Nordic 2023 guidelines for the diagnosis and treatment of lung neuroendocrine neoplasms.

Lung neuroendocrine neoplasms (NEN) are a heterogeneous population of neoplasms with different pathology, clinical behavior, and prognosis compared to the more common lung cancers. The diagnostic work-up and treatment of patients with lung- NEN has undergone major recent advances and new methods are currently being introduced into the clinic. These Nordic guidelines summarize and update the Nordic Neuroendocrine Tumor Group's current view on how to diagnose and treat lung NEN-patients and are meant to be useful in the daily practice for clinicians handling these patients. This review reflects our view of the current state of the art of diagnosis and treatment of patients with lung-NEN. Small cell lung carcinoma (SCLC) is not included in these guidelines.

Association between fibrosis markers and kidney function following peptide receptor radionuclide therapy in patients with neuroendocrine tumours.

Peptide receptor radionuclide therapy (PRRT) is a treatment for neuroendocrine tumours (NET). Renal impairment is a known side effect due to kidney fibrosis. We investigated the association between novel specific fibrosis markers and kidney function following PRRT. We included 38 patients who had all finished PRRT. In serum and urine, we analysed levels of three different fibrosis markers, PRO-C6 (type VI collagen formation), PRO-C3 (type III collagen formation) and C3M (type III collagen degradation). We determined kidney function by the 51Cr-EDTA plasma clearance. We used Wilcoxon rank sum test and Spearman's rank correlation to evaluate the association between the fibrosis markers and kidney function. We included 38 NET patients, 25 small-intestinal NET, 6 pancreatic NET, 2 pulmonary NET and 5 other types of NET. Median age was 69 years (IQR: 61-73). Median time from last PRRT to inclusion was 8 months (IQR: 3-20). We found significantly increased levels of serum PRO-C6 (p = .007) and urinary PRO-C6 (p = .033) and significantly decreased levels of urinary C3M (p = .035) in patients with impaired kidney function. Further, we observed a negative association between serum PRO-C6 and kidney function (rho = -0.33, p = .04) and a positive association between urinary C3M and kidney function (rho = 0.37, p = .02). We showed an association between the three fibrosis markers, serum PRO-C6, urinary PRO-C6 and urinary C3M and kidney function. These markers may help to improve the understanding of potential pathological tissue turnover and potentially improve monitoring of kidney function after PRRT in NET patients.

Labeled white blood cell/bone marrow single-photon emission computed tomography with computed tomography fails in diagnosing chronic periprosthetic shoulder joint infection.

BACKGROUND: Shoulder periprosthetic joint infections (PJI) caused by low-virulent bacteria pose a diagnostic challenge. Combined labeled leukocyte (WBC) and technetium 99m sulfur colloid bone marrow imaging (WBC/BM) is considered the radionuclide imaging gold standard for diagnosing lower limb PJI. However, it is laborious and expensive to perform, and documentation on shoulder arthroplasties is lacking. This study investigated WBC/BM single-photon emission computed tomography-computed tomography diagnostic performance in shoulder PJI. METHOD: All patients with a failed arthroplasty referred to a highly specialized shoulder department were scheduled for a diagnostic program including a WBC/BM. If an arthroplasty was revised, biopsy specimens were obtained and cultured for 14 days. The diagnostic performance of WBC/BM imaging was determined using biopsy specimens as a reference. RESULTS: Of the 49 patients who underwent a WBC/BM scan, 29 (59%) were revised. Infection was present in 11 patients, in whom 2 WBC/BM scans were true positive. The WBC/BM scan in 9 patients was false negative. The remaining 18 patients all had a true negative WBC/BM scan. WBC/BM showed a sensitivity 0.18 (95% confidence interval [CI], 0.00-0.41) and specificity 1.00 (95% CI, 1.00-1.00) in detecting shoulder PJI. The positive predictive value was 1.00 (95% CI, 1.00-1.00), and negative predictive value was 0.67 (95% CI, 0.49-0.84). No patients infected with Cutibacterium (formerly Propionibacterium) acnes resulted in a positive WBC/BM, nor had they preoperative or perioperative signs of infection. CONCLUSION: A positive WBC/BM was found only in patients with obvious PJI. Hence, the scan added nothing to the preoperative diagnosis. The WBC/BM single-photon emission computed tomography-computed tomography scan cannot be recommended as a screening procedure when evaluating failed shoulder arthroplasties for possible infection.

Effects of Peptide Receptor Radiotherapy in Patients with Advanced Paraganglioma and Pheochromocytoma: A Nation-Wide Cohort Study.

INTRODUCTION: Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence. METHOD: In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with 177Lu-Dotatate or 90Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals. RESULTS: We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations (p = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment (p = 0.083). CONCLUSIONS: The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to 131I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.

Skeletal "Superscan" With 11 C-Methionine PET/CT in Polycythemia Vera.

ABSTRACT: 11 C-methionine PET/CT for parathyroid adenoma localization on a 60-year-old woman known with polycythemia vera revealed highly methionine-avid red bone marrow, an uptake pattern that has previously been described in hematological disease such as multiple myeloma. An equivalent skeletal "superscan" pattern in polycythemia vera has been described with other PET tracers, but this case illustrates that this pattern can be seen with 11 C-methionine PET/CT as well and can be added to the list of potential pitfalls.

Incidental Finding of Pulmonary Embolism at Workup Before SIRT.

ABSTRACT: Selective internal radiation therapy (SIRT) is a catheter-guided treatment offered to selected patients with primary and secondary liver malignancies. SIRT is preceded by a workup procedure, where 99mTc-MAA (macroaggregated albumin) is injected in the tumor supplying artery/arteries followed by MAA scintigraphy. SIRT is frequently offered to patients with hepatocellular carcinoma (HCC), but large HCCs are known to be associated with a high risk of liver-to-lung shunting. We present a HCC patient case where a large lung-shunt enabled diagnosis of pulmonary embolism.

Practical kidney dosimetry in peptide receptor radionuclide therapy using [177Lu]Lu-DOTATOC and [177Lu]Lu-DOTATATE with focus on uncertainty estimates.

BACKGROUND: Kidney dosimetry after peptide receptor radionuclide therapy using 177Lu-labelled somatostatin analogues is a procedure with multiple steps. We present the SPECT/CT-based implementation at Aarhus University Hospital and evaluate the uncertainty of the various steps in order to estimate the total uncertainty and to identify the major sources of uncertainty. Absorbed dose data from 115 treatment fractions are reported. RESULTS: The total absorbed dose with uncertainty is presented for 59 treatments with [177Lu]Lu-DOTATOC and 56 treatments with [177Lu]Lu-DOTATATE. For [177Lu]Lu-DOTATOC the mean and median specific absorbed dose (dose per injected activity) is 0.37 Gy/GBq and 0.38 Gy/GBq, respectively, while for [177Lu]Lu-DOTATATE the median and mean are 0.47 Gy/GBq and 0.46 Gy/GBq, respectively. The uncertainty of the procedure is estimated to be about 13% for a single treatment fraction, where the absorbed dose calculation is based on three SPECT/CT scans 1, 4 and 7 days post-injection, while it increases to about 19% if only a single SPECT/CT scan is performed 1 day post-injection. CONCLUSIONS: The specific absorbed dose values obtained with the described procedure are comparable to those from other treatment sites for both [177Lu]Lu-DOTATOC and [177Lu]Lu-DOTATATE, but towards the lower end of the range of reported values. The estimated uncertainty is also comparable to that from other reports and judged acceptable for clinical and research use, thus proving the kidney dosimetry procedure a useful tool. The greatest reduction in uncertainty can be obtained by improved activity determination, partial volume correction and additional SPECT/CT scans.

68Ga-Prostate-Specific Membrane Antigen Uptake in a Pancreatic Neuroendocrine Tumor.

We present a 60-year-old man with known prostate cancer treated with robot-assisted radical prostatectomy. Prostate-specific antigen levels did not decline accordingly, and a second Ga-PSMA PET/CT demonstrated a new focus with high Ga-PSMA uptake in the pancreatic tail. A subsequent CT scan did not display the lesion as a typical pancreatic tumor, and a spleen scintigraphy was also negative excluding an ectopic intrapancreatic accessory spleen. Ga-DOTATOC PET/CT showed uptake in the same area of the pancreatic tail consistent with a neuroendocrine tumor. This case illustrates that neuroendocrine tumors can be important pitfalls in Ga-PSMA PET/CT performed in prostate cancer patients.

Extravasation of [177Lu]Lu-DOTATOC: case report and discussion.

BACKGROUND: In the case of extravasation of radioactive drugs used in peptide-receptor radionuclide therapy of neuroendocrine tumors, or in radionuclide therapy in general, rapid action is important to reduce or avoid complications. The literature on extravasation of drugs for radionuclide therapy is sparse. Based on the present case, we discuss handling and consequences of extravasation. Further, we demonstrate that dosimetry can aid in judging if the treatment of neuroendocrine tumors is satisfactory even after extravasation. CASE PRESENTATION: A case of extravasation of [177Lu]Lu-DOTATOC with a treatment strategy involving exercise and elevation of the affected arm and application of a compression bandage and heating is reported. Redistribution of the drug is verified and quantified by whole-body imaging and quantitative SPECT/CT and measurements of the dose rate at contact with the injection site. [177Lu]Lu-DOTATOC was redistributed to tumors and organs within 1 day. The patient did not report any discomfort during or after hospitalization, and no side effects related to extravasation were observed. Quantitative SPECT/CT scans at the subsequent treatment cycle of the same patient were analyzed for a comparison between the treatments. Dosimetry showed the treatments were similar with respect to the kidney and tumor absorbed doses. The radiation dose to the epidermal basal layer near the injection site was estimated and found to be consistent with the lack of side effects. CONCLUSIONS: The treatment of extravasation was successful, and the redistribution of the drug can be easily verified through measurement of the dose rate at contact with the skin. From the results of dosimetry, it was assessed that no change of the treatment course was necessary to compensate for a possibly incomplete treatment as a result of the extravasation.

Peptide receptor radionuclide therapy in gastroenteropancreatic NEN G3: a multicenter cohort study.

Peptide receptor radionuclide therapy (PRRT) is an established treatment of metastatic neuroendocrine tumors grade 1-2 (G1-G2). However, its possible benefit in high-grade gastroenteropancreatic (GEP) neuroendocrine neoplasms (NEN G3) is largely unknown. We therefore aimed to assess the benefits and side effects of PRRT in patients with GEP NEN G3. We performed a retrospective cohort study at 12 centers to assess the efficacy and toxicity of PRRT in patients with GEP NEN G3. Outcomes were response rate, disease control rate, progression-free survival (PFS), overall survival (OS) and toxicity. We included 149 patients (primary tumor: pancreatic n = 89, gastrointestinal n = 34, unknown n = 26). PRRT was first-line (n = 30), second-line (n = 62) or later-line treatment (n = 57). Of 114 patients evaluated, 1% had complete response, 41% partial response, 38% stable disease and 20% progressive disease. Of 104 patients with documented progressive disease before PRRT, disease control rate was 69%. The total cohort had median PFS of 14 months and OS of 29 months. Ki-67 21-54% (n = 125) vs Ki-67 ≥55% (n = 23): PFS 16 vs 6 months (P < 0.001) and OS 31 vs 9 months (P < 0.001). Well (n = 60) vs poorly differentiated NEN (n = 62): PFS 19 vs 8 months (P < 0.001) and OS 44 vs 19 months (P < 0.001). Grade 3-4 hematological or renal toxicity occurred in 17% of patients. This large multicenter cohort of patients with GEP NEN G3 treated with PRRT demonstrates promising response rates, disease control rates, PFS and OS as well as toxicity in patients with mainly progressive disease. Based on these results, PRRT may be considered for patients with GEP NEN G3.

Follicular thyroid cancer avid on C-11 Methionine PET/CT.

A case of follicular thyroid cancer with intense focal Methionine uptake on 11C-Methionine PET/CT is reported here. The use of 11C-Methionine PET in differentiated thyroid cancer is currently being investigated as a surrogate tracer compared to the more widely used 18F-FDG PET. This case illustrates the potential incremental value of this modality, not only in the localizing of parathyroid adenoma, but also indicating that 11C-Methionine PET might have a potential of increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake. LEARNING POINTS: 11C-Methionine PET/CT and 18F-Fluorocholine PET/CT often visualizes the parathyroid adenoma in case of negative Tc-99m-MIBI SPECT/CT.A cold nodule in Tc-99m Pertechnetat thyroid scintigraphy with a negative Sestamibi scintigraphy has a very low probability of being malignant.However, the pretest likelihood of thyroid cancer in a cold nodule with increased Sestamibi uptake is low.11C-Methionine PET might have a potential incremental value in increasing the pretest likelihood of thyroid malignancy in a cold nodule with highly increased Sestamibi uptake.

[Nuclear medicine techniques for selective internal radiotherapy of liver cancer].

Selective internal radiation therapy (SIRT) of hepatocellular carcinoma has been introduced at Aarhus University Hospital. 90Y-microspheres are implanted in the tumour by catheterization of the tumour feeding liver artery. Pretreatment angiography and test treatment using 99mTc-labelled particles followed by scintigraphy ensure a feasible and effective treatment. Post-treatment imaging of radiation from 90Y visualize the localization of microspheres. Currently, SIRT is also applied for liver metastases of neuroendocrine tumours. Future indications may include other liver tumours and metastases.

Presurgical localization of abnormal parathyroid glands using a single injection of Tc-99m sestamibi: comparison of high-resolution parallel-hole and pinhole collimators, and interobserver and intraobserver variation.

PURPOSE: Scintigraphy using Tc-99m sestamibi is sensitive in localizing abnormal parathyroid glands in patients with hyperparathyroid disease (HPT). Various methods have been described to increase the sensitivity of the single-tracer technique, such as SPECT, factor analysis of dynamic structures, and use of a pinhole collimator, but often the gain in sensitivity is accompanied by a loss of specificity. PURPOSE: In this study, the authors compared the sensitivity and specificity of side localization of the diseased gland(s) using the double-phase single-tracer method performed with and without the addition of a pinhole collimator in the early and late phases of imaging. The combined high-resolution parallel-hole and pinhole collimator imaging protocol was further validated by investigation of interobserver and intraobserver variation. MATERIALS AND METHODS: Forty-seven patients with primary HPT and 16 patients with secondary HPT examined from 1996 to 1999 with the Tc-99m sestamibi double-phase technique and who had subsequent surgery formed the basis of the study. Their histologic and follow-up data were also factored into this analysis. Tc-99m sestamibi (750 to 900 MBq; 18.9 to 24.3 mCi) was injected. Ten-minute neck and mediastinum images acquiring 1,000 K counts were obtained with the high-resolution parallel-hole collimator, and a neck image containing 500 K counts was obtained with the pinhole collimator. Two to three hours later, the same parallel-hole and pinhole collimator images were obtained that had the same acquisition time as the early images. Two observers who were nuclear medicine specialists independently viewed all the parallel-hole scintigrams and afterward all parallel-hole and pinhole scintigrams two times. RESULTS: Thirty-eight (81%) of the patients with primary HPT had a single adenoma. The sensitivity and specificity for the correct side of localization were 54% and 89%, respectively, using the high-resolution parallel-hole collimator, and 88% and 77%, respectively, with the addition of the pinhole collimator in all patients with primary HPT. In patients with secondary HPT, the sensitivity and specificity for localization of the correct side were 58% and 100%, respectively, using the high-resolution parallel-hole collimator, and 85% and 100%, respectively, with the addition of the pinhole collimator. The interobserver agreement was acceptable, with an overall agreement of 84% and a kappa value of 0.67. The intraobserver agreement was even better, with an overall agreement of 88% and 90% and kappa values of 0.76 and 0.79 for the two observers. CONCLUSIONS: Sensitivity is increased considerably when the pinhole collimator is added to the imaging protocol of parathyroid scintigraphy in patients with primary or secondary HPT. A loss of specificity occurred only in patients with primary HPT. The precision of the combined approach is very high.

Mediastinal staging in Non-Small-Cell Lung Carcinoma: computed tomography versus F-18-fluorodeoxyglucose positron-emission tomography and computed tomography.

BACKGROUND: After the diagnosis Non-Small-Cell Lung Carcinoma (NSCLC) has been established, consideration must turn toward the stage of disease, because this will impact directly on management and prognosis. Staging is used to predict survival and to guide the patient toward the most appropriate treatment regimen or clinical trial. Distinguishing malignant involvement of the mediastinal lymph nodes (N2 or N3) from the hilar lymph nodes, or no lymph nodes (N0 or N1) is critical, because malignant involvement of N2 or N3 lymph nodes usually indicates non-surgically resectable disease. The purpose of this study was to examine and compare CT versus integrated F18-FDG PET/low dose CT (FDG PET/CT) for mediastinal staging in NSCLC, and the desire was to safely distinguish between malignant and benign lesions without the need for invasive procedures. All results were controlled for reproducibility. METHODS: 114 participants with NSCLC were included in a prospective cohort study. Blinded CT and FDG PET/CT images were reviewed. The participants' mediastinums were staged based on lymph node sizes (CT), or on FDG uptake (FDG PET/CT). Reference standard was tissue sampling. RESULTS: We found that there was no measureable difference between CT and FDG PET/CT mediastinal staging results; overall two-thirds of the participants in the study were correctly staged, and almost one-third of the participants were falsely staged. CONCLUSION: Neither CT nor FDG PET/CT could obviate the need for further invasive staging prior to thoracotomy in patients with NSCLC; for that purpose, the results of both modalities were too meagre. Therefore, these patients still depend on invasive staging methods. In our study, invasive staging was accomplished by mediastinoscopy. However, today this is increasingly replaced by EBUS or EUS.

Characterization of pulmonary lesions in patients with suspected lung cancer: computed tomography versus [¹8F] fluorodeoxyglucose-positron emission tomography/computed tomography.

Pulmonary nodules are of high clinical importance, given they may prove to be an early manifestation of lung cancer. Pulmonary nodules are small, focal, radiographic opacities that may be solitary or multiple. A solitary pulmonary nodule is a single, small (<-30 mm in diameter) opacity. Larger opacities are called masses and are often malignant. As imaging techniques improve and more nodules are detected, the optimal management of pulmonary nodules remains unclear. However, the question of malignancy of any given nodule remains the same. A standard contrast-enhanced computed tomography (CT) scan is often the first examination, followed by a number of other examinations. The purpose of this study was to examine the clinical feasibility of CT versus integrated [18F]fluorodeoxyglucose-positron emission tomography (PET)/low-dose CT scan in patients with suspected lung cancer and pulmonary lesions on CT. All results were controlled for reproducibility. We found that when used early in the work-up of the lesions, CT raised the prevalence of lung cancer in the population to the point where further diagnostic imaging examination could be considered futile. We also found that the overall diagnostic accuracy, as well as the classification probabilities and predictive values of the two modalities were not significantly different; the reproducibility of these results was substantial.