Immune-monitoring of myelodysplastic neoplasms: Recommendations from the i4MDS consortium.

Advancements in comprehending myelodysplastic neoplasms (MDS) have unfolded significantly in recent years, elucidating a myriad of cellular and molecular underpinnings integral to disease progression. While molecular inclusions into prognostic models have substantively advanced risk stratification, recent revelations have emphasized the pivotal role of immune dysregulation within the bone marrow milieu during MDS evolution. Nonetheless, immunotherapy for MDS has not experienced breakthroughs seen in other malignancies, partly attributable to the absence of an immune classification that could stratify patients toward optimally targeted immunotherapeutic approaches. A pivotal obstacle to establishing "immune classes" among MDS patients is the absence of validated accepted immune panels suitable for routine application in clinical laboratories. In response, we formed International Integrative Innovative Immunology for MDS (i4MDS), a consortium of multidisciplinary experts, and created the following recommendations for standardized methodologies to monitor immune responses in MDS. A central goal of i4MDS is the development of an immune score that could be incorporated into current clinical risk stratification models. This position paper first consolidates current knowledge on MDS immunology. Subsequently, in collaboration with clinical and laboratory specialists, we introduce flow cytometry panels and cytokine assays, meticulously devised for clinical laboratories, aiming to monitor the immune status of MDS patients, evaluating both immune fitness and identifying potential immune "risk factors." By amalgamating this immunological characterization data and molecular data, we aim to enhance patient stratification, identify predictive markers for treatment responsiveness, and accelerate the development of systems immunology tools and innovative immunotherapies.

Genetic deletion of astrocytic calcineurin B1 prevents cognitive impairment and neuropathology development in acute and chronic mouse models of Alzheimer's disease.

Alzheimer's disease (AD) represents an urgent yet unmet challenge for modern society, calling for exploration of innovative targets and therapeutic approaches. Astrocytes, main homeostatic cells in the CNS, represent promising cell-target. Our aim was to investigate if deletion of the regulatory CaNB1 subunit of calcineurin in astrocytes could mitigate AD-related memory deficits, neuropathology, and neuroinflammation. We have generated two, acute and chronic, AD mouse models with astrocytic CaNB1 ablation (ACN-KO). In the former, we evaluated the ability of ß-amyloid oligomers (AßOs) to impair memory and activate glial cells once injected in the cerebral ventricle of conditional ACN-KO mice. Next, we generated a tamoxifen-inducible astrocyte-specific CaNB1 knock-out in 3xTg-AD mice (indACNKO-AD). CaNB1 was deleted, by tamoxifen injection, in 11.7-month-old 3xTg-AD mice for 4.4 months. Spatial memory was evaluated using the Barnes maze; ß-amyloid plaques burden, neurofibrillary tangle deposition, reactive gliosis, and neuroinflammation were also assessed. The acute model showed that ICV injected AßOs in 2-month-old wild type mice impaired recognition memory and fostered a pro-inflammatory microglia phenotype, whereas in ACN-KO mice, AßOs were inactive. In indACNKO-AD mice, 4.4 months after CaNB1 depletion, we found preservation of spatial memory and cognitive flexibility, abolishment of amyloidosis, and reduction of neurofibrillary tangles, gliosis, and neuroinflammation. Our results suggest that ACN is crucial for the development of cognitive impairment, AD neuropathology, and neuroinflammation. Astrocyte-specific CaNB1 deletion is beneficial for both the abolishment of AßO-mediated detrimental effects and treatment of ongoing AD-related pathology, hence representing an intriguing target for AD therapy.

A Nationwide Study of GATA2 Deficiency in Italy Reveals Novel Symptoms and Genotype-phenotype Association.

GATA2 deficiency is a rare disorder encompassing a broadly variable phenotype and its clinical picture is continuously evolving. Since it was first described in 2011, up to 500 patients have been reported. Here, we describe a cohort of 31 Italian patients (26 families) with molecular diagnosis of GATA2 deficiency. Patients were recruited contacting all the Italian Association of Pediatric Hematology and Oncology (AIEOP) centers, the Hematology Department in their institution and Italian societies involved in the field of vascular anomalies, otorhinolaryngology, dermatology, infectious and respiratory diseases. Median age at the time of first manifestation, molecular diagnosis and last follow-up visit was 12.5 (age-range, 2-52 years), 18 (age-range, 7-64 years) and 22 years (age-range, 3-64), respectively. Infections (39%), hematological malignancies (23%) and undefined cytopenia (16%) were the most frequent symptoms at the onset of the disease. The majority of patients (55%) underwent hematopoietic stem cell transplantation. During the follow-up rarer manifestations emerged. The clinical penetrance was highly variable, with the coexistence of severely affected pediatric patients and asymptomatic adults in the same pedigree. Two individuals remained asymptomatic at the last follow-up visit. Our study highlights new (pilonidal cyst/sacrococcygeal fistula, cholangiocarcinoma and gastric adenocarcinoma) phenotypes and show that lymphedema may be associated with null/regulatory mutations. Countrywide studies providing long prospective follow-up are essential to unveil the exact burden of rarer manifestations and the natural history in GATA2 deficiency.

A comparison of simplified protocols of personalized dosimetry in NEN patients treated by radioligand therapy (RLT) with [177Lu]Lu-DOTATATE to favor its use in clinical practice.

The role of internal dosimetry is usually proposed for investigational purposes in patients treated by RLT, even if its application is not yet the standard method in clinical practice. This limited use is partially justified by several concomitant factors that make calculations a complex process. Therefore, simplified dosimetry protocols are required. METHODS: In our study, dosimetric evaluations were performed in thirty patients with NENs who underwent RLT with [177Lu]Lu-DOTATATE. The reference method (M0) calculated the cumulative absorbed dose performing dosimetry after each of the four cycles. Obtained data were employed to assess the feasibility of simplified protocols: defining the dosimetry only after the first cycle (M1) and after the first and last one (M2). RESULTS: The mean differences of the cumulative absorbed doses between M1 and M0 were - 10% for kidney, - 5% for spleen, + 34% for liver, + 13% for red marrow, and + 37% for tumor lesions. Conversely, differences lower than ± 10% were measured between M2 and M0. CONCLUSION: Cumulative absorbed doses obtained with the M2 protocol resembled the doses calculated by M0, while the M1 protocol overestimated the absorbed doses in all organs at risk, except for the spleen.

Analysis of Pros and Cons in Using [68Ga]Ga-PSMA-11 and [18F]PSMA-1007: Production, Costs, and PET/CT Applications in Patients with Prostate Cancer.

The aim of this work is to compare [68Ga]Ga-PSMA-11 and [18F]PSMA-1007 PET/CT as imaging agents in patients with prostate cancer (PCa). Comparisons were made by evaluating times and costs of the radiolabeling process, imaging features including pharmacokinetics, and impact on patient management. The analysis of advantages and drawbacks of both radioligands might help to make a better choice based on firm data. For [68Ga]Ga-PSMA-11, the radiochemical yield (RCY) using a low starting activity (L, average activity of 596.55 ± 37.97 MBq) was of 80.98 ± 0.05%, while using a high one (H, average activity of 1436.27 ± 68.68 MBq), the RCY was 71.48 ± 0.04%. Thus, increased starting activities of [68Ga]-chloride negatively influenced the RCY. A similar scenario occurred for [18F]PSMA-1007. The rate of detection of PCa lesions by Positron Emission Tomography/Computed Tomography (PET/CT) was similar for both radioligands, while their distribution in normal organs significantly differed. Furthermore, similar patterns of biodistribution were found among [18F]PSMA-1007, [68Ga]Ga-PSMA-11, and [177Lu]Lu-PSMA-617, the most used agent for RLT. Moreover, the analysis of economical aspects for each single batch of production corrected for the number of allowed PET/CT examinations suggested major advantages of [18F]PSMA-1007 compared with [68Ga]Ga-PSMA-11. Data from this study should support the proper choice in the selection of the PSMA PET radioligand to use on the basis of the cases to study.

On site production of [18F]PSMA-1007 using different [18F]fluoride activities: practical, technical and economical impact.

BACKGROUND: Prostate-specific membrane antigen is overexpressed in prostate cancer and it is considered a good target for positron emission tomography/computed tomography imaging of primary cancer and recurrent/metastatic disease, as well as for radioligand therapy. Different PSMA-analogues labeled with [68Ga]gallium have been investigated, showing excellent imaging properties; however, only small amounts can be produced for each radiolabeling. Recently, a [18F]fluoride labeled PSMA-inhibitor, [18F]PSMA-1007, has been introduced, and it has ensured large-scale productions, overcoming this limitation of [68Ga]PSMAs. In this study, PSMA-1007 has been labeled with low (A), medium (B) and high (C) starting activities of [18F]fluoride, in order to verify if radiochemical yield, radiochemical purity and stability of [18F]PSMA-1007 were affected. These parameters have been measured in sixty-five consecutive batches. In addition, the estimation of [18F]PSMA-1007 production costs is provided. RESULTS: The radiochemical yield for low and medium activities of [18F]fluoride was 52%, while for the high one it decreased to 40%. The radiochemical purity was 99% for all three activities. [18F]PSMA-1007 did not show radiolysis up to 8 h after the end of synthesis, confirming that the radiopharmaceutical is stable and suitable to perform diagnostic studies in humans for a long period of time after the end of radiolabeling. Furthermore, radiochemical stability was demonstrated in fetal bovine serum at 4 °C and 37 °C for 120'. CONCLUSIONS: A starting activity of [18F]fluoride of 90 GBq (B) seems to be the best option enabling a final amount of about of 50 GBq of [18F]PSMA-1007, which is promising as it allows to: (a) perform a large number of scans, and/or (b) supply the radiopharmaceutical to any peripheral diagnostic centers in need.

Prognostic role of FDG PET/CT in patients with differentiated thyroid cancer treated with 131-iodine empiric therapy.

BACKGROUND: To assess the long-term prognostic value of F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) in patients with differentiated thyroid carcinoma (DTC) undergoing empiric radioiodine (RAI) therapy due to raising values of thyroglobulin (Tg). METHODS: Forty-nine patients with histological diagnosis of DTC (31 with papillary and 18 with follicular carcinoma) follow-up for a mean period of 7.9 ±â€Š5 years after empiric RAI therapy were retrospectively analyzed. RESULTS: FDG-PET/CT was negative in 15 (30.6%) patients and positive in 34 (69.4%), whereas postradioiodine therapy whole body scan (t-WBS) was negative in 16 (32.7%) and positive in 33 (67.3%) patients. FDG-PET/CT and t-WBS were in agreement in 32 patients (7 both negative and 25 both positive); on the contrary, in 17 patients there was disagreement between FDG-PET/CT and t-WBS (P =ns). At short-term follow-up, Tg normalized in 19 (38.8%) patients and was unchanged or increased in 30 (61.2%). Of the 15 patients with negative FDG-PET/CT, 11 (73.3%) showed Tg normalization, whereas of the 34 patients with positive FDG-PET/CT, only 8 (23.5%) had Tg normalization (χ =8.9, P < .005). At multivariate analysis, FDG-PET/CT and Tg normalization at short-term follow-up were independent predictors of disease-free survival (χ =26.3, P < .0001), while Tg normalization was the only variable associated with overall survival χ =7.2, P < .01). CONCLUSION: FDG-PET/CT in association with Tg normalization at short-term follow-up may be useful for long-term prognostic stratification in DTC patients.