Association of Upfront Peptide Receptor Radionuclide Therapy With Progression-Free Survival Among Patients With Enteropancreatic Neuroendocrine Tumors.

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy. Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31). Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.

Sequencing Life-Prolonging Agents in Castration-Resistant Prostate Cancer Patients: Comparison of Sequences With and Without 223Ra.

Background: The retrospective studies that have so far described the outcomes of the sequential use of life-prolonging agents (LPAs) did not include metastatic castration-resistant prostate cancer (mCRPC) patients who received radium-223 (223Ra) as part of their treatment. Consequently, it is not known whether including 223Ra in the therapeutic sequence has an impact on cumulative survival. The aim of this study was to evaluate this impact by comparing the cumulative overall survival (OS) in two series of mCRPC patients sequentially treated with two or three LPAs after first-line docetaxel (DOC), including 223Ra and not. Materials and Methods: The authors retrospectively reviewed the records of mCRPC patients with bone involvement alone who received two or three LPAs (including 223Ra) after first-line DOC. The control group was a contemporary series of mCRPC patients with bone involvement alone treated with sequences of two or three LPAs other than 223Ra after first-line DOC. Results: Median cumulative OS was 40.6 months in the 223Ra group of 78 patients and 36.2 months in the non-223Ra group of 186 patients (p = 0.08). OS outcomes were significantly influenced by the number of treatment lines, and baseline Eastern Cooperative Oncology Group performance status (PS) and prostate-specific antigen levels. Conclusions: To the best of the authors' knowledge, this is the first study designed to evaluate the impact of introducing 223Ra in the treatment sequences for mCRPC patients, and the results show that its use does not negatively affect cumulative OS.

Sequencing radium 223 and other life-prolonging agents in castration-resistant prostate cancer patients.

Background: Radium 223 (RA223) is currently administered as part of a therapeutic sequence with the other life-prolonging agents (LPAs) for metastatic castration-resistant prostate cancer (mCRPC). Patients & methods: We retrospectively reviewed the clinical records of patients who had received at least three LPAs including RA223. Results: Median overall survival (OS) from the start of first-line treatment was 39.8 months, with the patients who completed all six planned courses of RA223 having a longer OS than those who did not (53.2 vs 29.5 months; p < 0.0001). Conclusions: Our study confirms the activity of RA223 regardless of the treatment line in which it is administered and suggests that patient selection plays a central role in maximizing this activity.

Usefulness of PET-CT scan in recurrent thyroid cancer.

The aim of this paper is to discuss the risk of recurrence in patients with differentiated thyroid cancer and emphasize the importance of risk-group stratification, early recurrence identification and application of new imaging modalities, what is the PET-CT. Moreover, follow-up of patients with thyroid carcinoma should be carried out by specialized teams throughout life. Therefore, interdisciplinary case discussions in tumor conferences may improve the use of multimodal therapy especially in patients with poorly differentiated thyroid carcinomas. After baseline follow-up, if there is a suspicion of thyroid carcinoma, early PET-CT should be used for early detection and appropriate planning. Fortunately, due to the good localization possibility, the PET-CT enables a focused surgical procedure with avoidance of an unnecessary tumor search and thereby a reduction of the risk of injury of neighboring structures which is a concern with reoperative neck surgery.

The Additional Value of 18F-FDG PET and MRI in Patients with Glioma: A Review of the Literature from 2015 to 2020.

AIM: Beyond brain computed tomography (CT) scan, Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET) hold paramount importance in neuro-oncology. The aim of this narrative review is to discuss the literature from 2015 to 2020, showing advantages or complementary information of fluorine-18 fluorodeoxyglucose (18F-FDG) PET imaging to the anatomical and functional data offered by MRI in patients with glioma. METHODS: A comprehensive Pubmed/MEDLINE literature search was performed to retrieve original studies, with a minimum of 10 glioma patients, published from 2015 until the end of April 2020, on the use of 18F-FDG PET in conjunction with MRI. RESULTS: Twenty-two articles were selected. Combined use of the two modalities improves the accuracy in predicting prognosis, planning treatments, and evaluating recurrence. CONCLUSION: According to the recent literature, 18F-FDG PET provides different and complementary information to MRI and may enhance performance in the whole management of gliomas. Therefore, integrated PET/MRI may be particularly useful in gliomas, since it could provide accurate morphological and metabolic information in one-shoot examination and improve the diagnostic value compared to each of procedures.

Fracture risk and survival outcomes in metastatic castration-resistant prostate cancer patients sequentially treated with abiraterone acetate and RADIUM-223.

PURPOSE: To evaluate the fracture risk and survival outcomes in patients with metastatic castration-resistant prostate cancer (mCRPC) who received sequentially abiraterone acetate (AA) and radium 223 [223Ra]RaCl2 in the daily clinical practice. MATERIALS: We retrospectively reviewed the records of mCRPC patients who received [223Ra]RaCl2 immediately after progressing during an AA treatment line in everyday clinical practice. RESULTS: We reviewed data of a consecutive series of 94 mCRPC patients. Most of the patients (85.1%) received [223Ra]RaCl2 as second- or third-line treatment. [223Ra]RaCl2 treatment was well-tolerated; there were only four cases of grade 3 anaemia, two cases of grade 3 leukopenia and one case of grade 3 neutropenia. The overall fracture rate is 2.1%; one fracture was recorded during the course of [223Ra]RaCl2 treatment, and one was recorded 1 month after its end. The fractures both occurred at metastatic sites. Median OS from [223Ra]RaCl2 start was more than 14 months regardless of the treatment line when [223Ra]RaCl2 was administered. CONCLUSION: The findings of this study show that the treatment with [223Ra]RaCl2 immediately after AA was active and safe with a very low risk of a fracture. Thus, the present observational report makes a valuable contribution to the current debate concerning the risks and benefits of including [223Ra]RaCl2 in the therapeutic algorithm.

Recombinant human thyrotropin (rhTSH) versus Levo-thyroxine withdrawal in radioiodine therapy of differentiated thyroid cancer patients: differences in abdominal absorbed dose.

PURPOSE: In DTC patients, 131-radioiodine therapy has routinely been used for many years for thyroid remnant ablation after thyroid surgery. To date, two different strategies can be used to achieve sufficient TSH stimulation on thyroid remnant: (I) Levo-thyroxine withdrawal or (II) rhTSH stimulation. The aim of our study was to compare the abdominal absorbed dose ratio between differentiated thyroid cancer patients who underwent thyroid remnant ablation after either L-T4 withdrawal or rhTSH stimulation. METHODS: We reviewed the records of 63 patients affected by differentiated thyroid cancer. All patients underwent thyroid remnant ablation after either L-T4 withdrawal or rhTSH stimulation. A post-therapy whole-body scan was obtained 5 days after 131-radioiodine therapy. Qualitative and quantitative image analysis was performed. Quantitative analysis was performed by drawing seven regions of interest on the abdomen (anterior and posterior views) to estimate both the activity ratio (AR) and absorbed dose ratio (DR) obtained in patients treated in hypothyroidism or after rhTSH stimulation. RESULTS: The values of the activity and absorbed dose ratios obtained on each abdomen region (liver, stomach, ascending colon, transverse colon, descending colon, rectum, and small intestine) were always higher in patients treated after L-T4 withdrawal than after rhTSH stimulation with p-values of 0.000, 0.000, 0.001, 0.000, 0.022, 0.007, and 0.002, respectively. CONCLUSIONS: DTC patients treated with 131-radioiodine after rhTSH stimulation have lower abdominal radioiodine activity than hypothyroid patients. Our data could be of practical relevance in terms of patient management. The potential impact on rare radioiodine-related gastrointestinal side effects is to be established in specifically designed prospective studies.

Undetectable or low (<1 ng/ml) postsurgical thyroglobulin values do not rule out metastases in early stage differentiated thyroid cancer patients.

BACKGROUND: Differentiated thyroid cancer (DTC) work-up is based on (near)total-thyroidectomy plus thyroid remnant ablation (TRA) with 131-radioiodine in many patients, and long-life follow-up. 131I-post therapy whole body scan (pT-WBS) and serum thyroglobulin (Tg) are used in identifying metastatic patients. Some authors have evaluated the possibility of using post-surgical Tg (ps-Tg) values in deciding for or against TRA. The aim of our study was to verify the diagnostic accuracy of 131I-pT-WBS and SPECT/CT imaging (post-therapeutic imaging) compared to serum Tg levels in detecting metastases in early stage of DTC patients. RESULTS: Post-therapeutic imaging revealed metastases in 82 out of 570 (14.4%) patients. Metastases were successively confirmed by other diagnostic tools or by histology (sensitivity and PPV = 100%). Seventy-three out of 82 patients (90.2%) showed ps-Tg levels ≤1 ng/ml. In fifty-four per cent of patients, serum Tg levels at TRA remained ≤1 ng/ml. CONCLUSION: In conclusion, ps-Tg levels cannot be used in deciding for or against TRA. In early stage of DTC, post-therapeutic imaging (131I-pT-WBS and SPECT/CT) is an accurate method of detecting metastases, also in patients with stimulated serum Tg values ≤1 ng/ml. METHODS: We retrospectively reviewed the records of 570 consecutive patients affected by pT1-pT3 DTC (F = 450, M = 120), referred to our Nuclear Medicine Units in the last five years to perform TRA after (near)-total-thyroidectomy.All patients underwent TRA 3-4 months after thyroid surgery either in euthyroid or in hypothyroid state. Serum Tg values evaluated in post-surgical period and at TRA were matched with post-therapeutic imaging results.

Predictive and prognostic value of left ventricular mechanical dyssynchrony assessed by myocardial perfusion single photon emission computed tomography in asymptomatic patients under hemodialysis.

BACKGROUND: Patients under hemodialysis (HD) have an increased risk of major adverse cardiac events (MACEs). In these patients, myocardial perfusion scintigraphy (MPS) provides useful prognostic information. Left ventricular mechanical dyssynchrony (LVD) has been proven to predict all-cause death in patients under HD. It remains unclear, whether the same prognostic value pertains also to the prediction of MACEs. PATIENTS AND METHODS: Ninety patients under HD (duration range: 2-216 months) with neither history nor symptoms of coronary artery disease at the time of MPS were retrospectively evaluated. All underwent clinical evaluation and MPS with dipyridamole stress test. MPS was reprocessed to derive left ventricular ejection fraction (EF), perfusion scores [summed stress score (SSS) and summed difference score (SDS)] and LVD (phase histogram bandwidth and phase SD).ResultsMACEs were reported in 10 (11.1%) patients as assessed at more than 2 years of follow-up (median 29 months). At univariate analysis, a correlation was demonstrated between MACEs and LVD (P<0.001), BMI (P=0.04), ECG changes during stress (P=0.03), dyspnea (P=0.02), SSS (P=0.04) and SDS (P=0.02). At stepwise multivariate analysis, only LVD (P<0.001), SSS (P=0.01) and SDS (P=0.001) were independent predictors of MACEs. No thresholds of SSS or SDS showed predictive value (P=0.79 for SSS ≥4, P=0.10 for SSS >8 and P=0.66 for SDS ≥2). At survival analysis, patients with LVD had a significantly shorter MACE-free survival (P<0.001). This predictive value held true even in patients with an unremarkable pattern of perfusion. CONCLUSION: In asymptomatic patients without known coronary artery disease under HD, LVD is highly predictive of the onset of MACEs at more than 2 years of follow-up and provides incremental value over perfusion scores alone. A phase analysis on gated MPS should be routinely performed in these patients to yield useful prognostic information.

Association of parathyroid carcinoma and thyroid disorders: A clinical review.

Parathyroid carcinoma is a rare malignancy, which usually occurs as a sporadic disease, and less frequently in the setting of genetic syndromes. Despite the association of parathyroid and thyroid disorders being quite common, the coexistence of parathyroid carcinoma and thyroid disease is rare. We reviewed the pertinent literature. The terms "parathyroid carcinoma" and "thyroid disease, hyperthyroidism, thyrotoxicosis, hypothyroidism, thyroid nodule(s), Graves' disease, autonomously functioning thyroid nodules" were used both separately and in reciprocal conjunction to search MEDLINE for articles published from January 2007 to March 2016. The search was prompted by the observation of a never reported association of autonomously functioning thyroid nodules and parathyroid carcinoma. Two hundred and twenty-one parathyroid carcinoma patients have been described during the last 10 years. Neck ultrasonography and parathyroid scintigraphy are the most common instrumental studies used in detecting parathyroid lesions. Serum parathyroid hormone and calcium levels are high in the majority of parathyroid carcinoma patients. Only 21 patients with parathyroid carcinoma and thyroid disorders were found. Our patient is the first casual association between parathyroid carcinoma and autonomously functioning thyroid nodules reported in literature and diagnosed using parathyroid and thyroid scintigraphies. Parathyroid carcinoma is a very rare endocrine tumor and association with thyroid disease is not frequent. Parathyroid carcinoma pre-operative diagnosis is often difficult also because available literature data are not homogenous and there is not a common operative guideline. Our case confirms the role of parathyroid scintigraphy, encouraging the association with thyroid scintigraphy, especially in the presence of (multi)-nodular goiter in order to address the most appropriate surgical management.

Role of molecular imaging in the management of patients affected by inflammatory bowel disease: State-of-the-art.

AIM: To present the current state-of-the art of molecular imaging in the management of patients affected by inflammatory bowel disease (IBD). METHODS: A systematic review of the literature was performed in order to find important original articles on the role of molecular imaging in the management of patients affected by IBD. The search was updated until February 2016 and limited to articles in English. RESULTS: Fifty-five original articles were included in this review, highlighting the role of single photon emission tomography and positron emission tomography. CONCLUSION: To date, molecular imaging represents a useful tool to detect active disease in IBD. However, the available data need to be validated in prospective multicenter studies on larger patient samples.

(99m)Tc-Methoxy-Isobutyl-Isonitrile Scintigraphy Is a Useful Tool for Assessing the Risk of Malignancy in Thyroid Nodules with Indeterminate Fine-Needle Cytology.

BACKGROUND: Thyroid nodular disease is a very common clinical problem. The diagnostic algorithm includes laboratory tests, thyroid ultrasound (US), thyroid scintigraphy, and, if necessary, US-guided fine-needle aspiration cytology. However, cytology results are reported as indeterminate in a not negligible number of patients. This is a central problem in the workup of patients, since about 55-85% of those undergoing surgery do not have thyroid cancer at final histology diagnosis. The aim of this study was to evaluate prospectively the role of (99m)Tc-methoxy-isobutyl-isonitrile ((99m)Tc-MIBI) thyroid scintigraphy in differentiating malignant from benign thyroid nodules with indeterminate cytology using quantitative analysis. METHOD: One hundred five patients affected by nodular thyroid goiter and with a euthyroid or hypothyroid functional status were prospectively evaluated. All patients had a suspicious nodule ≥15 mm in maximal diameter on US. All nodules were "cold" on (99m)Tc-pertechnetate scintigraphy and had a cytological diagnosis of class III or IV according to the Bethesda system. Planar images of the thyroid were acquired 10 and 60 minutes after (99m)Tc-MIBI administration. All cold nodules were MIBI-positive. Using quantitative analysis, the MIBI washout index (WOind) was calculated as a percentage reduction value of mean MIBI nodular uptake between early (+10 minutes) and late (+60 minutes) scans. RESULTS: Subdividing the patients into positive and negative for malignancy (either including or excluding patients with Hürthle cell adenoma) and performing receiver operating characterist curve analysis, the optimal WOind cutoff in differentiating malignant from benign follicular lesions was set at -19%. The overall sensitivity and specificity of (99m)Tc-MIBI quantitative analysis in identifying patients with malignant lesions was 100% and 90.9%, respectively. However, after excluding patients with Hürthle cell adenomas from the negative patient group, the overall sensitivity and specificity both reached 100%. CONCLUSION: The use of MIBI scintigraphy using quantitative analysis in the workup of cold nodules with indeterminate cytology is suggested in order to stratify patient risk for a malignant lesion better, thus reducing the number of patients referred to surgery. Surgical treatment should be planned in those patients with a WOind up to -19%.

Thyroid remnant ablation in differentiated thyroid cancer: searching for the most effective radioiodine activity and stimulation strategy in a real-life scenario.

OBJECTIVE: Differentiated thyroid cancer is rare, but the incidence has been increasing in the last few decades. Early treatment is based on surgery and thyroid remnant ablation (TRA) by means of radioiodine therapy. Despite radioiodine being widely used for decades, the choice of ablative activity is generally empirical and no consensus has been reached to date. The aim of our study was to compare the efficacy and safety of different radioiodine activities. In addition, we compared the ablation rate in patients treated in the hypothyroid state or after recombinant human thyroid-stimulating hormone (rhTSH) administration, retrospectively reviewing the records of 471 patients affected by differentiated thyroid cancer. PATIENTS AND METHODS: Patients were subdivided into three groups on the basis of the different activities of radioiodine administered and taking into account the different approaches used to perform the therapy: thyroid hormonal withdrawal or rhTSH stimulation. RESULTS: The success of TRA was evaluated 12 months later. TRA was obtained in 62/79 (78.5%) in group A (1110 MBq in the hypothyroid state), 183/190 (96.3%) in group B [2220 MBq in the hypothyroid state or after rhTSH administration: 87/90 (97%) and 96/100 (96%) patients, respectively], 199/202 (98.5%) in group C [3700 MBq in hypothyroid state or after rhTSH administration: 98/100 (98%) and 101/102 (99%) patients, respectively]. CONCLUSION: Our data demonstrate that 2220 and 3700 MBq radioiodine are more effective compared with 1110 MBq in TRA, without significant differences between 2220 and 3700 MBq or between hypothyroidism and euthyroidism. We suggest rhTSH-aided TRA with 2220 MBq iodine-131, as this approach permits efficacious treatment, thereby reducing side effects, absorbed dose to body and hospital stay.

Can peptide receptor radionuclide therapy (PRRT) be useful in radioiodine-refractory differentiated thyroid cancer?

We report on a 70-year-old man affected by radioiodine-refractory differentiated thyroid cancer (DTC) in whom metastases were treated by peptide receptor radionuclide therapy (PRRT). Seven years before, patient had undergone total thyroidectomy. Pathological examination was conclusive for DTC. The patient underwent some radioiodine treatments (RaIT). The last post-therapy whole body scan (pT-WBS) performed five days after RaIT did not show abnormal radioiodine uptake but serum thyroglobulin (Tg) value was high in absence of thyroglobulin-antibodies (Tg-Ab). In-111 DTPA-pentetreotide scintigraphy showed several lung lesions with high somatostatin receptor density. Patient underwent PRRT using Lu-177 DOTATOC. pT-WBS scan confirmed the metastases already demonstrated by In-111 DTPA pentetreotide but radioiodine negative.