Subclinical Hypothyroidism: is it Really Subclinical with Aging?

No recent study has focused on clinical features of subclinical hypothyroidism (SCH), especially in older patients. TSH measurement has remarkably evolved these last 20 years and thus reconsideration is needed. In our prospective multicenter study (2012-2014) including 807 subjects aged <60 years (<60y) and 531 subjects ≥60 years (≥60y), we have monitored 11 hypothyroidism-related clinical signs (hCS) together with TSH, FT4, FT3 and anti-thyroperoxidase antibodies values. hCS expression has been compared in patients with SCH vs euthyroidism in each age group. The number of hCS above 60y of age were found to be more elevated in the euthyroid population (1.9 vs 1.6, p<0.01) than in the SCH population (2.3 vs 2.6, p=0.41) while increase in hCS is limited to SCH subjects in the <60y group (p<0.01). The percentage of subjects with at least 3 signs increased with SCH in the <60y group (42.6% vs 25.0%, p<0.01) but not ≥60y (34.4% vs 33.9%, p=0.96). In older individuals, only three hCS could be related to both SCH and a decreased T3/T4-ratio (0.26 vs 0.27, p<0.01), suggesting either a reduced activity of TSH, or an adaptive response with aging. While hCS are clearly associated with SCH in patients <60y, they are not so informative in older subjects. TSH measurements carried out on the basis of hCS need to be interpreted with caution in aged patients. A reassessment of the TSH reference range in older patients is clearly needed and should be associated to more appropriate monitoring of thyroid dysfunction.

A divalent hapten-peptide induces apoptosis in human non hodgkin lymphoma cell lines targeted by anti-CD20xanti-hapten bispecific antibodies.

PURPOSE: Bispecific antibody (bsMAb) pretargeting procedures use divalent hapten-peptides to stabilize the binding of the hapten-peptide on tumor cells by a process known as the affinity enhancement system. The goal of this study was to determine if a divalent hapten-peptide could induce apoptosis by cross-linking bsMAb bound to CD20. METHODS: Three forms of bsMAbs were prepared by coupling the IgG, F(ab')2, or Fab' of a humanized anti-CD20 antibody to a Fab' of a murine antibody directed against the hapten histamine-succinyl-glycine (HSG). A recombinant bsMAb with divalent binding to CD20 and monovalent binding to HSG was also examined. Induction of apoptosis on SU-DHL-6, RL, and Ramos cells was examined by propidium iodide staining, caspase-3 activation, and mitochondrial membrane potential collapse, and compared with induction by cross-linking an anti-CD20 IgG with an antispecies antibody. RESULTS: The various forms of bsMAb had differing baseline levels of apoptosis in the absence of the divalent HSG peptide. The addition of the divalent HSG peptide significantly increased the level of apoptosis seen with the Fab'xFab' bsMAb by 2.2- to 3.9-fold, as well as the F(ab')2xFab', IgGxFab', and the recombinant bsMAbs by approximately 1.5-fold. CONCLUSIONS: The addition of a divalent HSG peptide to various forms of bispecific anti-CD20 MAbs could enhance apoptotic signaling in several lymphoma cells. This effect was more consistently measured when the orientation of the anti-hapten-binding arm of the bsMAb was well defined, such as in the Fab'xFab' and recombinant forms of bsMAb.

SPECT imaging, immunohistochemical and behavioural correlations in the primate models of Parkinson's disease.

Dopamine active transporter (DAT) single photon emission computerised tomography (SPECT) is considered a useful and practical technique for early diagnosis of Parkinson's disease (PD) and assessment of its progression. The application of this technique, particularly as a surrogate marker for therapeutic and neuroprotective trials in Parkinsonism, however, is dependent on pathological validation. In the absence of human studies, we used 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) primate models of Parkinsonism to verify correlation between the SPECT, immunohistochemical and behavioural data. The DAT SPECT data correlated strongly and significantly with the substantia nigra pars compacta tyrosine hydroxylase and Nissl cell counts as well as the behavioural scores. Within the limitations of small numbers inherent to such studies, this data provides the first attempt at pathological validation of SPECT in primates.

Bispecific antibody pretargeting PET (immunoPET) with an 124I-labeled hapten-peptide.

UNLABELLED: We previously described a highly flexible bispecific antibody (bs-mAb) pretargeting procedure using a multivalent, recombinant anti-CEA (carcinoembryonic antigen) x anti-HSG (histamine-succinyl-glycine) fusion protein with peptides radiolabeled with 111In, 90Y, 177Lu, and 99mTc. The objective of this study was to develop a radioiodination procedure primarily to assess PET imaging with 124I. METHODS: A new peptide, DOTA-D-Tyr-D-Lys(HSG)-D-Glu-D-Lys(HSG)-NH2 (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid), was synthesized and conditions were established for radioiodination with yields of approximately 70% for 131I and 60% for 124I. Pretargeting with the 131I- and 124I-labeled peptide was tested in nude mice bearing LS174T human colonic tumors that were first given the anti-CEA x anti-HSG bs-mAb. Imaging (including small-animal PET) and necropsy data were collected at several intervals over 24 h. Comparisons were made between animals given 124I-anti-CEA Fab', 18F-FDG, the same peptide radiolabeled with 111In and pretargeted with the bs-mAb, and the radioiodinated peptide alone. RESULTS: The radioiodinated peptide alone cleared quickly from the blood with no evidence of tumor targeting, but when pretargeted with the bs-mAb, tumor uptake increased 70-fold, with efficient and rapid clearance from normal tissues, allowing clear visualization of tumor within 1-2 h. Tumor uptake measured at necropsy was 3- to 15-fold higher and tumor-to-blood ratios were 10- to 20-fold higher than those for 124I-Fab' at 1 and 24 h, respectively. Thyroid and stomach uptake was observed with the radioiodinated peptide several hours after injection (animals were not premedicated to reduce uptake in these tissues), but gastric uptake was much more pronounced with 124I-Fab'. Tumor visualization with 18F-FDG at approximately 1.5 h was also good but showed substantially more uptake in several normal tissues, making image interpretation in the pretargeted animals less ambiguous than with 18F-FDG. CONCLUSION: Bispecific antibody pretargeting has a significant advantage for tumor imaging over directly radiolabeled antibodies and could provide additional enhancements for oncologic imaging, particularly for improving targeting specificity as compared with 18F-FDG.

Therapeutic advantage of pretargeted radioimmunotherapy using a recombinant bispecific antibody in a human colon cancer xenograft.

PURPOSE: To assess if pretargeting, using a combination of a recombinant bispecific antibody (bsMAb) that binds divalently to carcinoembryonic antigen (CEA) and monovalently to the hapten histamine-succinyl-glycine and a (90)Y-peptide, improves therapeutic efficacy in a human colon cancer-nude mouse xenograft compared with control animals given (90)Y-humanized anti-CEA immunoglobulin G (IgG). EXPERIMENTAL DESIGN: Clearance and biodistribution were monitored by whole-body readings and necropsy. Animals were monitored for 34 weeks with a determination of residual disease and renal pathology in survivors. Hematologic toxicity was assessed separately in non-tumor-bearing NIH Swiss mice. RESULTS: Hematologic toxicity was severe at doses of 100 to 200 microCi of (90)Y-IgG, yet mild in the pretargeted animals given 500 or 700 microCi of the (90)Y-peptide. Evidence of end-stage renal disease was found at 900 microCi of the pretargeted (90)Y-peptide whereas animals given 700 microCi showed only mild renal pathology, similar to that seen in control animals given (90)Y-IgG. Biodistribution data indicated that the average amount of tumor radioactivity by a 700-microCi dose of the pretargeted peptide over a 96-hour period was increased 2.5-fold (48 microCi/g) compared with 150 microCi of (90)Y-IgG (18.9 microCi/g). At these doses, survival (i.e., time to progression to 2.5 cm(3)) was significantly improved (P < 0.04) compared with (90)Y-IgG, with ablation of about one third of the tumors, whereas viable tumor was present in all of the (90)Y-IgG-treated animals. CONCLUSION: Pretargeting increases the amount of radioactivity delivered to colorectal tumors sufficiently to improve the therapeutic index and responses as compared with conventional radioimmunotherapy.

Pharmacokinetics and dosimetry studies for optimization of anti-carcinoembryonic antigen x anti-hapten bispecific antibody-mediated pretargeting of Iodine-131-labeled hapten in a phase I radioimmunotherapy trial.

PURPOSE: Pharmacokinetics and dosimetry of hMN-14 x m734 bispecific monoclonal antibody (BsMAb) and (131)I-labeled di-diethylenetriaminepentaacetic acid-indium ((131)I-hapten) were studied to optimize pretargeted radioimmunotherapy. EXPERIMENTAL DESIGN: Thirty-five patients with carcinoembryonic antigen-expressing tumors were included. In a first group of 12 patients, (131)I-trace-labeled BsMAb doses were escalated from 10 to 100 mg/m(2), and 3.7 GBq of (131)I-hapten were administered 7 days later. In a second group, 12 patients received 75 mg/m(2) BsMAb and 2.6-4.2 GBq of (131)I-hapten 5 days later. The BsMAb dose was then reduced to 40 mg/m(2), and 10 patients received 1.9-5.5 GBq of (131)I-hapten. Blood samples were collected. Biodistribution was monitored by quantitative scintigraphy. RESULTS: Directly labeled BsMAb pharmacokinetics was described by two exponentials: half-lives were 8.1 h (2.0-18.1 h) and 48.2 h (22.8-79.4 h); blood clearance was 123 ml/h (64-195 ml/h). With a 7-day interval, 10 or 30 mg/m(2) BsMAb resulted in fast elimination and very low tumor uptake of hapten, whereas 50 or 100 mg/m(2) resulted in favorable tumor accretion. With 75 mg/m(2) BsMAb and a 5-day interval, hapten clearance was 152 ml/h (81-298 ml/h). Calculated radiation dose to tumor was 3.9 Gy/GBq (0.4-22.4 Gy/GBq) for the hapten, compared with 2.0 Gy/GBq (0.3-3.8 Gy/GBq) for the BsMAb, but hematological toxicity prevented dose escalation. Reduction of the BsMAb dose to 40 mg/m(2) accelerated hapten clearance to 492 ml/h (113-2544 ml/h) and reduced hematological toxicity without compromising tumor uptake [5.2 Gy/GBq (0.5-12.6 Gy/GBq)]. CONCLUSIONS: Optimized BsMAb doses and time interval will allow for the administration of higher, tumoricidal, activity doses.

Intraoperative and postoperative gamma detection of somatostatin receptors in bone-invasive en plaque meningiomas.

OBJECTIVE: Scintigraphy with a radiolabeled somatostatin analog ((111)In-diethylenetriaminepenta-acetic acid octreotide) detects the somatostatin receptors that are found in vitro in all meningiomas. Previous studies have proved the benefit of radioimmunoguided surgery, with a hand-held gamma probe, for the assessment and removal of neuroendocrine tumors. We conducted a study to determine whether intraoperative radiodetection of somatostatin receptors is feasible and could increase the probability of complete meningioma resection, especially for bone-invasive en plaque meningiomas, which are difficult to control surgically. METHODS: Eighteen patients with en plaque sphenoid wing and cranial convexity meningiomas were studied by preoperative and postoperative somatostatin receptor scintigraphy. In 10 of them, intraoperative radiodetection with a hand-held gamma probe was performed 24 hours after the intravenous administration of (111)In-diethylenetriaminepenta-acetic acid octreotide. This procedure was combined with a computer-aided navigation system. RESULTS: All preoperative scintigrams were positive. Intraoperative gamma probe detection was achieved for the invaded bone, dura, and periorbit of sphenoid wing meningiomas. The average tumor/nontumor count ratio was 2:1, with a maximum of 12:1, thus allowing precise detection capable of defining the tumor margins. In three cases of sphenoid wing meningiomas, postoperative scintigrams were helpful for the determination of recurrences that magnetic resonance imaging failed to detect. CONCLUSION: These preliminary data show that intraoperative radiodetection of somatostatin receptors with a hand-held gamma probe is feasible and may be helpful to guide the surgical removal of bone-invasive en plaque meningiomas. Preoperative and postoperative scintigraphy may be useful for the management and follow-up of patients with these tumors.