Unconventional non-amino acidic PET radiotracers for molecular imaging in gliomas.

PURPOSE: The objective of this review was to explore the potential clinical application of unconventional non-amino acid PET radiopharmaceuticals in patients with gliomas. METHODS: A comprehensive search strategy was used based on SCOPUS and PubMed databases using the following string: ("perfusion" OR "angiogenesis" OR "hypoxia" OR "neuroinflammation" OR proliferation OR invasiveness) AND ("brain tumor" OR "glioma") AND ("Positron Emission Tomography" OR PET). From all studies published in English, the most relevant articles were selected for this review, evaluating the mostly used PET radiopharmaceuticals in research centers, beyond amino acid radiotracers and 2-[18F]fluoro-2-deoxy-D-glucose ([18F]FDG), for the assessment of different biological features, such as perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological characteristics in patients with glioma. RESULTS: At present, the use of non-amino acid PET radiopharmaceuticals specifically designed to assess perfusion, angiogenesis, hypoxia, neuroinflammation, cell proliferation, tumor invasiveness, and other biological features in glioma is still limited. CONCLUSION: The use of investigational PET radiopharmaceuticals should be further explored considering their promising potential and studies specifically designed to validate these preliminary findings are needed. In the clinical scenario, advancements in the development of new PET radiopharmaceuticals and new imaging technologies (e.g., PET/MR and the application of the artificial intelligence to medical images) might contribute to improve the clinical translation of these novel radiotracers in the assessment of gliomas.

Serial scanning with 99mTc-3, 3-diphosphono-1, 2-propanodicarboxylic acid (99mTc-DPD) for early detection of cardiac amyloid deposition and prediction of clinical worsening in subjects carrying a transthyretin gene mutation.

BACKGROUND: To determine the capability of 99mTc-DPD scintigraphy to detect early cardiac involvement and predict clinical worsening in transthyretin (TTR) gene mutation patients. METHODS: Eleven mutated subjects with normal interventricular septum (IVS) thickness, NT-proBNP level and no cardiac symptoms underwent three seriate 99mTc-DPD scans (visually and semiquantitatively analyzed), and was followed-up for 5-8-years. RESULTS: Six patients showed no myocardial accumulation in all scans. Increased IVS thickness occurring in one patient 4 years after the last scan was the only abnormal finding in these patients; no cardiac symptoms developed during the follow-up. In three patients, cardiac radiotracer uptake was found at enrollment; other laboratory/instrumental abnormal findings occurred later and cardiac symptoms developed during the follow-up period. Two patients had a negative 99mTc-DPD scan at enrollment and showed cardiac uptake in the following scans. Increased mean left-ventricular (LV) wall thickness was found 3 years after positive scintigraphy; NT-proBNP increased later in one patient. These patients developed cardiac symptoms during the follow-up period. CONCLUSIONS: 99mTc-DPD scan detects cardiac involvement in subjects with TTR gene mutation earlier than ECG, echocardiography and biochemical markers, occurring some years before the fulfillment of current diagnostic criteria for cardiac amyloidosis. A positive 99mTc-DPD scan predicts cardiac symptoms onset.

Impact of the SARS-CoV2 pandemic dissemination on the management of neuroendocrine neoplasia in Italy: a report from the Italian Association for Neuroendocrine Tumors (Itanet).

INTRODUCTION: The organization of the healthcare system has significantly changed after the recent COVID-19 outbreak, with a negative impact on the management of oncological patients. The present survey reports data collected by the Italian Association for Neuroendocrine Tumors on the management of patients with neuroendocrine neoplasia (NEN) during the pandemic dissemination. METHODS: A survey with 57 questions was sent to NEN-dedicated Italian centers regarding the management of patients in the period March 9, 2020, to May 9, 2020 RESULTS: The main modification in the centers' activity consisted of decreases in newly diagnosed NEN patients (- 76.8%), decreases in performed surgical procedures (- 58%), delays to starting peptide receptor radionuclide therapy (45.5%), postponed/canceled follow-up examinations (26%), and canceled multidisciplinary teams' activity (20.8%). A low proportion of centers (< 10%) reported having to withdraw systemic anti-tumor medical treatment due to concerns about the pandemic situation, whereas PRRT was withdrawn from no patients. CONCLUSION: Although the COVID-19 outbreak induced the centers to reduce some important activities in the management of NEN patients, the Italian network was able to provide continuity in care without withdrawing anti-tumor treatment for the majority of patients.

Peptide receptor radionuclide therapy for aggressive pituitary tumors: a monocentric experience.

In aggressive pituitary tumors (PT) showing local invasion or growth/recurrence despite multimodal conventional treatment, temozolomide (TMZ) is considered a further therapeutic option, while little data are available on peptide receptor radionuclide therapy (PRRT). We analyzed PRRT effectiveness, safety and long-term outcome in three patients with aggressive PT, also reviewing the current literature. Patient #1 (F, giant prolactinoma) received five cycles (total dose 37 GBq) of 111In-DTPA-octreotide over 23 months, after unsuccessful surgery and long-term dopamine-agonist treatment. Patient #2 (M, giant prolactinoma) underwent two cycles (12.6 GBq) of 177Lu-DOTATOC after multiple surgeries, radiosurgery and TMZ. In patient #3 (F, non-functioning PT), five cycles (29.8 GBq) of 177Lu-DOTATOC followed five surgeries, radiotherapy and TMZ. Eleven more cases of PRRT-treated aggressive PT emerged from literature. Patient #1 showed tumor shrinkage and visual/neurological amelioration over 8-year follow-up, while the other PTs continued to grow causing blindness and neuro-cognitive disorders (patient #2) or monolateral amaurosis (patient #3). No adverse effects were reported. Including the patients from literature, 4/13 presented tumor shrinkage and clinical/biochemical improvement after PRRT. Response did not correlate with patients' gender or age, neither with used radionuclide/peptide, but PRRT failure was significantly associated with previous TMZ treatment. Overall, adverse effects occurred only in two patients. PRRT was successful in 1/3 of patients with aggressive PT, and in 4/5 of those not previously treated with TMZ, representing a safe option after unsuccessful multimodal treatment. However, at present, considering the few data, PRRT should be considered only in an experimental setting.

Combined BRAFV600E analysis and 99mTc-MIBI scintigraphy can be a useful diagnostic tool in differentiated thyroid cancer patients with incomplete bio-chemical response to first radioiodine therapy (RAIT): a pilot investigation.

PURPOSE: The aim of the present study was to evaluate the possible diagnostic role of the combined performance of BRAF mutation analysis and MIBI scintigraphy in papillary thyroid cancer (PTC) patients with incomplete bio-chemical response to first radioiodine therapy (RAIT) performed for thyroid remnant ablation. METHODS: The records of 15 PTC patients with bio-chemical incomplete response to first RAIT were retrospectively analyzed. BRAFV600E analysis on primary tumor samples was obtained in all cases along with neck ultrasonography and 99mTc-MIBI scintigraphy of the neck-thorax regions at first follow-up. All patients then underwent RAIT with high radioiodine activities. A post-therapy whole-body scan (pT-WBS) was acquired 5-7 days after RAIT. RESULTS: Abnormal radioiodine uptake was found in 10 out of the 15 patients (67%, 131I+ve), while in the remaining 33%, no abnormal radioiodine uptake was detected (5/15, 131I-ve). Abnormal tracer uptake was found in 6 out of 10 131I+ve patients at 99mTc-MIBI scintigraphy (MIBI+ve). BRAFV600E mutation was not found in the majority of 131I+ve patients (9 out of 10 BRAFV600E-ve). On the contrary, in the 5 131I-ve patients, 99mTc-MIBI scintigraphy did not show any abnormal tracer uptake (MIBI-ve), while BRAFV600E mutation was present (BRAFV600E+ve). Thus, in our series, the association between MIBI-ve scintigraphy and BRAF+ve mutation was a useful diagnostic tool in predicting negative pT-WBS outcome. CONCLUSION: Albeit obtained in a small retrospective series, our results suggest that the combination of BRAFV600E+ve mutation and MIBI-ve scintigraphy may be considered a negative prognostic clue, which predicts the absence of radioiodine uptake at pT-WBS in DTC patients with incomplete bio-chemical response to first RAIT.

Multicentre clinical evaluation of the new highly sensitive Elecsys® thyroglobulin II assay in patients with differentiated thyroid carcinoma.

OBJECTIVE: A highly sensitive thyroglobulin assay (Elecsys® Tg II, Roche Diagnostics, Penzberg, Germany) has become available for monitoring patients with differentiated thyroid cancer (DTC). Here, we evaluated the clinical performance of Elecsys® Tg II assay in a multicentre patients series and compare it with the established Access® Tg assay (Beckman Coulter, Brea, CA, USA). DESIGN: Retrospective analysis on prospectively selected patients in four thyroid cancer referral centres with uniform DTC management. PARTICIPANTS: All DTC cases diagnosed, treated and followed up in four tertiary referral centres for thyroid cancer since January 2005 (n = 1456) were retrieved, and predefined selection criteria were applied to prevent relevant enrolment biases. A series of 204 patients was finally selected for this study. MEASUREMENTS: Samples had been stored at -80°C. Tg was measured by fully automated immunometric Elecsys® Tg II and Access® Tg assays in a centralized laboratory. RESULTS: Two hundred and four DTC were finally included. Of these, 10.8% had structural recurrence (sREC), and 81.4% showed no evidence of disease (NED) at the end of follow-up. There was a significant analytical bias between methods that cannot be used interchangeably. Using ROC curve analysis, the best basal and rhTSH-stimulated Tg cut-offs to detect sREC were 0.41 µg/L and 1.82 µg/L for Elecsys® and 0.36 µg/L and 1.62 µg/L for Access® assay, respectively. Using Cox proportional hazard regression, Tg was the only independent predictor of cancer relapse. CONCLUSIONS: Using appropriate assay-specific cut-offs, the clinical performance of the Elecsys® Tg II assay was comparable to that provided by the well-established Access® Tg assay.

Differentiating malignant from benign thyroid nodules with indeterminate cytology by 99mTc-MIBI scan: a new quantitative method for improving diagnostic accuracy.

Quantitative 99mTc-MIBI thyroid scintigraphy is a useful tool in differentiating malignant from benign thyroid nodules with indeterminate cytology. The aim of our report is to compare the diagnostic performance of different quantitative methods. We prospectively evaluated 20 patients affected by a thyroid nodule with 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 99mTc-MIBI administration and two different quantitative methods applied (i.e. wash-out index, WOind; retention index, R.I.). All patients underwent lobectomy or thyroidectomy and final histological findings were matched with MIBI results obtained with both quantitative methods. Four out of 20 patients had a final histological result of differentiated thyroid cancer, while benign findings were found in the remaining cases. Overall sensitivity, specificity, accuracy, PPV and NPV were 100% in all for the WOind and 100%, 57.1%, 62.5%, 25% for the R.I., respectively. In conclusion 99mTc-semiquantitative MIBI thyroid scintigraphy with WOind calculation is highly accurate in differential diagnosis of nodules with indeterminate cytology reading.

Targeting MKK3 as a novel anticancer strategy: molecular mechanisms and therapeutical implications.

Mitogen-activated protein kinase kinase 3 (MAP2K3, MKK3) is a member of the dual specificity protein kinase group that belongs to the MAP kinase kinase family. This kinase is activated by mitogenic or stress-inducing stimuli and participates in the MAP kinase-mediated signaling cascade, leading to cell proliferation and survival. Several studies highlighted a critical role for MKK3 in tumor progression and invasion, and we previously identified MKK3 as transcriptional target of mutant (mut) p53 to sustain cell proliferation and survival, thus rendering MKK3 a promising target for anticancer therapies. Here, we found that targeting MKK3 with RNA interference, in both wild-type (wt) and mutp53-carrying cells, induced endoplasmic reticulum stress and autophagy that, respectively, contributed to stabilize wtp53 and degrade mutp53. MKK3 depletion reduced cancer cell proliferation and viability, whereas no significant effects were observed in normal cellular context. Noteworthy, MKK3 depletion in combination with chemotherapeutic agents increased tumor cell response to the drugs, in both wtp53 and mutp53 cancer cells, as demonstrated by enhanced poly (ADP-ribose) polymerase cleavage and reduced clonogenic ability in vitro. In addition, MKK3 depletion reduced tumor growth and improved biological response to chemotherapeutic in vivo. The overall results indicate MKK3 as a novel promising molecular target for the development of more efficient anticancer treatments in both wtp53- and mutp53-carrying tumors.

Mutant p53 gains new function in promoting inflammatory signals by repression of the secreted interleukin-1 receptor antagonist.

The TP53 tumor-suppressor gene is frequently mutated in human cancer. Missense mutations can add novel functions (gain-of-function, GOF) that promote tumor malignancy. Here we report that mutant (mut) p53 promotes tumor malignancy by suppressing the expression of a natural occurring anti-inflammatory cytokine, the secreted interleukin-1 receptor antagonist (sIL-1Ra, IL1RN). We show that mutp53 but not wild-type (wt) p53 suppresses the sIL-1Ra production in conditioned media of cancer cells. Moreover, mutp53, but not wtp53, binds physically the sIL-1Ra promoter and the protein-protein interaction with the transcriptional co-repressor MAFF (v-MAF musculoaponeurotic fibrosarcoma oncogene family, protein F) is required for mutp53-induced sIL-1Ra suppression. Remarkably, when exposed to IL-1 beta (IL-1ß) inflammatory stimuli, mutp53 sustains a ready-to-be-activated in vitro and in vivo cancer cells' response through the sIL-1Ra repression. Taken together, these results identify sIL-1Ra as a novel mutp53 target gene, whose suppression might be required to generate a chronic pro-inflammatory tumor microenvironment through which mutp53 promotes tumor malignancy.

The WRN and MUS81 proteins limit cell death and genome instability following oncogene activation.

Oncogene-induced replication stress is recognized as the primary cause of accumulation of DNA damage and genome instability in precancerous cells. Although the molecular mechanisms responding to such type of replication perturbation are not fully characterized, it has been speculated that their dysfunction may enhance genome instability and accelerate tumor progression. Here, we show that the WRN protein, a member of the human RecQ helicases, is necessary to sustain replication fork progression in response to oncogene-induced replication stress. Loss of WRN affects cell cycle progression and results in enhanced accumulation of double-strand breaks and instability at common fragile sites in cells experiencing oncogene-induced replication stress. Moreover, we demonstrate that double-strand breaks, observed upon oncogene over-expression, depend on the MUS81 endonuclease, which represents a parallel pathway collaborating with WRN to prevent cell death. Overall, our findings give insights into the mechanisms protecting replication forks in cells experiencing oncogene-induced replication stress, and identify factors that, when mutated or dysfunctional, may enhance genome instability in precancerous cells. In addition, because concomitant depletion of WRN and MUS81 causes synthetic sickness in cells growing under oncogene-induced replication stress, our results support the possibility of targeting cancer cells with an impaired replication fork recovery pathway by a specific inactivation of the other parallel pathway.

First demonstration of the effectiveness of peptide receptor radionuclide therapy (PRRT) with 111In-DTPA-octreotide in a giant PRL-secreting pituitary adenoma resistant to conventional treatment.

In prolactin-secreting giant adenomas, cabergoline treatment is the first line approach. Surgery and/or radiotherapy are indicated when the tumour is resistant to medical treatment and continues growing, causing visual field impairment. Data concerning other therapeutic approach are scanty. Although PRL-secreting tumours may express somatostatin receptors type 2, 3 and 5, somatostatin analogs treatment is generally ineffective and peptide receptor radionuclide therapy (PRRT) has never been reported. A 58 year-old woman complaining of severe neurological symptoms caused by a giant prolactinoma, relapsing after surgery and not-responding to dopamine-agonists and octreotide LAR treatment, underwent four cycles of PRRT with 111-Indium-DTPA-octreotide with remarkable tumour shrinkage and a significant improvement in clinical conditions. No side effects were reported. This is the first report on the effectiveness and safety of PRRT with radio-labelled somatostatin analogs in a patient with aggressive giant prolactinoma resistant to conventional treatment.

Association of autonomously functioning thyroid nodules with Hashimoto's thyroiditis: study on a large series of patients.

OBJECTIVE: Autonomously functioning thyroid nodules (AFTNs) associated with Hashimoto's thyroiditis (HT) are rarely reported. This study evaluates the magnitude of such association, elaborating the clinical and biochemical characteristics of HT and AFTN. MATERIALS AND METHODS: We reviewed the records of our patients with thyroid nodules, including serum TSH, free T4 and T3, Tg-Ab, TPO-Ab, ultrasonography, Tc-99m Sodium Pertechnetate scintigraphy (performed in overt or subclinical hyperthyroid patients). HT patients with coexisting AFTN(s) (group A) were compared with patients with AFTNs alone (group B, n=267). RESULTS: 80 patients (65 women and 15 men; F:M ratio 4.3:1; age 57±15 years) had AFTN(s) and coexisting HT. Except 9 patients who were under methimazole, all had suppressed (<0.01 mU/L) or low (<0.4 mU/L) TSH; 17/71 (24%) had increased FT4 and/or FT3. Subclinical hyperthyroidism prevailed over frank hyperthyroidism in group A (76 vs. 24%), but not in group B (56 vs. 44%) ( P=0.005). Group A patients had lower serum FT3 (∼0.6 pmol/L or 9%) and FT4 (∼0.9 pmol/L or 4%) as compared to group B. The maximum diameter of the AFTN(s) was 8% smaller in group A as compared with group B, thus matching the said difference in FT3. A positive correlation between nodule size and age was found only in group B ( P=0.015). CONCLUSION: Even if difference in the size of nodules between groups A and B does not reach statistical significance, the chronic intrathyroid lymphocytic infiltration of HT may decrease the tendency of the AFTNs to grow and diminish their degree of functioning.

An analytical model for improving absorbed dose calculation accuracy in non spherical autonomous functioning thyroid nodule.

AIM: Patients candidate to radioiodine treatment of autonomous functioning thyroid nodule (AFTN) are characterized by a wide range of nodule volumes with different shapes. To optimize the treatment, pretherapeutic dosimetry should account also for the dependence of deposited energy on the nodule geometry. METHODS: We developed a Monte Carlo code in Geant4 to simulate the interaction of beta and gamma radiations emitted by Na-131I into ellipsoidal volumes of soft tissue homogeneously uptaking the radionuclide, surrounded by a simplified antropomorphic phantom. We simulated 9 volumes between 0.1 and 50 cm3, each one with 8 different ellipsoidal shapes. We considered the data of 10 patients affected by AFTN, whose nodule volumes were in the range 1-40 cm3, who underwent radioiodine therapy following the traditional dosimetric approach. The patients underwent ultrasonographic (US) study, in order to determine the nodule volume, and radioiodine thyroid uptake measurements between 3 and 168 hours after radioiodine tracer dose administration. RESULTS: We found an analytical relationship between the average deposited energy and the ellipsoid's semiaxes and we included it in the formula for the calculation of activity to be administered, A0. For the 10 patients studied, A0 calculated with our approach ranges from +9% to -2% with respect to the one calculated with the traditional formula. CONCLUSION: The proposed model, accounting for the dependence of beta and gamma absorbed fractions from nodule volume and shape, can lead to a more accurate estimation of A0 during AFTN therapy. Since the measurement of nodule axes is routinely obtained from pretherapeutic US, our approach can be introduced in the clinical practice without changing the diagnostic pre-therapeutic protocol.

Absorbed fractions for electrons in ellipsoidal volumes.

We applied a Monte Carlo simulation in Geant4 in order to calculate the absorbed fractions for monoenergetic electrons in the energy interval between 10 keV and 2 MeV, uniformly distributed in ellipsoids made from soft tissue. For each volume, we simulated a spherical shape, four oblate and four prolate ellipsoids, and one scalene shape. For each energy and for every geometrical configuration, an analytical relationship between the absorbed fraction and a 'generalized radius' was found, and the dependence of the fit parameters from electron energy is discussed and fitted by proper parametric functions. With the proposed formulation, the absorbed fraction for electrons in the 10-2000 keV energy range can be calculated for all volumes and for every ellipsoidal shape of practical interest. This method can be directly applied to evaluation of the absorbed fraction from the radionuclide emission of monoenergetic electrons, such as Auger or conversion electrons. The average deposited energy per disintegration in the case of extended beta spectra can be evaluated through integration. Two examples of application to a pure beta emitter such as (90)Y and to (131)I, whose emission include monoenergetic and beta electrons plus gamma photons, are presented. This approach represent a generalization of our previous studies, allowing a comprehensive treatment of absorbed fractions from electron and photon sources uniformly distributed in ellipsoidal volumes of any ellipticity and volume, in the whole range of practical interest for internal dosimetry in nuclear medicine applications, as well as in radiological protection estimations of doses from an internal contamination.

Absorbed fractions for photons in ellipsoidal volumes.

We studied through Monte Carlo simulation in Geant4 the absorbed fractions for photons, characterized by energies ranging from 10 keV to 1000 keV, which can be emitted by gamma radionuclides uniformly distributed in ellipsoidal volumes of soft tissue. The same analytical relationship between absorbed fraction and the 'generalized radius' as introduced in a previous paper was found, and the dependence of its parameters rho(0) and s on photon energy is discussed and fitted by suitably chosen parametric functions. As a consequence, the absorbed fraction for photons in the 10-1000 keV energy range can be calculated for all volumes and for every ellipsoidal shape of practical interest. Such results can be a useful complement for the dosimetry of beta- and gamma-emitting radionuclides during internal radiotherapy or gamma emitters employed in diagnostic nuclear medicine.