Prognostic value of [18F]-FDG PET/CT in patients with meta-static breast cancer treated with cyclin-dependent inhibitors.

Objective: The addition of cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) to endocrine therapy impressively improved the outcome of patients with hormone receptor-positive metastatic breast cancer. Despite their great efficacy, not all patients respond to treatment and many of them develop acquired resistance. The aim of this retrospective study was to assess the role of [18F]-FDG PET/CT in predicting PFS and OS in breast cancer patients treated with CDK4/6i. Methods: 114 patients who performed an [18F]-FDG PET/CT scan before (PET1) and 2-6 months (PET2) after starting treatment were retrospectively enrolled. Metabolic response was evaluated by EORTC, PERCIST and Deauville Score and correlated to PFS and OS. Results: In patients who did not progress at PET2 (n = 90), PFS rates were not significantly different between classes of response by EORTC and PERCIST. Conversely, patients showing a Deauville score ≤3 had a longer PFS (median PFS 42 vs 21.0 months; p = 0.008). A higher total metabolic tumor volume at PET1 (TMTV1) was also associated with a shorter PFS (median 18 vs 42 months; p = 0.0026). TMTV1 and Deauville score were the only independent prognostic factors for PFS at multivariate analysis and their combination stratified the population in four definite classes of relapse risk. Conversely, the above parameters did not affect OS which was only influenced by a progressive metabolic disease at PET2 (3-years survival rate 29.8 vs 84.9%; p<0.0001). Conclusion: TMTV and metabolic response by Deauville score were significant prognostic factors for PFS in patients with breast cancer treated with CDK4/6i. Their determination could help physicians to select patients who may need a closer follow up.

Predicting time to treatment in follicular lymphoma on watchful waiting using baseline metabolic tumour burden.

PURPOSE: Asymptomatic patients with follicular lymphoma (FL) and a low tumour burden can be followed without initial therapy, a strategy called watchful waiting (WW). Prediction of the time to treatment (TTT) is still a challenge. We investigated the prognostic value of baseline total metabolic tumour volume (TMTV) and whole-body total lesion glycolysis (WB-TLG) to predict TTT in patients with FL on WW. METHODS: We conducted a retrospective study of 54 patients with FL (grade 1-3a) diagnosed between June 2013 and December 2019, staged with FDG PET/CT, and managed on WW. Median age was 62 years (range 34-85), stage was advanced (III-IV) in 57%, and FLIPI score was intermediate to high (≥ 2) in 52% of the patients. RESULTS: The median TMTV and WB-TLG were 7.1 and 43.3, respectively. With a median follow-up of 59 months, 41% of patients started immuno-chemotherapy. The optimal cut-points to identify patients with TTT within 24 months were 14 for TMTV (AUC 0.70; 95% CI 51-88) and 64 for WB-TLG (AUC 0.71; 95% CI 52-89) (p < 0.005). The probability of not having started treatment within 24 months was 87% for TMTV < 14 and 53% for TMTV ≥ 14 (p < 0.005). TMTV was independent of the FLIPI score for TTT prediction. Patients with both FLIPI ≥ 2 and TMTV ≥ 14 had only an 18% probability of not having started treatment at 36 months, while this probability was 75% in patients with TMTV < 14. CONCLUSION: Metabolic tumour volume parameters may add information to clinical scores to better predict TTT and better stratify patients for interventional studies.

90Y-DOTA-Nimotuzumab: Synthesis of a Promising ß- Radiopharmaceutical.

BACKGROUND: Nimotuzumab is a humanized anti-epidermal growth factor receptor (EGFR) monoclonal antibody, nowadays used for tumour immunochemotherapy. This study aimed to label the conjugate DOTA-nimotuzumab with yttrium-90, in order to provide a ß- emitting radioimmunoconjugate (90Y-DOTA-nimotuzumab) potentially useful to assess the feasibility of a new radio-guided surgery approach. METHODS: The synthesis of 90Y-DOTA-nimotuzumab was performed in two days. Nimotuzumab was conjugated with a 50-fold excess of DOTA and then labelled with 90Y3+. The 90Y-DOTA-nimotuzumab preparation was optimized considering several parameters such as pH, temperature and reaction volume. Moreover, the 90Y-DOTA-nimotuzumab stability was evaluated in human plasma. RESULTS: The radioimmunoconjugate 90Y-DOTA-nimotuzumab was obtained with a radiochemical purity greater than 96%, and showed a good stability at 20°C as well as at 37°C in human plasma. CONCLUSIONS: The optimized conditions for a mild and easy preparation of 90Y-DOTA-nimotuzumab joined to a promising stability under physiological conditions suggest to propose this radioimmunoconjugate as a potential diagnostic radiopharmaceutical for ß- radio-guided surgery.

Oropharyngoesophageal Scintigraphy in a Case of Complex Swallowing Disorders After a Major Oral Surgery.

ABSTRACT: A 75-year-old woman had an occasional finding of a left tonsil mass for dysphagia, which resulted a high-grade squamous carcinoma. Therefore, the patient was sent to have a left pharyngectomy. After the pharyngectomy, the patient reported persistent swallowing disorders and nasal reflux. Consequently, she had an oropharyngoesophageal scintigraphy, demonstrating irregular oral and pharyngeal swallowing phases and confirming reflux episodes into the rhinopharynx and into the oropharynx. In line with these findings, the patient was send to rehabilitation; the abnormal functional mechanisms, previously identified by the scintigraphy, allowed to guide the speech therapy, with a progressive clinical improvement.

Clinical characteristics of metabolic associated fatty liver disease (MAFLD) in subjects with myotonic dystrophy type 1 (DM1).

BACKGROUND: Myotonic dystrophy type 1 (DM1) is a rare inherited neuromuscular disease associated with insulin resistance, and its association with metabolically associated fatty liver disease (MAFLD) has never been explored in prospective studies. The aim of this study was to assess the clinical features of MAFLD in DM1 patients. METHODS: We investigated the prevalence and the diagnostic features of MAFLD in a cohort of 29 outpatient fully characterized DM1 patients; afterward, we compared the selected cohort of DM1-MAFLD individuals with a propensity-matched cohort of non-DM1-MAFLD RESULTS: 13/29 (44.83%) DM1 patients received a clinical diagnosis of MAFLD. Compared to DM1 patients with normal liver, DM1-MAFLD individuals showed a higher male prevalence (p = 0.008), BMI (p = 0.014), HOMA score (p = 0.012), and GGT levels (p = 0.050). The statistical comparison showed that the DM1-MAFLD group had a more severe MAFLD according to the FIB4 score than non-DM1-MAFLD patients. This association of a more severe form of liver disease with DM1 remained significant after logistic regression analysis (OR: 6.12, 95% CI 1.44- 26.55).

11C-Methionine PET/CT in patients with primary hyperparathyroidism and inconclusive pre-operative imaging work-up: diagnostic accuracy and role of semi-quantitative analysis.

OBJECTIVE: 11C-Methionine PET/CT (C-MET) is a promising method in detecting abnormal parathyroid glands in patients with primary hyperparathyroidism (PHPT). The first aim of the study was to evaluate which is the diagnostic role of C-MET in patients with PHPT and inconclusive pre-operative imaging. Second, we aimed to investigate whether C-MET semi-quantitative parameters may reflect biochemical and histological characteristics of involved glands. METHODS: Patients with PHPT, undergoing C-MET after an inconclusive pre-operative imaging and having a parathyroid surgery, were retrospectively included. C-MET visual and semi-quantitative assessment was performed. Parameters, as SUVmax, SUVpeak, SUVmean, functional lesion volume (FLV) and total lesion activity (TLA), were measured for each detected lesion; SUVmean, FLV and TLA were calculated on 40-90% thresholds of SUVmax to define SUVmean40-90, FLV40-90 and TLA40-90, respectively. Results were correlated with patients' clinical-laboratory (calcium and PTH values) and histological data (size and weight of excised glands). Mann-Whitney test was used and P value < 0.05 was considered significant. RESULTS: Thirty-eight patients (36 female, age: 57.69 ± 15.13 years) were included. Pre-operative median calcium and PTH values were 11.1 mg/dl [interquartile range (IQR) 10.6-11.5] and 154.6 pg/ml (IQR 101.8-227.0), respectively. C-MET showed a parathyroid uptake in 30 out of thirty-eight patients (78.9%). Among 42 nodules excised, C-MET correctly detected the side of the neck (right/left) in 30/42 with sensitivity, specificity and accuracy of 79, 75 and 79%, respectively. C-MET correctly identified the exact position (superior/inferior) in 27/42 with sensitivity, specificity and accuracy of 75, 50 and 71%, respectively. SUVpeak, FLV50-70 and TLA40-70 were significantly (P < 0.05) higher in patients with higher PTH results. The histological size resulted significantly (P < 0.05) higher in abnormal glands with higher SUVmax, SUVpeak, FLV40-80 and TLA40-90, the weight was higher in glands with higher SUVpeak, SUVmean40-50, FLV40-80 and TLA40-90. CONCLUSIONS: C-MET showed a good performance in detecting hyperfunctioning parathyroid glands in PHPT patients with inconclusive pre-operative imaging. Semi-quantitative PET-derived parameters closely correlated with PTH as well as with size and weight of the excised gland, thus reflecting some biochemical and histological characteristics of involved glands.

Incidental Finding of an Ovarian Carcinoid on 11C-Methionine PET/CT.

A 68-year-old woman with a history of multiple myeloma on regular hematological follow-up and with no previous relevant gynecological diseases was found to have an incidental focal uptake by the right ovary at C-methionine PET/CT (C-MET). Transvaginal ultrasound was then performed showing a 2-cm solid right ovarian mass with irregular borders and moderate vascularization at color Doppler examination. Therefore, the patient underwent bilateral salpingectomy, and the final histological results revealed a rare presentation of mature teratoma with insular carcinoid tumor arising from the right ovary.

High Prevalence and Gender-Related Differences of Gastrointestinal Manifestations in a Cohort of DM1 Patients: A Perspective, Cross-Sectional Study.

Myotonic dystrophy type 1 (DM1, MIM #160900), the most common muscular dystrophy among adults, is a multisystem disorder, which affects, besides the skeletal muscle, several other tissues and/or organs, including the gastrointestinal apparatus, with manifestations that frequently affect the quality of life of DM1 patients. So far, only few, mainly retrospective studies evaluated this specific topic in DM1, so we performed a perspective study, enrolling 61 DM1 patients who underwent an extensive diagnostic protocol, including administration of the Gastrointestinal Symptom Rating Scale (GSRS), a validated patient-reported questionnaire about GI symptoms, laboratory tests, liver US scan, and an intestinal permeability assay, in order to characterize frequency and assess correlations regarding specific gastrointestinal manifestations with demographic or other DM1-related features. Our results in our DM1 cohort confirm the high frequency of various gastrointestinal manifestations, with the most frequent being constipation (45.9%). γGT levels were pathologically increased in 65% of DM1 patients and GPT in 29.82%; liver ultrasound studies showed steatosis in 34.4% of patients. Significantly, 91.22% of DM1 patients showed signs of altered intestinal permeability at the specific assay. We documented a gender-related prevalence and severity of gastrointestinal manifestations in DM1 females compared to DM1 males, while males showed higher serum GPT and γGT levels than females. Correlation studies documented a direct correlation between severity of muscle weakness estimated by MIRS score and γGT and alkaline phosphatase levels, suggesting their potential use as biomarkers of muscle disease severity in DM1.

Radioguided surgery with ß- radiation in pancreatic Neuroendocrine Tumors: a feasibility study.

The possibility to use ß- decaying isotopes for radioguided surgery (RGS) has been recently proposed, and first promising tests on ex-vivo samples of Meningioma and intestinal Neuroendocrine Tumor (NET) have been published. This paper reports a study of the uptake of 68Ga-DOTATOC in pancreatic NETs (pNETs) in order to assess the feasibility of a new RGS approach using 90Y-DOTATOC. Tumor and healthy pancreas uptakes were estimated from 68Ga-DOTATOC PET/CT scans of 30 patients with pNETs. From the obtained SUVs (Standardised Uptake Value) and TNRs (Tumor Non tumor Ratio), an analysis algorithm relying on a Monte Carlo simulation of the detector has been applied to evaluate the performances of the proposed technique. Almost all considered patients resulted to be compatible with the application of ß--RGS assuming to administer 1.5 MBq/kg of activity of 90Y-DOTATOC 24 h before surgery, and a sampling time of few seconds. In just 2 cases the technique would have required a mildly increased amount of activity or of sampling time. Despite a high physiological uptake of 68Ga-DOTATOC in the healthy pancreas, the proposed RGS technique promises to be effective. This approach allows RGS to find application also in pancreatic diseases, where traditional techniques are not viable.

Radioguided surgery with ß radiation: a novel application with Ga68.

Radio Guided Surgery is a technique helping the surgeon in the resection of tumors: a radiolabeled tracer is administered to the patient before surgery and then the surgeon evaluates the completeness of the resection with a handheld detector sensitive to emitted radiation. Established methods rely on γ emitting tracers coupled with γ detecting probes. The efficacy of this technique is however hindered by the high penetration of γ radiation, limiting its applicability to low background conditions. To overtake such limitations, a novel approach to RGS has been proposed, relying on ß- emitting isotopes together with a dedicated ß probe. This technique has been proved to be effective in first ex-vivo trials. We discuss in this paper the possibility to extend its application cases to 68Ga, a ß+ emitting isotope widely used today in nuclear medicine. To this aim, a retrospective study on 45 prostatic cancer patients was performed, analysing their 68Ga-PSMA PET images to asses if the molecule uptake is enough to apply this technique. Despite the expected variability both in terms of SUV (median 4.1, IQR 3.0-6.1) and TNR (median 9.4, IQR 5.2-14.6), the majority of cases have been found to be compatible with ß-RGS with reasonable injected activity and probing time (5 s).

Bile Collection Detected With BrIDA Scintigraphy in a Patient With Hepatocellular Carcinoma.

A 47-year-old man, with a history of anabolic steroid abuse, developed hepatic adenomatosis and multifocal hepatocellular carcinoma. He underwent ultrasound and CT follow-up, showing multiple solid and fluid hepatic lesions. Consequently, hospitalization was required because of high fever (up to 39°C), weakness, and anorexia. An abdominal CT scan revealed an enlargement of one of the intrahepatic fluid collections. Biochemical and microbiological analyses of a fluid sample showed bilirubin and bile acids as well as Streptococcus cristatus and Enterobacter cloacae. Thus, the patient underwent Tc-trimethylbromo-iminodiacetic acid scintigraphy, demonstrating bile collection in the lesion with a flow from a bile duct.

Mass spectrometry characterization of DOTA-Nimotuzumab conjugate as precursor of an innovative ß- tracer suitable in radio-guided surgery.

The aim of the present work has been the mass spectrometry characterization of the Nimotuzumab (NIM) antibody chemically modified with the bifunctional chelating agent para-S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraaza cyclododecanetetraacetic acid (p-SCN-Bn-DOTA). The conjugate, upon labeling with the pure ß--emitter 90Y3+, could represent a promising candidate as radiotracer for an innovative radio-guided surgery (RGS) technique, developed and patented by researchers of our group, which uses a probe system for intraoperative detection of tumor residues exploiting the selective uptake of ß--emitting tracers. The results reported in this study show that multiple DOTA molecules bind to lysine residues of both light and heavy chains of the antibody and, probably, some of them are linked to the variable region of antibody. Moreover, the new mass spectrometric analysis highlights the presence of unreacted NIM in the final product. The information obtained by this work is of fundamental importance in the perspective to utilize this conjugate as a radiocompound after its labeling with 90Y3+ radioisotope. Indeed, the conjugation efficiency and the presence of unreacted NIM affect the specific activity of the final radiotracer which binds specific receptor.

Feasibility of beta-particle radioguided surgery for a variety of "nuclear medicine" radionuclides.

PURPOSE: Beta-particle radioguided tumor resection may potentially overcome the limitations of conventional gamma-ray guided surgery by eliminating, or at least minimizing, the confounding effect of counts contributed by activity in adjacent normal tissues. The current study evaluates the clinical feasibility of this approach for a variety of radionuclides. Nowadays, the only ß- radioisotope suited to radioguided surgery is 90Y. Here, we study the ß- probe prototype capability to different radionuclides chosen among those used in nuclear medicine. METHODS: The counting efficiency of our probe prototype was evaluated for sources of electrons and photons of different energies. Such measurements were used to benchmark the Monte Carlo (MC) simulation of the probe behavior, especially the parameters related to the simulation of the optical photon propagation in the scintillation crystal. Then, the MC simulation was used to derive the signal and the background we would measure from a small tumor embedded in the patient body if one of the selected radionuclides is used. RESULTS: Based on the criterion of detectability of a 0.1 ml tumor for a counting interval of 1 s and an administered activity of 3 MBq/kg, the current probe yields a detectable signal over a wide range of Standard Uptake Values (SUVs) and tumor-to-non-tumor activity-concentration ratios (TNRs) for 31Si, 32P, 97Zr, and 188Re. Although efficient counting of 83Br, 133I, and 153Sm proved somewhat more problematic, the foregoing criterion can be satisfied for these isotopes as well for sufficiently high SUVs and TNRs.

Prospective electromyographic evaluation of functional postthyroidectomy voice and swallowing symptoms.

BACKGROUND: Voice and swallowing symptoms following thyroidectomy in the absence of any demonstration of laryngeal nerves injury are usually considered a functional outcome of uncomplicated operations, mainly related to scar formation and emotional reaction. They could be related to unapparent laryngeal nerve or cricothyroid (CT) muscle injuries detectable only by laryngeal electromyography (LEMG). We correlated such symptoms with LEMG patterns. METHODS: A total of 33 consenting patients undergoing total thyroidectomy (TT) were enrolled. Video-strobolaryngoscopy (VSL), acoustic voice analysis (AVA), and maximum phonation time (MPT) were performed preoperatively and 3 months postoperatively. Subjective evaluation of voice (Voice Impairment Score, or VIS) and swallowing (Swallowing Impairment Score, or SIS) were obtained preoperatively and 1 and 3 months postoperatively. At 1 month postoperatively LEMG was performed examining thyroarytenoid (TA) and CT muscles to evaluate the inferior laryngeal nerve (ILN) and the external branch of the superior laryngeal nerve (EBSLN), respectively. RESULTS: One patient experienced transient vocal cord palsy and was excluded. The remaining 32 patients completed the postoperative evaluation. No significant difference was found between preoperative and postoperative AVA and MPT parameters. Mean VIS was significantly worse than preoperatively 1 and 3 months after TT. No significant difference was found between preoperative and postoperative SIS. LEMG evaluation of TA muscle showed decreased voluntary activity and spontaneous fibrillation potentials in one patient. LEMG of the CT muscle did not reveal any sign of EBSLN injury. CONCLUSIONS: Patients frequently complain of subjective symptoms early after TT. LEMG demonstrated the absence of subclinical laryngeal nerve injury in all but one patient, confirming their functional nature.

Long-term outcome of functional post-thyroidectomy voice and swallowing symptoms.

BACKGROUND: Voice and swallowing symptoms are frequently reported early after thyroidectomy even in the absence of laryngeal nerves injury. We evaluated the short-term and long-term outcomes of these functional alterations. METHODS: Consenting patients undergoing total thyroidectomy (TT) were enrolled. Videolaryngostroboscopy (VSL), acoustic voice analysis (AVA), and maximum phonation time (MPT) were performed pre-operatively, 3 months postoperatively, and >1 year postoperatively. Subjective evaluation of voice (Voice Impairment Score=VIS) and swallowing (Swallowing Impairment Score=SIS) were obtained pre-operatively, as well as 1 week, 1 month, 3 months, and >1 year postoperatively. RESULTS: The long-term evaluation was completed in 110 patients. The percentage of patients with symptoms 1 week after operation was significantly higher than preoperatively, whereas it was significantly lower at long-term evaluation. VIS was significantly worse than pre-operatively, 1 week, 1 month, and 3 months after surgery, but it was similar to pre-operative >1 year after TT. SIS was significantly worse 1 week after thyroidectomy but not 1 month and 3 months after thyroidectomy, and it was significantly lower than the pre-operative >1 year after TT. CONCLUSION: Vocal and swallowing symptoms are frequent after TT. In the absence of laryngeal nerve injury, after an initial impairment, late after operation, patients experienced subjective amelioration of their voice and swallowing performances, which may be related to the resolution of compressive symptoms.

Video-assisted thyroidectomy significantly reduces the risk of early postthyroidectomy voice and swallowing symptoms.

BACKGROUND: Voice and swallowing symptoms are frequently reported after thyroidectomy even in absence of objective voice alterations. We evaluated the influence of the video-assisted approach on voice and swallowing outcome of thyroidectomy. METHODS: Sixty-five patients undergoing total thyroidectomy (TT) were recruited. Eligibility criteria were: nodule size