Pituitary Function after High-Dose 177Lu-DOTATATE Therapy and Long-Term Follow-Up.
Ontology highlight
ABSTRACT: Introduction
The pituitary gland has a high expression of somatostatin receptors and is therefore a potential organ at risk for radiation-induced toxicity after 177Lu-DOTATATE treatment.Objective
To study changes in pituitary function in patients with neuroendocrine tumors (NETs) treated with dosimetry-based 177Lu-DOTATATE to detect possible late toxicity.Methods
68 patients from a phase II clinical trial of dosimetry-based, individualized 177Lu-DOTATATE therapy were included in this analysis. Patients had received a median of 5 (range 3-9) treatment cycles of 7.4 GBq/cycle. Median follow-up was 30 months (range 11-89). The GH/IGF-1 axis, gonadotropins, and adrenal and thyroid axes were analyzed at baseline and on a yearly basis thereafter. Percent changes in hormonal levels over time were analyzed statistically using a linear mixed model and described graphically using box plots. The absorbed radiation dose to the pituitary was estimated based on post-therapeutic imaging, and the results analyzed versus percent change in IGF-1 levels over time.Results
A statistically significant decrease in IGF-1 levels was found (p < 0.005), which correlated with the number of treatment cycles (p = 0.008) and the absorbed radiation dose (p = 0.03). A similar decrease, although non-significant, was seen in gonadotropins in postmenopausal women, while in men there was an increase during the first years after therapy, after which the levels returned to baseline. No change was observed in the adrenal or thyroid axes.Conclusions
No signs of severe endocrine disorders were detected, although a significant decrease in the GH/IGF-1 axis was found, where dosimetric analyses indicated radiation-induced damage to the pituitary gland as a probable cause.
SUBMITTER: Sundlov A
PROVIDER: S-EPMC8117394 | biostudies-literature |
REPOSITORIES: biostudies-literature
Similar Datasets
Project description:BACKGROUND:The role of concomitant peptide receptor radionuclide therapy (PRRT) and capecitabine therapy has shown benefit in gastroenteropancreatic neuroendocrine tumors. However, data reporting its role in paraganglioma (PGL) patients is lacking. The aim of this study was to evaluate the role of combined capecitabine and 177Lu-DOTATATE in malignant PGL patients. METHODS:In this retrospective, single-institutional, single-arm, observational study, data of consecutive advanced stage PGL patients treated with concomitant 177Lu-DOTATATE-capecitabine therapy, between July 2009 and March 2017, were collected and analyzed. RESULTS:Twenty-five PGL patients received an average dose of 22.86?±?9.54 (14.43-50) GBq 177Lu-DOTATATE and 1250?mg/m2 capecitabine from days 0 to 14, commencing on the morning of PRRT. The median overall survival (OS) was not attained in this patient cohort; however, the median PFS was 32?months. Morphological response according to RECIST 1.1 criteria was achieved in 28% (7/25) patients. Biochemical response with >?50% reduction in chromogranin A levels was observed in 28% of the patients. CONCLUSIONS:Our data confirm that 177Lu-DOTATATE-capecitabine therapy is effective in achieving an objective response in 28% and symptomatic response in 43% patients. In comparison to published PRRT monotherapy outcomes in PGL, we did not observe any great advantage of concomitant therapy; however, it could be due to under-powered study. We recommend a large randomized trial to prove or disprove the utility of capecitabine as a radiosensitizer for PRRT in PGL patients.
| S-EPMC6365580 | biostudies-literature
Project description:Canavan disease is a hereditary leukodystrophy caused by mutations in the aspartoacylase gene (ASPA), leading to loss of enzyme activity and increased concentrations of the substrate N-acetyl-aspartate (NAA) in the brain. Accumulation of NAA results in spongiform degeneration of white matter and severe impairment of psychomotor development. The goal of this prospective cohort study was to assess long-term safety and preliminary efficacy measures after gene therapy with an adeno-associated viral vector carrying the ASPA gene (AAV2-ASPA). Using noninvasive magnetic resonance imaging and standardized clinical rating scales, we observed Canavan disease in 28 patients, with a subset of 13 patients being treated with AAV2-ASPA. Each patient received 9 × 10(11) vector genomes via intraparenchymal delivery at six brain infusion sites. Safety data collected over a minimum 5-year follow-up period showed a lack of long-term adverse events related to the AAV2 vector. Posttreatment effects were analyzed using a generalized linear mixed model, which showed changes in predefined surrogate markers of disease progression and clinical assessment subscores. AAV2-ASPA gene therapy resulted in a decrease in elevated NAA in the brain and slowed progression of brain atrophy, with some improvement in seizure frequency and with stabilization of overall clinical status.
| S-EPMC3794457 | biostudies-literature
Project description:Since 2006 when we last reviewed the literature concerning the use of purine analogues in hairy cell leukaemia (HCL), results from several new and updated series have been published. Here we examine these reports and consider their implications for patient management. The two purine analogues pentostatin and cladribine remain the first-line treatments of choice for all patients with HCL. Although they have not been compared in randomised trials, they appear to be equally effective. A complete response is important for the long-term outcome and we look at how best this can be achieved. Evidence is emerging which supports the use of either purine analogue plus an anti-CD20 monoclonal antibody after relapse, though questions remain concerning the scheduling of the monoclonal antibody. Patients refractory to the purine analogues may require alternative agents.
| S-EPMC5509559 | biostudies-literature
Project description:BackgroundCD19-specific chimeric antigen receptor (CAR) T cells induce high rates of initial response among patients with relapsed B-cell acute lymphoblastic leukemia (ALL) and long-term remissions in a subgroup of patients.MethodsWe conducted a phase 1 trial involving adults with relapsed B-cell ALL who received an infusion of autologous T cells expressing the 19-28z CAR at the Memorial Sloan Kettering Cancer Center (MSKCC). Safety and long-term outcomes were assessed, as were their associations with demographic, clinical, and disease characteristics.ResultsA total of 53 adults received 19-28z CAR T cells that were manufactured at MSKCC. After infusion, severe cytokine release syndrome occurred in 14 of 53 patients (26%; 95% confidence interval [CI], 15 to 40); 1 patient died. Complete remission was observed in 83% of the patients. At a median follow-up of 29 months (range, 1 to 65), the median event-free survival was 6.1 months (95% CI, 5.0 to 11.5), and the median overall survival was 12.9 months (95% CI, 8.7 to 23.4). Patients with a low disease burden (<5% bone marrow blasts) before treatment had markedly enhanced remission duration and survival, with a median event-free survival of 10.6 months (95% CI, 5.9 to not reached) and a median overall survival of 20.1 months (95% CI, 8.7 to not reached). Patients with a higher burden of disease (≥5% bone marrow blasts or extramedullary disease) had a greater incidence of the cytokine release syndrome and neurotoxic events and shorter long-term survival than did patients with a low disease burden.ConclusionsIn the entire cohort, the median overall survival was 12.9 months. Among patients with a low disease burden, the median overall survival was 20.1 months and was accompanied by a markedly lower incidence of the cytokine release syndrome and neurotoxic events after 19-28z CAR T-cell infusion than was observed among patients with a higher disease burden. (Funded by the Commonwealth Foundation for Cancer Research and others; ClinicalTrials.gov number, NCT01044069 .).
| S-EPMC6637939 | biostudies-literature
Project description:177Lu‑DOTATATE was recently approved for the treatment of somatostatin receptor (SSTR)‑positive neuroendocrine tumors (NETs). However, despite impressive response rates, complete responses are rare. Heat shock protein 90 (HSP90) inhibitors have been suggested as suitable therapeutic agents for NETs, as well as a potential radiosensitizers. Consequently, the aim of this study was to investigate whether the HSP90‑inhibitor onalespib could reduce NET cell growth and act as a radiosensitizer when used in combination with 177Lu‑DOTATATE. The NET cell lines BON, NCI‑H727 and NCI‑H460, were first characterized with regards to 177Lu‑DOTATATE uptake and sensitivity to onalespib treatment in monolayer cell assays. The growth inhibitory effects of the monotherapies and combination treatments were then examined in three‑dimensional multicellular tumor spheroids. Lastly, the molecular effects of the treatments were assessed. 177Lu‑DOTATATE uptake was observed in the BON and NCI‑H727 cells, while the NCI‑H460 cells exhibited no detectable uptake. Accordingly, 177Lu‑DOTATATE reduced the growth of BON and NCI‑H727 spheroids, while no effect was observed in the NCI‑H460 spheroids. Onalespib reduced cell viability and spheroid growth in all three cell lines. Furthermore, the combination of onalespib and 177Lu‑DOTATATE exerted synergistic therapeutic effects on the BON and NCI‑H727 spheroids. Western blot analysis of BON spheroids revealed the downregulation of epidermal growth factor receptor (EGFR) and the upregulation of γ H2A histone family member X (γH2AX) following combined treatment with onalespib and 177Lu‑DOTATATE. Moreover, flow cytometric analyses revealed a two‑fold increase in caspase 3/7 activity in the combination group. In conclusion, the findings of this study demonstrate that onalespib exerts antitumorigenic effects on NET cells and may thus be a feasible treatment option for NETs. Furthermore, onalespib was able to synergistically potentiate 177Lu‑DOTATATE treatment in a SSTR‑specific manner. The radiosensitizing mechanisms of onalespib involved the downregulation of EGFR expression and the induction of apoptosis. Consequently, the combination of onalespib and 177Lu‑DOTATATE may prove to be a promising strategy with which to improve therapeutic responses in patients with NETs. Further studies investigating this strategy in vivo regarding the therapeutic effects and potential toxicities are warranted to expand these promising findings.
| S-EPMC6831206 | biostudies-literature
Project description:AIMS:Peptide receptor radionuclide therapy (PRRT) is in clinical use today to treat metastatic neuroendocrine tumors. Infused, radiolabeled, somatostatin analog peptides target tumors that are killed by irradiation damage. The peptides, however, are also retained in kidneys due to glomerular filtration, and the administered doses must be limited to avoid kidney damage. The human radical scavenger and antioxidant, α1-microglobulin (A1M), has previously been shown to protect bystander tissue against irradiation damage and has pharmacokinetic and biodistribution properties similar to somatostatin analogs. In this study, we have investigated if A1M can be used as a renal protective agent in PRRT. RESULTS:We describe nephroprotective effects of human recombinant A1M on the short- and long-term renal damage observed following lutetium 177 (177Lu)-DOTATATE (150 MBq) exposure in BALB/c mice. After 1, 4, and 8 days (short term), 177Lu-DOTATATE injections resulted in increased formation of DNA double-strand breaks in the renal cortex, upregulated expression of apoptosis and stress response-related genes, and proteinuria (albumin in urine), all of which were significantly suppressed by coadministration of A1M (7 mg/kg). After 6, 12, and 24 weeks (long term), 177Lu-DOTATATE injections resulted in increased animal death, kidney lesions, glomerular loss, upregulation of stress genes, proteinuria, and plasma markers of reduced kidney function, all of which were suppressed by coadministration of A1M. Innovation and Conclusion: This study demonstrates that A1M effectively inhibits radiation-induced renal damage. The findings suggest that A1M may be used as a radioprotector during clinical PRRT, potentially facilitating improved tumor control and enabling more patients to receive treatment.
| S-EPMC6477591 | biostudies-literature
Project description:To evaluate the long-term efficacy and factors involved in the recurrence and persistence of subretinal fluid (SRF) after half-dose photodynamic therapy (PDT) for chronic central serous chorioretinopathy (CSC).In this retrospective observational case series, 79 eyes (73 patients) with chronic CSC were treated with half-dose PDT and followed up for at least 3 years. They were divided into successful (64 eyes) and unsuccessful (15 eyes) groups based on SRF absorption and disease recurrence after one PDT session. Age, best-corrected visual acuity (BCVA), central foveal thickness, neuroretinal thickness, height of SRF, subfoveal choroidal thickness, window defect area detected by fluorescein angiography, and PDT spot area were compared between the groups. Factors associated with PDT success and BCVA at 3 years were investigated.LogMAR BCVA improved from 0.21±0.24 to 0.08±0.16 (P<0.001) at 3 years after PDT. Compared with the unsuccessful group, the successful group had a significantly younger mean age (50.5±9.7 vs. 56.5±9.1 years, P = 0.032) and better baseline BCVA (0.18±0.23 vs. 0.32±0.25, P = 0.034). Other parameters were not significantly different. Multivariate analyses showed that unsuccessful PDT was significantly associated with lower baseline BCVA (P = 0.026) and older age (P = 0.029) and that BCVA at 3 years after PDT was positively associated with baseline BCVA (P<0.001).Half-dose PDT has a long-term efficacy in chronic CSC. Relatively early PDT may improve anatomic and functional outcomes of chronic CSC.
| S-EPMC5524407 | biostudies-literature
Project description:BackgroundThe permanence of neuromuscular adaptations following anterior cruciate ligament reconstruction is not known. The aim of this study was to compare bilateral muscle co-contraction indices, time to peak ground reaction force, and timing of muscle onset between anterior cruciate ligament reconstruction subjects 10-15 years post reconstruction with those of matched uninjured controls during a one-leg hop landing.MethodsNine healthy controls and 9 reconstruction subjects were recruited. Clinical and functional knee exams were administered. Lower limb co-contraction indices, time to peak ground reaction force, and muscle onset times were measured bilaterally. Differences in clinical and functional outcomes were assessed with unpaired t-tests, and mixed model repeated measures were used to examine effects of group, limb and interaction terms in electromyography measures.Findings89% of control knees were clinically "normal", whereas only 33% of reconstructed knees were "normal". Anterior cruciate ligament-reconstructed subjects tended to achieve shorter functional hop distances but demonstrated symmetrical lower limb electromyography measures that were no different from those of controls' with the exception that biceps femoris activation was delayed bilaterally prior to ground contact but was greater during the injury risk phase of landing.InterpretationWith the exception of hamstring activation, lower limb electromyography measures were largely similar between ligament-reconstructed and matched control subjects, which was in contrast to the clinical findings. This result brings into question the significance of neuromuscular function at this long-term follow-up but raises new questions regarding the role of symmetry and pre-injury risk.
| S-EPMC7855572 | biostudies-literature
Project description:PurposeAnti-CD19 chimeric antigen receptors (CARs) are artificial fusion proteins that cause CD19-specific T-cell activation. Durability of remissions and incidence of long-term adverse events are critical factors determining the utility of anti-CD19 CAR T-cell therapy, but long-term follow-up of patients treated with anti-CD19 CAR T cells is limited. This work provides the longest follow-up of patients in remission after anti-CD19 CAR T-cell therapy.MethodsBetween 2009 and 2015, we administered 46 CAR T-cell treatments to 43 patients (ClinicalTrials.gov identifier: NCT00924326). Patients had relapsed B-cell malignancies of the following types: diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma (DLBCL/PMBCL; n = 28), low-grade B-cell lymphoma (n = 8), or chronic lymphocytic leukemia (CLL; n = 7). This report focuses on long-term outcomes of these patients. The CAR used was FMC63-28Z; axicabtagene ciloleucel uses the same CAR. Cyclophosphamide plus fludarabine conditioning chemotherapy was administered before CAR T cells.ResultsThe percentages of CAR T-cell treatments resulting in a > 3-year duration of response (DOR) were 51% (95% CI, 35% to 67%) for all evaluable treatments, 48% (95% CI, 28% to 69%) for DLBCL/PMBCL, 63% (95% CI, 25% to 92%) for low-grade lymphoma, and 50% (95% CI, 16% to 84%) for CLL. The median event-free survival of all 45 evaluable treatments was 55 months. Long-term adverse effects were rare, except for B-cell depletion and hypogammaglobulinemia. Median peak blood CAR-positive cell levels were higher among patients with a DOR of > 3 years (98/µL; range, 9-1,217/µL) than among patients with a DOR of < 3 years (18/µL; range, 0-308/μL, P = .0051).ConclusionComplete remissions of a variety of B-cell malignancies lasting ≥ 3 years occurred after 51% of evaluable anti-CD19 CAR T-cell treatments. Remissions of up to 9 years are ongoing. Late adverse events were rare.
| S-EPMC7655016 | biostudies-literature
Project description:Background and objectiveEndoscopic valve therapy is a treatment modality in patients with advanced emphysema and absent interlobar collateral ventilation (CV). So far, long-term outcome following valve implantation has been insufficiently evaluated. The aim of this study was to investigate the real-world efficacy of this interventional therapy over 3 years.MethodsFrom 2006 to 2013, 256 patients with severe emphysema in whom absent CV was confirmed underwent valve therapy. The 3-year effectiveness was evaluated by pulmonary function testing (VC, FEV1, RV, TLC), 6-minute-walk test (6-MWT) and dyspnea questionnaire (mMRC). Long-term outcome was also assessed according to the radiological outcome following valve placement.ResultsOf 256 patients treated with valves, 220, 200, 187, 100 and 66 patients completed the 3-month, 6-month, 1-year, 2-year and 3-year follow-up (FU) visit, respectively. All lung function parameters, 6-MWT and mMRC were significantly improved at 3- and 6-month FU. At 1-year FU, patients still experienced a significant improvement of all outcome parameters expect VC (L) and TLC (%). At 2 years, RV (L and %) and TLC (L and %) remained significantly improved compared to baseline. Three years after valve therapy, sustained significant improvement in mMRC was observed and the proportion of patients achieving a minimal clinically important difference from baseline in RV and 6-MWT was still 71% and 46%, respectively. Overall, patients with complete lobar atelectasis exhibited superior treatment outcome with 3-year responder rates to FEV1, RV and 6-MWT of 10%, 79% and 53%, respectively.ConclusionsPatients treated by valves experienced clinical improvement over 1 year following valve therapy. Afterwards, clinical benefit gradually declines more likely due to COPD progression.
| S-EPMC6681249 | biostudies-literature