201 cases with cancer lesions > 1 cm, other than FTC (Follicular TC)/ HTC (Hürthle cell TC) subjected to primary LTT, inadequate procedures were undertaken in 81 due to absent, Bethesda I or II FNAC categories, preoperatively. Complications at completion of surgery in this particular setting were 0.5% for RLN palsy (n = 1) and 1% (n = 2) for hypoparathyroidism 6 months postoperatively. The overall postoperative complication rate was higher in primary TT vs. LTT for RLN palsy (4.8% [n = 67] vs. 2.4% [n = 23]; p = 0.003) and permanent hypoparathyroidism (6.8% [n = 95] vs. 0.8% [n = 8]; p < 0.0001). CONCLUSIONS: FNAC results appear to affect surgical planning in TC as intermediate FNAC categories lead more often to LTT. Overall, inadequate procedures necessitating completion surgery are encountered in up to 15% of TC patients subjected to LTT due to absent, inconclusive, or misleading FNAC, preoperatively. However, completion of thyroidectomy in this setting did not yield significant surgical morbidity. Primary LTT is a safer primary approach compared to TT in respect of RLN palsy and permanent hypoparathyroidism complication rates; therefore, primary TT should probably be reserved for lesions > 1 cm or even larger with suspicion for malignancy or malignant FNAC.

Validating the risk of hypoparathyroidism after total thyroidectomy in a population-based cohort: plea for improved follow-up.

BACKGROUND: A previous nationwide study from Sweden showed that the rate of permanent hypoparathyroidism is high and under-rated in the Swedish Quality Register. This retrospective population-based study aimed to validate the rate and diagnosis of permanent hypoparathyroidism found in the previous study. A secondary aim was to assess the relationship between the rate of low parathyroid hormone (PTH) levels within 24 h after surgery and the rate of permanent hypoparathyroidism. METHODS: All patients who underwent total thyroidectomy from 2005 to 2015 in a region of Sweden were included. Data were retrieved from local health records, the National Patient Registry, the Swedish Prescribed Drug Registry, and the Swedish Quality Register. A strict definition of permanent hypoparathyroidism was used, including biochemical data and attempts to stop the treatment. RESULTS: A total of 1636 patients were included. Altogether, 143 patients (8.7 per cent) developed permanent hypoparathyroidism. Of these, 102 (6.2 per cent) had definitive permanent hypoparathyroidism, whereas 41 (2.5 per cent) had possible permanent hypoparathyroidism, because attempts to stop the treatment were lacking (28) or patients were lost to follow-up (13). The agreement between the Swedish Quality Register and the chart review was 29.3 per cent. A proportion of 23.2 per cent with a PTH level below the reference value corresponded to a 6.7 per cent rate of permanent hypoparathyroidism. CONCLUSION: The risk of permanent hypoparathyroidism after total thyroidectomy is high. Some patients are overtreated because attempts to stop the treatment are lacking. Quality registers might underestimate the risk of permanent hypoparathyroidism. Approximately one-quarter of all patients with low PTH levels immediately after surgery developed permanent hypoparathyroidism.

The parathyroid glands control calcium levels in the blood. If they do not make enough hormone, calcium levels are low. Parathyroid dysfunction can happen after thyroid surgery, if the glands are hurt or removed by mistake. This is a problem because people with this condition may have symptoms and need ongoing treatment with vitamin D and calcium. They might also face other health issues and need regular visits to their doctor. Finding out how often long-term parathyroid dysfunction happens can be tricky because it requires a full year of follow-up and attempts to stop the treatment. This information is often missing from many studies and registers. Some recent studies have shown that this condition is more common than previously thought. It would be helpful to have a quick way to know how common long-term parathyroid gland dysfunction will be within a unit or hospital, without having to wait for the follow-up. This would help doctors to assess how good they are at taking care of patients. It would also support research on new methods to avoid parathyroid dysfunction. The goal of the study was to see how often long-term parathyroid dysfunction occurs after thyroid surgery, using a strict definition and complete long-term follow-up. Another aim was to assess the link between low parathyroid hormone levels right after surgery and the rate of long-term parathyroid dysfunction. All individuals who had the entire thyroid gland removed for benign disease between 2005 and 2015 in a region of Sweden were included. Data were collected from local health records at six hospitals. Patient information, surgical details, blood tests, and treatment details were gathered from the medical charts. Data were also collected from the national quality register. A high rate of long-term parathyroid dysfunction was seen in this large study of 1636 patients, Some patients may have been overtreated, because no attempts had been made to stop the treatment. The rate of long-term parathyroid dysfunction in patients with a normal early parathyroid hormone level was very low. About 23 per cent of all patients had a low early parathyroid hormone level, which corresponded to a 6.7 per cent rate of long-term parathyroid dysfunction. The authors believe that parathyroid hormone measurement could help predict the rate of permanent hypoparathyroidism, but more studies are needed to be sure.

Peritoneal Bridging Versus Nonclosure in Laparoscopic Ventral Hernia Repair: A Randomized Controlled Trial.

Introduction: Postoperative seroma and pain are common problems following laparoscopic intraperitoneal onlay mesh (IPOM) repair of ventral hernias. These adverse outcomes may be avoided by dissecting and using the peritoneum in the hernial sac to bridge the hernia defect. Methods: This was a patient- and outcome assessor-blinded, parallel-design, randomized controlled trial comparing nonclosure and peritoneal bridging approaches in patients scheduled for elective midline ventral hernia repair. The primary endpoint was seroma volume on ultrasonography. The secondary endpoints were postoperative pain, recurrence, and complications. Results: Between November 2018 and December 2020, 112 patients were randomized, of whom 60 were in the nonclosure group and 52 were in the peritoneal bridging group. The seroma volume in the nonclosure and peritoneal bridging groups were 17 cm3 (6-53 cm3) versus 0 cm3 (0-26 cm3) at 1-month follow-up (P = 0.013). The median volume was zero at the 3-, 6-, and 12-month follow-ups in both groups. No significant differences were observed in early postoperative pain (P = 0.447) and in recurrence rate (P = 0.684). There were 4 (7%) and 1 (2%) perioperative complications that lead to reoperations in simple IPOM (sIPOM) and IPOM with peritoneal bridging (IPOM-pb), respectively. Conclusions: Seroma was less prevalent after IPOM-pb at 1-month follow-up compared with sIPOM, with similar postoperative pain 1 week after index surgery in both groups. At subsequent follow-ups, the differences in seroma were not statistically significant. Further studies are required to confirm these results. Trial registration (NCT04229940).

Effect of the SARS-CoV-2 pandemic on planned and emergency hernia repair in Sweden: a register-based study.

PURPOSE: The COVID-19 has had a profound impact on the health care delivery in Sweden, including deprioritization of benign surgeries during the COVID-19 pandemic. The aim of this study was to assess the effect of COVID-19 pandemic on emergency and planned hernia repair in Sweden. METHODS: Data on hernia repairs from January 2016 to December 2021 were retrieved from the Swedish Patient Register using procedural codes. Two groups were formed: COVID-19 group (January 2020-December 2021) and control group (January 2016-December 2019). Demographic data on mean age, gender, and type of hernia were collected. RESULTS: This study showed a weak negative correlation between the number of elective hernia repairs performed each month during the pandemic and the number of emergency repairs carried out during the following 3 months for inguinal hernia repair (p = 0.114) and incisional hernia repair (p = 0.193), whereas there was no correlation for femoral or umbilical hernia repairs. CONCLUSION: The COVID-19 pandemic had a great impact on planned hernia surgeries in Sweden, but our hypothesis that postponing planned repairs would increase the risk of emergency events was not supported.

Long term outcome after toxic nodular goitre.

BACKGROUND: The purpose of treating toxic nodular goitre (TNG) is to reverse hyperthyroidism, prevent recurrent disease, relieve symptoms and preserve thyroid function. Treatment efficacies and long-term outcomes of antithyroid drugs (ATD), radioactive iodine (RAI) or surgery vary in the literature. Symptoms often persist for a long time following euthyroidism, and previous studies have demonstrated long-term cognitive and quality of life (QoL) impairments. We report the outcome of treatment, rate of cure (euthyroidism and hypothyroidism), and QoL in an unselected TNG cohort. METHODS: TNG patients (n = 638) de novo diagnosed between 2003-2005 were invited to engage in a 6-10-year follow-up study. 237 patients responded to questionnaires about therapies, demographics, comorbidities, and quality of life (ThyPRO). Patients received ATD, RAI, or surgery according clinical guidelines. RESULTS: The fraction of patients cured with one RAI treatment was 89%, and 93% in patients treated with surgery. The rate of levothyroxine supplementation for RAI and surgery, at the end of the study period, was 58% respectively 64%. Approximately 5% of the patients needed three or more RAI treatments to be cured. The patients had worse thyroid-related QoL scores, in a broad spectrum, than the general population. CONCLUSION: One advantage of treating TNG with RAI over surgery might be lost due to the seemingly similar incidence of hypothyroidism. The need for up to five treatments is rarely described and indicates that the treatment of TNG can be more complex than expected. This circumstance and the long-term QoL impairments are reminders of the chronic nature of hyperthyroidism from TNG.

Heterogeneity of Small Intestinal Neuroendocrine Tumors Metastasis: Biologic Patterns of a Series with Virchow's Node Involvement.

Small intestinal neuroendocrine tumors (SI-NETs) may rarely metastasize to the left supraclavicular lymph nodes, also known as Virchow's node metastasis (VM). Data on prevalence, prognostic significance, and clinical course of disease for SI-NET patients with VM is limited. In this retrospective analysis of 230 SI-NET patients treated at two tertiary referral centers, we found nine patients with VM (prevalence 3.9%). Among those, there were 5 females and median age at SI-NET and VM diagnosis was 61 and 65 years, respectively. Two patients had G1 tumors and five G2, while two tumors were of unspecified grade (median Ki67: 7%, range 2-15%). Four patients presented with synchronous VM, whereas five developed metachronous VM after a median of twenty-four months (range: 4.8-117.6 months). Hepatic metastases were present in seven patients, extrahepatic metastases (EM) in eight (six para-aortic distant lymph node metastases, one lung and one pancreatic metastasis), whereas peritoneal carcinomatosis (PC) in two patients. We used a control group of 18 age- and sex-matched SI-NET patients from the same cohort with stage IV disease but no extra-abdominal metastases. There was no difference in best-recorded response to first line treatment according to RECIST 1.1 as well as progression-free survival (PFS) between patients with VM and those in the control group (Chi-square test p = 0.516; PFS 71.7 vs. 106.9 months [95% CI 38.1-175.8]; log-rank p = 0.855). In addition, median overall survival (OS) of SI-NET patients with VM did not differ from those in the control group (138.6 [95% CI 17.2-260] vs. 109.9 [95% CI 91.7-128] months; log-rank p = 0.533). In conclusion, VM, although relatively rare in patients with SI-NETs, is more often encountered in patients with G2 tumors and established distant para-aortic lymph node metastases. The presence of VM in SI-NET patients does not seem to impact patients' survival outcomes and treatment responses, when compared to age- and sex-matched SI-NET patients with stage IV disease confined in the abdomen.

European Thyroid Association and Cardiovascular and Interventional Radiological Society of Europe 2021 Clinical Practice Guideline for the Use of Minimally Invasive Treatments in Malignant Thyroid Lesions.

The growing detection of papillary thyroid microcarcinomas (PTMCs) is paralleled by an increase in surgical procedures. Due to the frequent indolent nature, cost, and risk of surgery, active surveillance (AS) and ultrasound-guided minimally invasive treatments (MITs) are in suitable cases of incidental PTMC proposed as alternatives to thyroidectomy. Surgery and radioiodine are the established treatments for relapsing cervical differentiated thyroid carcinoma (DTC) metastases. But radioiodine refractoriness, risk of surgical complications, adverse influence on quality of life, or declining repeat surgery have led to AS and MIT being considered as alternatives for slow-growing DTC nodal metastases. Also, for distant radioiodine-refractory metastases not amenable to surgery, MIT is proposed as part of a multimodality therapeutic approach. The European Thyroid Association and the Cardiovascular and Interventional Radiological Society of Europe commissioned these guidelines for the appropriate use of MIT. Based on a systematic PubMed search, an evidence-based approach was applied, and both knowledge and practical experience of the panelists were incorporated to develop the manuscript and the specific recommendations. We recommend that when weighing between surgery, radioiodine, AS, or MIT for DTC, a multidisciplinary team including members with expertise in interventional radiology assess the demographic, clinical, histological, and imaging characteristics for appropriate selection of patients eligible for MIT. Consider TA in low-risk PTMC patients who are at surgical risk, have short life expectancy, relevant comorbidities, or are unwilling to undergo surgery or AS. As laser ablation, radiofrequency ablation, and microwave ablation are similarly safe and effective thermal ablation (TA) techniques, the choice should be based on the specific competences and resources of the centers. Use of ethanol ablation and high-intensity focused ultrasound is not recommended for PTMC treatment. Consider MIT as an alternative to surgical neck dissection in patients with radioiodine refractory cervical recurrences who are at surgical risk or decline further surgery. Factors that favor MIT are previous neck dissection, presence of surgical complications, small size metastases, and <4 involved latero-cervical lymph nodes. Consider TA among treatment options in patients with unresectable oligometastatic or oligoprogressive distant metastases to achieve local tumor control or pain palliation. Consider TA, in combination with bone consolidation and external beam radiation therapy, as a treatment option for painful bone metastases not amenable to other established treatments.

Novel Experimental Technique to Create Size-Controlled Retroperitoneal Bleeding in the Infrarenal Aorta of Anesthetized Pigs.

OBJECTIVE: Rupture of abdominal aortic aneurysm (rAAA) with a contained retroperitoneal hematoma is potentially fatal. Physiological studies are difficult to perform in patients suffering from life-threatening conditions such as rAAA. A translational model of the condition is therefore needed. The aim was to develop and validate an endovascular animal model for retroperitoneal bleeding of the abdominal aorta with contained hematoma. METHODS: In anesthetized pigs, a puncture hole was made in the posterolateral portion of the infrarenal aorta by an Outback re-entry catheter device. The hole was gradually enlarged using angioplasty balloons to a specific diameter of either 4 mm (n = 6), 6 mm (n = 7), or 8 mm (n = 6). Onset of bleeding was verified by angiography and macroscopically examined on completion of the experiments. Survival up to 180 min was the primary outcome. Hemodynamic and metabolic markers in arterial blood were secondary outcomes. RESULTS: Aortic injury with a contained retroperitoneal hematoma was achieved in all animals. Survival rate at 180 min after onset of bleeding was higher in the 4 mm group compared to the 6 mm (P = 0.021) and 8 mm groups (P = 0.002), but not when comparing the 6 mm and 8 mm groups. Systemic hypotension, arterial acidosis, and lactatemia were provoked in the 6 mm and 8 mm groups but not in the 4 mm group. CONCLUSIONS: A porcine model for a controlled contained left posterolateral retroperitoneal bleeding was created using endovascular methods and validated. This model makes it possible to study the pathophysiology of a retroperitoneal hematoma.

Cardiovascular Toxicities Secondary to Biotherapy and Molecular Targeted Therapies in Neuroendocrine Neoplasms: A Systematic Review and Meta-Analysis of Randomized Placebo-Controlled Trials.

A broad spectrum of novel targeted therapies with prime antitumor activity and/or ample control of hormonal symptoms together with an overall acceptable safety profile have emerged for patients with metastatic neuroendocrine neoplasms (NENs). In this systematic review and quantitative meta-analysis, the PubMed, EMBASE, Cochrane Central Register of Controlled Trials and clinicaltrials.gov databases were searched to assess and compare the safety profile of NEN treatments with special focus on the cardiovascular adverse effects of biotherapy and molecular targeted therapies (MTTs). Quality/risk of bias were assessed using GRADE criteria. Placebo-controlled randomized clinical trials (RCTs) in patients with metastatic NENs, including medullary thyroid cancer (MTC) were included. A total of 3695 articles and 122 clinical trials registered in clinicaltrials.gov were screened. We included sixteen relevant RCTs comprising 3408 unique patients assigned to different treatments compared with placebo. All the included studies had a low risk of bias. We identified four drug therapies for NENs with eligible placebo-controlled RCTs: somatostatin analogs (SSAs), tryptophan hydroxylase (TPH) inhibitors, mTOR inhibitors and tyrosine kinase inhibitors (TKI). Grade 3 and 4 adverse effects (AE) were more often encountered in patients treated with mTOR inhibitors and TKI (odds ratio [OR]: 2.42, 95% CI: 1.87-3.12 and OR: 3.41, 95% CI: 1.46-7.96, respectively) as compared to SSAs (OR:0.77, 95% CI: 0.47-1.27) and TPH inhibitors (OR:0.77, 95% CI: 0.35-1.69). MTOR inhibitors had the highest risk for serious cardiac AE (OR:3.28, 95% CI: 1.66-6.48) followed by TKIs (OR:1.51, 95% CI: 0.59-3.83). Serious vascular AE were more often encountered in NEN patients treated with mTOR inhibitors (OR: 1.72, 95% CI: 0.64-4.64) and TKIs (OR:1.64, 95% CI: 0.35-7.78). Finally, patients on TKIs were at higher risk for new-onset or exacerbation of pre-existing hypertension (OR:3.31, 95% CI: 1.87-5.86). In conclusion, SSAs and TPH inhibitors appear to be safer as compared to mTOR inhibitors and TKIs with regards to their overall toxicity profile, and cardiovascular toxicities in particular. Special consideration should be given to a patient-tailored approach with anticipated toxicities of targeted NEN treatments together with assessment of cardiovascular comorbidities, assisting clinicians in treatment selection and early recognition/management of cardiovascular toxicities. This approach could improve patient compliance and preserve cardiovascular health and overall quality of life.

Clinical Utility of 18F-FDG PET in Neuroendocrine Tumors Prior to Peptide Receptor Radionuclide Therapy: A Systematic Review and Meta-Analysis.

The role of 18F-FDG PET in patients with variable grades of neuroendocrine tumors (NETs) prior to peptide receptor radionuclide therapy (PRRT) has not been adequately elucidated. We aimed to evaluate the impact of 18F-FDG PET status on disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in neuroendocrine tumor (NET) patients receiving PRRT. We searched the MEDLINE, Embase, Cochrane Library, and Web of Science databases up to July 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5091 articles were screened. In 12 studies, 1492 unique patients with NETs of different origins were included. The DCR for patients with negative 18F-FDG PET status prior to PRRT initiation was 91.9%, compared to 74.2% in patients with positive 18F-FDG PET status (random effects odds ratio (OR): 4.85; 95% CI: 2.27-10.36). Adjusted analysis of pooled hazard ratios (HRs) confirmed longer PFS and OS in NET patients receiving PRRT with negative 18F-FDG PET (random effects HR:2.45; 95%CIs: 1.48-4.04 and HR:2.25; 95% CIs:1.55-3.28, respectively). In conclusion, 18F-FDG PET imaging prior to PRRT administration appears to be a useful tool in NET patients to predict tumor response and survival outcomes and a negative FDG uptake of the tumor is associated with prolonged PFS and OS.

The Role of Serum 5-HIAA as a Predictor of Progression and an Alternative to 24-h Urine 5-HIAA in Well-Differentiated Neuroendocrine Neoplasms.

Our aim was to investigate the clinical utility of serum 5HIAA for disease surveillance and diagnostic purposes in a cohort of patients with well-differentiated neuroendocrine neoplasms (WD-NENs). Forty-eight patients with WD-NENs and concurrent serum and urinary 5HIAA testing, as well as CT/MRI imaging, were included. Analysis of matching-pairs did not reveal any association between RECIST 1.1 responses and changes in serum 5HIAA levels (p = 0.673). In addition, no correlation was evident between RECIST 1.1 responses and >10%, >25% or >50% changes in serum 5HIAA levels (Fisher's exact test p = 0.380, p > 0.999, and p > 0.999, respectively). The presence of liver metastases and extensive liver tumor involvement were associated with higher serum 5HIAA levels (p = 0.045 and p = 0.041, respectively). We also confirmed a strong linear correlation between the measurements of serum and urine 5HIAA (n = 24, r = 0.791, p < 0.0001). The concordance rate of serum and urinary 5HIAA positivity at standardized laboratory cut-offs was 75%. In patients with normal renal function tests, the concordance between the two methods was as high as 89%, and a sensitivity and specificity of 80% and 88.9%, respectively, was evident (Cohen's kappa coefficient = 0.685). In conclusion, serum 5HIAA performs well compared to urinary testing for diagnostic purposes, mainly in advanced disease stages, and corresponds well to liver tumor burden. However, it is not adequate to predict tumor progression.

A Plasma Protein Biomarker Strategy for Detection of Small Intestinal Neuroendocrine Tumors.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are difficult to diagnose in the early stage of disease. Current blood biomarkers such as chromogranin A (CgA) and 5-hydroxyindolacetic acid have low sensitivity (SEN) and specificity (SPE). This is a first preplanned interim analysis (Nordic non-interventional, prospective, exploratory, EXPLAIN study [NCT02630654]). Its objective is to investigate if a plasma protein multi-biomarker strategy can improve diagnostic accuracy (ACC) in SI-NETs. METHODS: At the time of diagnosis, before any disease-specific treatment was initiated, blood was collected from patients with advanced SI-NETs and 92 putative cancer-related plasma proteins from 135 patients were analyzed and compared with the results of age- and sex-matched controls (n = 143), using multiplex proximity extension assay and machine learning techniques. RESULTS: Using a random forest model including 12 top ranked plasma proteins in patients with SI-NETs, the multi-biomarker strategy showed SEN and SPE of 89 and 91%, respectively, with negative predictive value (NPV) and positive predictive value (PPV) of 90 and 91%, respectively, to identify patients with regional or metastatic disease with an area under the receiver operator characteristic curve (AUROC) of 99%. In 30 patients with normal CgA concentrations, the model provided a diagnostic SPE of 98%, SEN of 56%, and NPV 90%, PPV of 90%, and AUROC 97%, regardless of proton pump inhibitor intake. CONCLUSION: This interim analysis demonstrates that a multi-biomarker/machine learning strategy improves diagnostic ACC of patients with SI-NET at the time of diagnosis, especially in patients with normal CgA levels. The results indicate that this multi-biomarker strategy can be useful for early detection of SI-NETs at presentation and conceivably detect recurrence after radical primary resection.

Association of a Palliative Surgical Approach to Stage IV Pancreatic Neuroendocrine Neoplasms with Survival: A Systematic Review and Meta-Analysis.

The role of primary tumor resection in patients with pancreatic neuroendocrine neoplasms (PanNENs) and unresectable distant metastases remains controversial. We aimed to evaluate the effect of palliative primary tumor resection (PPTR) on overall survival (OS) in this setting. We searched the MEDLINE, Embase, Cochrane Library, Web of Science and SCOPUS databases up to January 2020 and used the Newcastle-Ottawa scale (NOS) criteria to assess quality/risk of bias. A total of 5661 articles were screened. In 10 studies, 5551 unique patients with stage IV PanNEN and unresectable metastases were included. The five-year OS for PanNEN patients undergoing PPTR in stage IV was 56.6% vs. 23.9% in the non-surgically treated patients (random effects relative risk (RR): 1.70; 95% CI: 1.53-1.89). Adjusted analysis of pooled hazard ratios (HR) confirmed longer OS in PanNEN patients undergoing PPTR (random effects HR: 2.67; 95% CI: 2.24-3.18). Cumulative OS analysis confirmed an attenuated survival benefit over time. The complication rate of PPTR was as high as 27%. In conclusion, PPTR may exert a survival benefit in stage IV PanNEN. However, the included studies were subject to selection bias, and special consideration should be given to PPTR anchored to a multimodal treatment strategy. Further longitudinal studies are warranted, with long-term follow-up addressing the survival outcomes associated with surgery in stage IV disease.

Effects of beta-blocker therapy on mortality after elective colon cancer surgery: a Swedish nationwide cohort study.

OBJECTIVE: Colon cancer surgery remains associated with substantial postoperative morbidity and mortality despite advances in surgical techniques and care. The trauma of surgery triggers adrenergic hyperactivation which drives adverse stress responses. We hypothesised that outcome benefits are gained by reducing the effects of hyperadrenergic activity with beta-blocker therapy in patients undergoing colon cancer surgery. This study aims to test this hypothesis. DESIGN: Retrospective cohort study. SETTING AND PARTICIPANTS: This is a nationwide study which includes all adult patients undergoing elective colon cancer surgery in Sweden over 10 years. Patient data were collected from the Swedish Colorectal Cancer Registry. The national drugs registry was used to obtain information about beta-blocker use. Patients were subdivided into exposed and unexposed groups. The association between beta-blockade, short-term and long-term mortality was evaluated using Poisson regression, Kaplan-Meier curves and Cox regression. PRIMARY AND SECONDARY OUTCOMES: Primary outcome of interest was 1-year all-cause mortality. Secondary outcomes included 90-day all-cause and 5-year cancer-specific mortality. RESULTS: The study included 22 337 patients of whom 36.1% were prescribed preoperative beta-blockers. Survival was higher in patients on beta-blockers up to 1 year after surgery despite this group being significantly older and of higher comorbidity. Regression analysis demonstrated significant reductions in 90-day deaths (IRR 0.29, 95% CI 0.24 to 0.35, p<0.001) and a 43% risk reduction in 1-year all-cause mortality (adjusted HR 0.57, 95% CI 0.52 to 0.63, p<0.001) in beta-blocked patients. In addition, cancer-specific mortality up to 5 years after surgery was reduced in beta-blocked patients (adjusted HR 0.80, 95% CI 0.73 to 0.88, p<0.001). CONCLUSION: Preoperative beta-blockade is associated with significant reductions in postoperative short-term and long-term mortality following elective colon cancer surgery. Its potential prophylactic effect warrants further interventional studies to determine whether beta-blockade can be used as a way of improving outcomes for this patient group.

Pathogenesis and Clinical Management of Mesenteric Fibrosis in Small Intestinal Neuroendocine Neoplasms: A Systematic Review.

Mesenteric fibrosis (MF) constitutes an underrecognized sequela in patients with small intestinal neuroendocrine neoplasms (SI-NENs), often complicating the disease clinical course. The aim of the present systematic review, carried out by Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology, is to provide an update in evolving aspects of MF pathogenesis and its clinical management in SI-NENs. Complex and dynamic interactions are present in the microenvironment of tumor deposits in the mesentery. Serotonin, as well as the signaling pathways of certain growth factors play a pivotal, yet not fully elucidated role in the pathogenesis of MF. Clinically, MF often results in significant morbidity by causing either acute complications, such as intestinal obstruction and/or acute ischemia or more chronic conditions involving abdominal pain, venous stasis, malabsorption and malnutrition. Surgical resection in patients with locoregional disease only or symptomatic distant stage disease, as well as palliative minimally invasive interventions in advanced inoperable cases seem clinically meaningful, whereas currently available systemic and/or targeted treatments do not unequivocally affect the development of MF in SI-NENs. Increased awareness and improved understanding of the molecular pathogenesis of MF in SI-NENs may provide better diagnostic and predictive tools for its timely recognition and intervention and also facilitates the development of agents targeting MF.

Correlating the Bethesda System for Reporting Thyroid Cytopathology with Histology and Extent of Surgery: A Review of 21,746 Patients from Four Endocrine Surgery Registries Across Two Continents.

BACKGROUND: The Bethesda system for cytopathology (TBSRTC) is a 6-tier diagnostic framework developed to standardize thyroid cytopathology reporting. The aim of this study was to determine the risk of malignancy (ROM) for each Bethesda category. METHODS: Thyroidectomy-related data from 314 facilities in 22 countries were entered into the following outcome registries: CESQIP (North America), Eurocrine (Europe), SQRTPA (Sweden) and UKRETS (UK). Demographic, cytological, pathologic and extent of surgery data were mapped into one dataset and analyzed. RESULTS: Out of 41,294 thyroidectomy patient entries from January 1, 2015, to June 30, 2017, 21,746 patients underwent both thyroid FNA and surgery. A comparison of cytology and surgical pathology data demonstrated a ROM for Bethesda categories 1 to 6 of 19.2%, 12.7%, 31.9%, 31.4%, 77.8% and 96.0%, respectively. Male patients had a higher rate of malignancy for every Bethesda category. Secondary analysis demonstrated a high ROM in male patients with Bethesda 3 category aged 31-35 years (52.1%, 95% confidence interval (CI) 37.9-66.2%), aged 36-40 years (55.9%, 95% CI 39.2-72.6%) and aged 41-45 years (46.9%, 95% CI 33-60.9%). Patients with Bethesda 5 and 6 scores were more likely to undergo total thyroidectomy (65.9% and 84.6%); for patients with Bethesda scores 2 and 3, a higher percentage of females underwent total thyroidectomy compared to males in spite of a higher ROM for males. CONCLUSIONS: These data demonstrate that Bethesda categories 1-4 are associated with a higher ROM compared to the first edition of TBSRTC, especially in male patients, and validate findings from the second edition of TBSRTC.