Synthesis and automated fluorine-18 radiolabeling of new PSMA-617 derivatives with a CuAAC radiosynthetic approach

In the last decade, the development of new radiopharmaceuticals for the imaging and therapy of prostate cancer has been a highly active and important area of research, especially focusing on the prostate-specific membrane antigen (PSMA), an antigen which is upregulated in prostate, as well as in other tumor cells. A large variety of PSMA ligands have been radiolabeled, to date. Among the various derivatives, PSMA-617 resulted to be one of the most interesting in terms of interaction with the antigen and clinical properties, and its lutetium-177 labeled version has recently been approved by regulatory agencies for therapeutic purposes. For this reasons, the radiolabeling with fluorine-18 of a PSMA-617 derivative might be of interest. Beside other methodologies to radiolabel macromolecules with fluorine-18, the “click-chemistry” approach resulted to be very useful, and the copper-catalyzed azide-alkyne cycloaddition (CuAAC) is considered one of most efficient and reliable. This paper proposes the synthesis of a suitable precursor for the radiolabeling with fluorine-18 of a new PSMA-617 derivative. The whole radiosynthetic procedure has been fully automated, and the final product, which proved to be stable in plasma, has been obtained with radiochemical yield and purity suitable for subsequent preclinical studies.     

Family Mismatched Allogeneic Stem Cell Transplantation for Myelofibrosis: Report from the Chronic Malignancies Working Party of European Society for Blood and Marrow Transplantation

This analysis included 56 myelofibrosis (MF) patients transplanted from family mismatched donor between 2009 and 2015 enrolled in the European Society for Blood and Marrow Transplantation database. The median age was 57years (range, 38 to 72); 75% had primary MF and 25% had secondary MF. JAK2 V617F was mutated in 61%. Donors were HLA mismatched at 2 or more loci. Stem cells were sourced from bone marrow in 66% and peripheral blood in 34%. The median CD34⁺ cell dose was 4.8?×?10⁶/kg (range, 1.7 to 22.9; n?=?43). Conditioning was predominantly myeloablative in 70% and reduced intensity in the remainder. Regimens were heterogeneous with thiotepa, busulfan, fludarabine, and post-transplant cyclophosphamide used in 59%. The incidence of neutrophil engraftment by 28days was 82% (range, 70% to 93%), at a median of 21days (range, 19 to 23). At 2years the cumulative incidence of primary graft failure was 9% (95% CI 1% to 16%) and secondary graft failure was 13% (95% CI 4% to 22%). The cumulative incidence of acute graft-versus-host disease (GVHD) grades II to IV and III to IV was 28% (95% CI 16% to 40%) and 9% (95% CI 2% to 17%) at 100days. The cumulative incidence of chronic GVHD at 1 year was 45% (95% CI 32% to 58%), but the cumulative incidence of death without chronic GVHD by 1 year was 20% (95% CI 10% to 31%). With a median follow-up of 32 months, the 1- and 2-year overall survival was 61% (95% CI 48% to 74%) and 56% (95% CI 41% to 70%), respectively. The 1- and 2- year progression-free survival was 58% (95% CI 45% to 71%) and 43% (95% CI 28% to 58%), respectively, with a 2-year cumulative incidence of relapse of 19% (95% CI 7% to 31%). The 2-year nonrelapse mortality was 38% (95% CI 24% to 51%). This retrospective study of MF allo-SCT using family mismatched donors demonstrated feasibility of the approach, timely neutrophil engraftment in over 80% of cases, and acceptable overall and progression-free survival rates with relapse rates not dissimilar to the unrelated donor setting. However, strategies to minimize the risk of graft failure and the relatively high nonrelapse mortality need to be used, ideally in a multicenter prospective fashion.     

Buccal micronucleus cytome assay in primary school children: A descriptive analysis of the MAPEC_LIFE multicenter cohort study

Background

Recent data support the hypothesis that genetic damage occurring early in life during childhood can play an important role in the development of chronic diseases in adulthood, including cancer.

Autologous Bone Marrow Transplantation for the Treatment of Multiple Sclerosis

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system and represents one of the leading causes of neurologic disability in young adults. Current treatments for MS have shown limited efficacy in patients with either a progressive or an aggressive disease course. Hematopoietic stem cell transplantation (HSCT) has been proposed to control or even cure refractory cases of MS. Indeed, HSCT is able to temporarily eradicate the autoreactive cells and to reset the aberrant immune response to self-antigens. In the last decade, owing to the growing experience in selecting the most appropriate patients to transplant and the recent advances in chemotherapeutic and support regimens, the transplant-related mortality of autologous HSCT in MS patients dropped down to 1,3 % and the progression-free survival ranges from 47 % to 100 %. Altogether, these data support autologous HSCT as a possible second-line therapy for refractory MS.     

Allogeneic hematopoietic stem cell transplantation for neuromyelitis optica

Neuromyelitis optica is a rare neurological autoimmune disorder characterized by a poor prognosis. Immunosuppression can halt disease progression, but some patients are refractory to multiple treatments, experiencing frequent relapses with accumulating disability. Here we report on durable clinical remissions after allogeneic hematopoietic stem cell transplantation in 2 patients suffering from severe forms of the disease. Immunological data evidenced disappearance of the pathogenic antibodies and regeneration of a naive immune system of donor origin. These findings correlated with evident clinical and radiological improvement in both patients, warranting extended clinical trials to investigate this promising therapeutic option. ANN NEUROL 2014;75:447–453     

Long-term complete response in metastatic poorly-differentiated neuroendocrine rectal carcinoma with a multimodal approach: A case report

BACKGROUNDNeuroendocrine gastrointestinal tumors (NETs) are rare and have different natural behaviors. Surgery is the gold standard treatment for local disease while radiotherapy has been demonstrated to be ineffective. Poorly differentiated neuroendocrine carcinomas (NECs) represent only 5%-10% of digestive NETS. Due to aggressive growth and rapid metastatic diffusion, early diagnosis and a multidisciplinary approach are mandatory. The role of surgery and radiotherapy in this setting is still debated, and chemotherapy remains the treatment of choice.CASE SUMMARYA 42-year-old male with an ulcerated bleeding rectal lesion was diagnosed with a NEC G3 (Ki67 index > 90%) on May 2015 and initially treated with 3 cycles of first-line chemotherapy, but showed early local progressive disease at 3 mo and underwent sphincter-sparing open anterior low rectal resection. In September 2015, the first post-surgery total-body computed tomography (CT) scan showed an early pelvic disease relapse. Therefore, systemic chemotherapy with FOLFIRI was started and the patient obtained only a partial response. This was followed by pelvic radiotherapy (50 Gy). On April 2016, a CT scan and 18F-fluorodeoxyglucose positron emission tomography imaging showed a complete response (CR) of the pelvic lesion, but pathological abdominal inter-aortocaval lymph nodes were observed. Due to disease progression of abdominal malignant nodes, the patient received radiotherapy at 45 Gy, and finally obtained a CR. As of January 2021, the patient has no symptoms of relapse and no late toxicity after chemotherapy or radiotherapy.CONCLUSIONThis case demonstrates how a multimodal approach can be successful in obtaining long-term CR in metastatic sites in patients with high grade digestive NECs.     

Psychosis in a cocaine-dependent patient with ADHD during treatment with methylphenidate

Objective

The objective was to report a case of experienced psychosis during the treatment with methylphenidate (MPH) in a cocaine-dependent adult treated for attention-deficit/hyperactivity disorder (ADHD) with comorbid cocaine dependence.

Conclusion

ADHD is a frequent comorbidity in substance use disorder (SUD) patients. MPH may be effective in treating ADHD symptoms in SUD patients, thus preventing possible adverse outcomes. Cocaine-induced psychosis may be a risk factor for development of psychosis in the presence of a concurrent treatment with MPH.