Iatrogenic hypoglycemia in patients with type 2 diabetes: comparison of insulin analog premixes and human insulin premixes.

Severe iatrogenic--or therapy-induced--hypoglycemia has been associated with mortality rates as high as 10% in patients with type 2 diabetes mellitus (T2DM), and is therefore one of the most significant barriers to glucose management in this patient population. Therapy with modern insulin analogs has been shown to cause significantly less hypoglycemic episodes than human insulins in basal-bolus regimens. This systematic review examines whether a similar benefit has been observed with the insulin analog premixes (aspart 70/30, lispro 75/25, or lispro 50/50) relative to human insulin premix (human 70/30). Consistent with a prior meta-analysis, the results presented here reconfirm that overall hypoglycemia risk is similar after treatment with either an analog premix or a human premix in many populations of patients with T2DM. However, several studies found a benefit for the analog premixes in a subset of patients who were under more challenging glucometabolic conditions, in particular those later in disease progression or those undergoing post-injection exercise. Pharmacokinetic and pharmacodynamic studies indicate that this may occur because a larger proportion of total analog premix activity is absorbed and utilized during the immediate postprandial period, when it is most acutely needed, compared with human premixes. Consequently, with analog premixes, less insulin activity is available during the inter-meal fasting period, when hypoglycemia is most likely to occur. Given the clinical significance of iatrogenic hypoglycemia, these potential hypoglycemic benefits of analog premixes relative to human premixes in some patients with T2DM may need to be factored into the therapeutic decision-making process.

Mild decreases in white blood cell and platelet counts are present one year after radioactive iodine remnant ablation.

BACKGROUND: Bone marrow suppression after multiple, high-dose radioactive iodine (RAI) therapies is well described. However, changes in the peripheral complete blood count (CBC) that may occur after a single treatment of RAI such as that commonly used for routine remnant ablation is much less well studied. In this retrospective trial, we examined the rate of persistent anemia, leukopenia, and thrombocytopenia 1 year after a single RAI administration. METHODS: Peripheral blood counts at baseline were compared to those obtained 1 year after RAI remnant ablation in 206 consecutive thyroid cancer patients. Analyses were performed to determine the potential impact of both the method of preparation (recombinant human thyroid stimulating hormone [rhTSH] vs. thyroid hormone withdrawal) and administered activity of (131)I on hemoglobin, white blood cell (WBC), and platelet counts. RESULTS: Comparison of the baseline CBC before RAI ablation (median administered activity of approximately 3700 MBq or 100 mCi) with the follow-up CBC done 1 year later demonstrated a statistically significant decline in total WBC (6.7 +/- 2.1 x 10(9) vs. 6.0 +/- 1.8 x 10(9)/L, p < 0.001; 9.7% below the reference range at 1-year follow-up) and platelet (272 +/- 67 vs. 250 +/- 65 x 10(9)/L, p < 0.001; 5.8% below the reference range at 1-year follow-up) with no significant change in hemoglobin (1.40 +/- 0.14 vs. 1.40 +/- 0.14 g/L or 14.0 +/- 1.4 vs. 14.0 +/- 1.4 g/dL; 1.5% below the reference range at 1-year follow-up). There were no significant clinical complications observed during the 1-year follow-up period. The changes in total WBC and platelets were not related to the method of preparation or the administered activity of RAI. CONCLUSION: A single RAI treatment of approximately 3700 MBq (100 mCi) after thyroidectomy is associated with a statistically significant, mild decline in WBC and platelet counts that persists for at least 1 year after ablation. Given the small magnitude of the changes and the lack of clinically significant adverse events, these observations should not decrease the use of RAI ablation in moderate to high-risk patients in whom the benefits of ablation are likely to outweigh these minor risks.

Recombinant human TSH-assisted radioactive iodine remnant ablation achieves short-term clinical recurrence rates similar to those of traditional thyroid hormone withdrawal.

UNLABELLED: Recent studies have confirmed that radioactive iodine therapy after recombinant human TSH (rhTSH) stimulation effectively ablates the normal thyroid remnant. However, no published study has determined the effectiveness of rhTSH preparations on the important endpoint of disease recurrence. METHODS: Disease recurrence was retrospectively assessed a median of 2.5 y after radioiodine remnant ablation (RRA) in 394 consecutive thyroid cancer patients (93% papillary, 71% female, 47+/-15 y old [mean +/- SD], median (131)I dose of 3,996 MBq [108 mCi]). RESULTS: Similar rates of clinically evident disease recurrence (4% rhTSH vs. 7% thyroid hormone withdrawal [THW], P=not statistically significant) and residual thyroid bed uptake without other evidence of persistent disease (4% rhTSH vs. 7% THW, P=not statistically significant) were seen in the 320 patients undergoing rhTSH-assisted RRA and the 74 patients prepared for RRA by THW. When the definition of no clinical evidence of disease included a suppressed thyroglobulin level of less than 1 ng/mL and a stimulated thyroglobulin level of less than 2 ng/mL, rhTSH-assisted RRA was associated with significantly higher rates of no clinical evidence of disease (74% rhTSH vs. 55% THW, P=0.02) and significantly lower rates of persistent disease (19% rhTSH vs. 32% THW, P=0.02) than was RRA after THW. Patients selected for rhTSH-assisted RRA were older (48+/-15 vs. 44+/-15 y, P=0.03) and received a slightly higher administered activity of (131)I (median, 4,033 MBq [109 mCi] vs. 3,811 MBq [103 mCi], P=0.01) but did not differ with respect to sex, histology, disease stage, or mean time to recurrence (19+/-9 mo for rhTSH vs. 20+/-16 mo for THW). CONCLUSION: rhTSH-assisted RRA is associated with rates of clinically evident disease recurrence and persistent uptake in the thyroid bed that are similar to those for traditional THW.

Papillary thyroid cancer: monitoring and therapy.

The last 10 years have seen a major paradigm shift in the management of thyroid cancer, with greater reliance on serum thyroglobulin and neck ultrasonography, and less emphasis on routine diagnostic whole-body radioactive iodine scanning for detection of recurrent disease. As our follow-up tests become more sensitive for detection of recurrent disease, we are finding many asymptomatic patients who have low-level persistent disease many years after initial therapy that may or may not benefit from additional testing and therapy. These difficult issues have been addressed by at least five different sets of guidelines published recently by various thyroid specialty organizations around the world. In this article, the authors compare and contrast the recommendations from the various guidelines in an attempt to define areas of consensus and explore possible reasons for differing recommendations.

Impact of pregnancy on serum thyroglobulin and detection of recurrent disease shortly after delivery in thyroid cancer survivors.

OBJECTIVE: Since pregnancy can stimulate thyroid growth, we examined the effect of pregnancy on recurrence and serum thyroglobulin (Tg) shortly after delivery in thyroid cancer survivors. DESIGN: Retrospective analysis of thyroid cancer survivors who became pregnant after completing initial therapy. MAIN OUTCOME: 36 women (age 34 +/- 4 years) who became pregnant a median of 4.3 years after initial therapy for differentiated thyroid cancer were evaluated a median of 4 months after delivery. As part of their initial therapy, 23 women underwent total thyroidectomy with radioactive iodine remnant ablation (RRA), six had total thyroidectomy without RRA, and seven underwent lobectomy without RRA. Following total thyroidectomy with or without RRA, no evidence of recurrence was detected in the early postpartum period in women with negative prepregnancy ultrasound and either undetectable or low suppressed Tg levels. However, disease progression was documented as enlargement of a previously stable cervical lymph node in one of three patients and a marked rise in serum Tg without evidence of structural disease progression in a patient with previously stable distant metastases. When analyzed based on initial therapy, the mean suppressed Tg after delivery was not significantly different than the prepartum value. However, eight women had Tg values after delivery more than 20% higher than the baseline Tg before pregnancy (three with known disease, five with no clinical evidence of disease). CONCLUSION: In thyroid cancer survivors, pregnancy is unlikely to cause clinically significant disease recurrence in the early postpartum period when structural imaging studies confirm the absence of residual disease but can occasionally be associated with progression of known metastatic lesions. Even though the serum Tg did not differ significantly before and after pregnancy, the long-term implications of minor rise in serum Tg seen in some individual patients cannot be assessed without longer studies in larger cohorts.

Serum peptide profiling: identifying novel cancer biomarkers for early disease detection.

Recent advances in mass spectrometry have enabled the identification of hundreds of low molecular weight (LMW) peptides that have previously been difficult to detect in human serum. Serum peptide patterns can now be analyzed using commercially available statistical programs to identify potential peptide patterns that may correlate with the presence or absence of specific diseases. A serum peptide profile (SPP), which is unique to each patient, can be created and compared to a known SPP from a specific disease. The SPP thus serves as a potential early stage biomarker prior to the clinical manifestation of disease. A unique and automated technology platform has been developed by members of the Protein Center at Memorial Sloan-Kettering Cancer Center (MSKCC). It involves a magnetic bead-based approach to extract LMW peptides from serum, placing them by robotic automation on a stainless steel MALDI-TOF target plate, subjecting them to mass spectrometric analysis, and using GeneSpring software to analyze the peptide patterns. Human serum from a cohort of 27 patients with metastatic thyroid cancer and 32 controls were analyzed on the MSKCC platform. 549 individual LMW peptides were identified. A SPP composed of 98 discriminatory LMW peptides was able to distinguish between the two groups of serum samples with high statistical accuracy. We believe that our automated system will serve as a model for future biotechnology laboratories in the quest for hidden diagnostic clues that may be detected by simply analyzing a drop of blood.

The bioartificial thyroid: a biotechnological perspective in endocrine organ engineering for transplantation replacement.

A new concept for ex situ endocrine organ bioengineering is presented, focused on the realization of a human bioartificial thyroid gland. It is based on the theoretical assumption and experimental evidence that symmetries in geometrical coordinates of the thyroid tissue remain invariant with respect to developmental, physiological or pathophysiological transformations occuring in the gland architecture. This topological arrangement is dependent upon physical connections established between cells, cell adhesion molecules and extracellular matrix, leading to the view that the thyroid parenchyma behaves like a deformable "putty", moulded onto an elastic stromal/vascular scaffold (SVS) dictating the final morphology of the gland. In particular, we have raised the idea that the geometry of the SVS per se provides pivotal epigenetic information to address the genetically-programmed, thyrocyte and endothelial/vascular proliferation and differentiation towards a functionally mature gland, making organ form a pre-requirementfor organ function. A number of experimental approaches are explored to obtain a reliable replica of a human thyroid SVS, and an informatic simulation is designed based on fractal growth of the thyroid intraparenchymal arterial tree. Various tissue-compatible and degradable synthetic or biomimetic polymers are discussed to act as a template of the thyroid SVS, onto which to co-seed autologous human thyrocyte (TPC) and endothelial/vascular (EVPC) progenitor cells. Harvest and expansion of both TPC and EVPC in primary culture are considered, with specific attention to the selection of normal thyrocytes growing at a satisfactory rate to colonize the synthetic matrix. In addition, both in vitro and in vivo techniques to authenticate TPC and EVPC lineage differentiation are reviewed, including immunocytochemistry, reverse trascriptase-polymerase chain reaction, flow cytomery and proteomics. Finally, analysis of viability of the thyroid construct following implantation in animal hosts is proposed, with the intent to obtain a bioartificial thyroid gland morphologically and functionally adequate for transplantation. We believe that the biotechnological scenario proposed herein may provide a template to construct other, more complex and clinically-relevant bioartificial endocrine organs ex situ, such as human pancreatic islets and the liver, and perhaps a new approach to brain bioengineering.

Serum peptidome patterns that distinguish metastatic thyroid carcinoma from cancer-free controls are unbiased by gender and age.

Serum peptidomics is a special form of functional proteomics. The small number of blood proteins that are the source of most prominent peptides in human serum serve as a substrate pool for commonly occurring and/or cancer-derived proteases. Exoprotease activities in particular, when superimposed on the ex vivo coagulation and complement degradation pathways, contribute to generation of not only cancer-specific but also "cancer type"-specific serum peptides. Following development of a unique, semiautomated serum peptide profiling platform and after completing investigations to eliminate common experimental bias, we have now studied possible effects of gender and age on serum peptidomes of 200 healthy men and women, ages 20-80, and of 60 patients (30 men and 30 women) with metastatic thyroid carcinomas. Extensive MALDI-TOF MS and data analysis suggested negligible contributions of both age and gender to the serum peptidome patterns except that healthy men and women under 35 years, but not older individuals, could be distinguished with approximately 70% accuracy. Considering the more advanced age of most patients, this finding is unlikely to interfere with peptidomics analysis of most cancers. By examining patient samples and age/gender-matched controls followed by variability analysis of either demographic or disease (versus control) groups, we could conclusively rule out demographic bias. An optimized, 12-peptide ion thyroid cancer signature was then developed, enabling classification of an independent validation set with 95% sensitivity and 95% specificity (binomial confidence intervals, 75.1-99.9%). Ten of these peptides had previously been assigned to signature patterns of other solid tumor cancers. One of the two newly discovered peptides was dehydro-Ala(3)-fibrinopeptide A. As we expand this study to include hundreds of thyroid cancer patients, the peptide signature will be adjusted, further validated, and then evaluated in a clinical setting used either independently or in combination with existing markers.