CHANGES IN SERUM CONCENTRATIONS OF THYROID HORMONES AND THYROID HORMONE-BINDING PROTEINS DURING EARLY INFANCY Studies in Healthy Fullterm, Small-for-gestational Age and Preterm Infants Aged 7 to 240 Days

Abstract. Serum concentrations of thyrotropin (TSH), thyroxine (T₄), triiodothyronine (T₃), thyroxine-binding globulin (TBG), prealbumin (TBPA) and albumin (Alb) were determined in 492 blood samples from 127 fullterm (FT), 91 small-for-gestational age (SGA) and 88 preterm (PT) healthy infants aged 7 to 240 days. Serum T ₄ decreased about 20% during the first month of life. In infants aged 7–49 days, serum T₄ concentrations were significantly lower in SGA than in FT infants, and even lower values were found in PT infants. Serum T ₃ increased 50–70% reaching maximal values by 50–79 days of life. Serum T₃ levels were higher in FT than in SGA infants throughout the observation period. In PT infants serum T₃ increased from low values to levels which exceeded those of SGA and FT infants by 120–240 days of life. Serum TSH level did not change with age and was 5 mU/1 in all infants. Serum TBG values were high compared to normal adult values and did not change significantly with age. Comparable serum TBG values were found in FT, SGA and PT infants. Serum TBPA increased with age. Serum TBPA increased gradually in FT infants. In SGA infants serum TBPA increased from low values to levels which by 120–240 days of life exceeded those of PT and FT infants. In PT infants a decrease in serum TBPA appeared before the rise commenced. Serum Alb increased gradually in FT, SGA and PT infants during the observation period. Serum Alb in PT infants aged 30–119 days was lower than those in FT infants with similar ages. These physiological changes in serum concentrations of thyroid hormones and hormone-binding proteins during early infancy should be considered when interpreting thyroid function tests in infants with various maturity.     

Analysis of dose distribution in gamma knife radiosurgery for multiple targets

Purpose: The aim of this study is to evaluate the actual effect of irradiation for other targets in dose planning for the treatment of multiple metastases with Gamma Knife.

Methods and Materials: We analyzed dose distributions for 51 targets in 10 patients with metastatic brain tumors who underwent radiosurgery with Gamma Knife for the treatment of more than one target in one session. We made dose plans with every attempt to include as many targets as possible and calculate dose distributions separately for each dose matrix. We also calculated the composite dose distribution by including the effect of all shots used. We compared these noncomposite and composite dose distributions.

Results: The differences in the mean target dose between the noncomposite dose distribution and the composite one ranged from 0.0 to 4.5 Gy with a mean of 1.5 Gy and was more than 2 Gy in 12 (24%) targets. The difference tended to be larger when targets were small in volume and/or the number of targets was large.

Conclusions: The effect of irradiation from the shots for other targets was not negligible in some cases. This difference of dose distribution should be considered in the analysis of clinical outcomes of cases with multiple targets treated in one session.     

Subcutaneous administration of hepatitis B immune globulin in combination with lamivudine following orthotopic liver transplantation: effective prophylaxis against recurrence

Prophylaxis against recurrent hepatitis B virus (HBV) infection with hepatitis B immune globulin (HBIG), in combination with antiviral agents such as lamivudine, has allowed transplantation for this condition to become feasible and accepted. Current protocols allow for HBIG administration either intravenously or intramuscularly. To date, there has been no reported experience with the subcutaneous route of post-transplant HBIG delivery. We report our experience of a 60-yr-old man for whom liver transplantation was performed for chronic HBV. HBIG was administered intramuscularly during the anhepatic phase of surgery. The finding of a portal vein thrombosis requiring repeated thrombectomy necessitated chronic anticoagulation. Post-operatively, HBIG was administered subcutaneously, in four separate injections, for a daily dose of 2170 IU along with continued lamivudine dosing. Hepatitis B surface antibody (anti-HBs) titres reached a serum concentration of >500 IU/L by seven d post-transplant and approximately 1000 IU/L by nine d post-transplant. Five months post-transplant, with continued combination of subcutaneous HBIG and lamivudine, there has been no recurrent HBV infection and anti-HBs titres have been at target levels. Our experience suggests that subcutaneous delivery of HBIG may be a feasible consideration when intramuscular/intravenous dosing is not possible.     

Low dose antithymocyte globulin for the treatment of older patients with aplastic anaemia

We report 14 older patients with aplastic anaemia (AA) who were treated with ‘low dose’ antithymocyte globulin (ATG). The aims of the study were to assess the efficacy and safety of reduced dose ATG in patients over the age of 60 years. Median age was 71 years (range 62–74 years). At the study endpoint (response to treatment at 6 months) 12 patients were evaluable. All patients received lymphoglobuline (horse ATG; Genzyme) at a dose of 0.5 vials/10 kg/day for 5 days (5 mg/kg/day, equivalent to one-third of the standard dose). There were no deaths attributed to ATG. Two patients died during follow-up, from sepsis and anaphylaxis following platelet transfusion, respectively. Only one of the 12 evaluable patients responded to treatment and remains transfusion independent at 14 months after ATG. These results suggest that this lower dose of ATG, though well tolerated, had low efficacy in the treatment of AA.     

A comparison of survival rates for treatment of melanoma metastatic to the brain

Introduction: A retrospective review of 91 patients with brain metastases from malignant melanoma treated at New York University Medical Center between 1989-1999. Overall survival was the outcome evaluated. Methods: Charts of 91 patients having malignant melanoma with brain metastases were reviewed. Cases were stratified according to therapy: surgical excision, surgical excision plus whole brain radiation therapy, gamma knife stereotactic radiosurgery, gamma knife stereotactic radiosurgery plus whole brain radiation therapy, and whole brain radiation therapy alone. Patients treated with gamma knife stereotactic radiosurgery plus radiation therapy were combined with patients treated with surgical excision plus radiation therapy and compared to those treated with radiation therapy alone. Prognostic characteristics of the two groups were compared and survival curves were generated using the Kaplan-Meier method. The Cox proportional hazards model was used to control for prognostic factors that differed between the groups. Results: Patients treated with gamma knife stereotactic radiosurgery or surgical excision plus radiation therapy were younger, less likely to present with symptoms, and presented with fewer metastases to the brain than patients treated with radiation therapy alone. A survival benefit of 7.3 months (p = 0.05) was found to be associated with gamma knife radiosurgery or surgical excision plus radiation therapy over radiation therapy alone after controlling for differences in age, number of brain lesions, and presence of symptoms. Discussion: This retrospective study of 91 patients treated for melanoma metastases to the brain attempts to examine the effectiveness of different treatments in prolonging survival. Our results suggest that surgical excision or stereotactic radiosurgery with gamma knife in addition to radiation therapy may be more effective than radiation alone at prolonging survival for patients with a limited number of brain lesions. Conclusion: Survival of patients with melanoma metastases to the brain may be prolonged by treatment with gamma knife stereotactic radiosurgery or surgical excision plus whole brain radiation therapy.     

Early metabolic changes in metastatic brain tumors after Gamma Knife radiosurgery:<Superscript>1</Superscript>H-MRS study

Evaluation of early metabolic changes in metastatic brain tumors after Gamma Knife radiosurgery was performed by long-echo (TR, 2000ms; TE, 136 ms; 128–236 acquisitions) volume-selected single-voxel proton magnetic resonance spectroscopy (MRS). Eighty-five brain metastases in 81 patients were investigated before treatment and 16–18h thereafter. Standard metabolic ratios, namelyN-acetylaspartate (NAA)/creatine (Cr), phosphorylcholine/glycerophosphorylcholine (Cho)/Cr, NAA/Cho, lactate (Lac)/Cr, and mobile lipids (Lip)/Cr, were calculated, and comparison of their values before and after irradiation was done. No volumetric changes of any neoplasm were found in any case on the next day after treatment. At the same time, significant reduction of Cho/Cr (P<0.001) and NAA/Cr (P<0.01) ratios on the proton MRS of the tumor was disclosed. Reduction of Cho/Cr ratio was significantly more prominent in neoplasms with higher pretreatment Cho/Cr ratios (P<0.001) and heterogeneous contrast enhancement (P<0.01). Reduction of NAA/Cr ratio was predominantly determined by its pretreatment value (P<0.001). The observed decrease of Cho/Cr ratio probably reflects inhibition of proliferative activity and early apoptotic cell loss, whereas reduction of NAA/Cr may result from radiation-induced modulation of neuronal activity in the peritumoral brain tissue. Serial proton MRS represents a valuable diagnostic tool for evaluation of metabolic changes in intracranial neoplasms after radiosurgical treatment.     

Excipient effects on gastrointestinal transit and drug absorption in beagle dogs

Previous work has shown that polyethylene glycol 400 (PEG 400) has an accelerating effect on gastrointestinal transit and a modulating influence on drug absorption in humans. The aim of this study was to assess the impact of various excipients, PEG 400, propylene glycol, d--tocopheryl-polyethylene glycol-1000 succinate (TPGS) and Labrasol on gastrointestinal transit and drug absorption in four beagle dogs using scintigraphy. Each dog received, on five separate occasions, water (control) or a dose of excipient equivalent to 1 g PEG 400, 2 g propylene glycol, 1 g TPGS or 2 g Labrasol dissolved in water and administered in the form of two capsules. The model drugs ampicillin (200 mg) and antipyrine (100 mg) were co-administered in the capsules. The capsule solutions were radiolabelled with technetium-99m to follow their transit using a dual-headed gamma camera, and blood samples were collected to determine drug pharmacokinetics. On a separate occasion, the drugs were dissolved in saline and given intravenously. The capsules rapidly disintegrated in the stomach liberating their liquid contents. The mean small intestinal transit times for the different treatments (control, PEG 400, propylene glycol, TPGS and Labarasol) were 183, 179, 195, 168 and 154 min, respectively. The corresponding mean absolute oral bioavailability figures were 36, 32, 39, 42 and 32% for ampicillin and 76, 74, 85, 73 and 74% for antipyrine, respectively. The transit and bioavailability data for the excipient treatments were not significantly different from the control. In summary, these excipients, at the doses administered, have limited influence on gastrointestinal transit and drug absorption in beagle dogs.     

Effect of image uncertainty on the dosimetry of trigeminal neuralgia irradiation

OBJECTIVE: Our objective was to quantify the uncertainty in localization of the trigeminal nerve (TGN) with magnetic resonance imaging (MRI) and computed tomography (CT) and to determine the effect of this uncertainty on gamma-knife dose delivery. METHODS: An MR/CT test phantom with 9, 0.6-mm diameter, copper rings was devised. The absolute ring positions in stereotactic space were determined by the angiographic module of the LGP software. The standard deviation, sigma, in the difference between the absolute and MR-measured or CT-measured coordinates of the rings was determined. The trigeminal nerve in 52 previously treated patients was contoured and expanded by 1sigma and 2sigma margins to model the uncertainty in the location of the nerve. For gamma-knife treatment, a single isocenter was used and was located at the distal cisternal portion of the trigeminal nerve root. Irradiation methods included a 4-mm collimator, 90 Gy to isocenter and a 4&8-mm collimator, 70 Gy to isocenter. A patient outcome survey that sampled pain relief and morbidity was done. RESULTS: The MR coordinate sigma was 0.7 mm left-right, 0.8 mm anterior-posterior, and 0.6 mm superior-inferior, and the CT coordinate sigma was 0.4 mm left-right, 0.2 mm anterior-posterior, and 0.2 mm superior-inferior. A 45% higher dose line covered the TGN with the 4&8-mm method. No significant increase in pain reduction or morbidity occurred. CONCLUSIONS: The uncertainty of target location by MRI is more than twice that found in CT imaging. The 4&8-mm collimator method covers the trigeminal root cross section with a higher isodose line than does the 4-mm method. This higher dose did not significantly reduce pain or increase morbidity.     

Postmenopausal levels of sex hormones and risk of breast carcinoma in situ: results of a prospective study

We report on a prospective study to assess the association of postmenopausal serum levels of sex hormones with subsequent risk of breast carcinoma in situ. We conducted a case-control study nested within the cohort of the New York University Women's Health Study, a large prospective study documenting a positive association of circulating levels of estrogens and androgens with invasive breast cancer. The study included 69 cases of incident in situ carcinoma and 134 individually matched controls. No statistically significant trend of increasing risk with increasing level of any of the hormones was observed. Odds ratios (95% CIs) for the highest tertile relative to the lowest were 1.10 (0.51-2.39) for estradiol, 0.95 (0.41-2.19) for estrone, 1.63 (0.69-3.88) for testosterone, 0.99 (0.44-2.24) for androstenedione, 0.99 (0.45-2.20) for dehydroepiandrosterone sulfate and 0.81 (0.38-1.74) for sex hormone-binding globulin. Adjusting for potential confounders did not materially affect the results, nor did limiting the analysis to the 59 cases of ductal carcinoma in situ, the lesion thought to be the direct precursor of most invasive breast cancers. Our results are at variance with the positive associations observed in this same cohort with risk of invasive breast cancer. Possible explanations for our results include lack of power, an effect of sex hormones limited to the progression from in situ to invasive tumors, overrepresentation of indolent tumors or an effect of sex hormones on the induction of only a subset of in situ tumors, those that would develop into invasive tumors.