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Supplementary Table 1 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I α regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor β (TGFβ) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFβ pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFβ. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFβ stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFβ-induced apoptosis. This cross-talk between the PKA and the TGFβ signaling pathways reveals a new mechanism of endocrine tumorigenesis. [Cancer Res 2009;69(18):7278–84]

Supplementary Table 2 from Inactivation of the Carney Complex Gene 1 (Protein Kinase A Regulatory Subunit 1A) Inhibits SMAD3 Expression and TGFβ-Stimulated Apoptosis in Adrenocortical Cells

ContextPapillary thyroid microcarcinomas (PMC) defined as tumors ≤10 mm in diameter (including pT1a and pT3 according to the latest pTNM classification) have good prognosis, although recurrence is possible. Clinicians are interested in using a scoring system for predicting recurrences.ObjectiveTo identify the prognostic factors for recurrence in patients with PMC and to develop a scoring system based on lymph node involvement, multifocality, and sex. To determine the impact of extrathyroidal invasion (ETI) and a threshold value for analyzing multifocality.MethodsSingle-center retrospective study of a cohort of 1669 patients with PMC managed from 1960 to 2007. The Kaplan–Meier survival rate and prognostic factors of events were analyzed using log-rank tests and uni- and multivariate Cox model-based analyses. A scoring system was proposed.ResultsSixty-eight recurrences were observed. Initial lymph node metastases (P=0.0001), multifocality (P=0.05), and male sex (P=0.01) were significantly associated with recurrence, although there was a period effect (after 1990). PMC size was not a significant variable. Our scoring system allows us to separate patients into three risk groups according to their recurrence-free probability. For PMC Nx patients, total foci size of multifocal tumors >20 mm was significantly associated with recurrence (PConclusionOur scoring system classifies recurrence risk. In PMC Nx patients, multifocality is important in planning therapeutic strategies. Recurrence probability of pT3 PMC appears lower if RAI ablation is performed.

The cyclic AMP signaling pathway can be altered at multiple levels in endocrine tumors. Its central component is the protein kinase A (PKA). Carney complex (CNC) is a hereditary multiple neoplasia syndrome resulting from inactivating mutations of the gene encoding the PKA type I α regulatory subunit (PRKAR1A). Primary pigmented nodular adrenocortical disease is the most frequent endocrine tumor of CNC. Transforming growth factor β (TGFβ) regulates adrenal cortex physiology and signals through SMAD2/3. We used an interference approach to test the effects of PRKAR1A inactivation on PKA and TGFβ pathways and on apoptosis in adrenocortical cells. PRKAR1A silencing stimulates PKA activity and increases transcriptional activity of a PKA reporter construct and expression of the endogenous PKA target, NR4A2, under basal conditions or after forskolin stimulation. PRKAR1A inactivation also decreased SMAD3 mRNA and protein levels via PKA, altering the cellular response to TGFβ. SMAD3 expression was also inhibited by adrenocorticorticotropic hormone in the mouse adrenal gland and by forskolin in H295R cells. TGFβ stimulates apoptosis in H295R cells, and this effect was counteracted by PRKAR1A inactivation. PRKAR1A silencing decreased the percentage of apoptotic cells and the cleavage of apoptosis mediators [caspase-3, poly(ADP-ribose) polymerase, and lamin A/C]. Inactivating mutations of PRKAR1A observed in adrenocortical tumors alter SMAD3, leading to resistance to TGFβ-induced apoptosis. This cross-talk between the PKA and the TGFβ signaling pathways reveals a new mechanism of endocrine tumorigenesis. [Cancer Res 2009;69(18):7278–84]

It is crucial to estimate renal function in diabetic patients. However, formulas are inadequate in this population whereas creatinine clearance (C(cr)) on a 24-h urine collection may be valuable only if we can improve its reproducibility.To evaluate in diabetic patients whether standardised procedures of 24-h urine collection improve the day-to-day variability in creatinine urinary excretion and the subsequent precision of the measured C(cr).The C(cr) from two consecutive 24-h urine collections was measured in 201 consecutive diabetic inpatients. Procedures of 24-h urine collection were standardised, and implementation was supervised at a diabetes clinic.Pearson's correlation coefficients of the two 24-h creatinine urinary excretion were significant (r(2)=0.64 in women and r(2)=0.65 in men, p0.0001) but the daily variability in creatinine urinary excretion was high (14.9% in women and 17.4% in men). As a consequence, the agreement between the two consecutive measurements of C(cr) was poor. First, Bland-Altman plots showed large 95% limits of agreement (-34.3 to 34.6 mL/min/1.73 m(2) in women and -39.0 to 52.0 mL/min/1.73 m(2) in men). Secondly, there was a poor agreement for classifying patients according to the National Kidney Foundation classification90, 60-89.9, 30-59.9, and30 mL/min/1.73 m(2) (Kappa coefficients=0.61, 0.42, 0.65, and 0.74, respectively).Despite standardised procedures of 24-h urine collection, day-to-day variability in creatinine urinary excretion in adult diabetic men and women remains important, and may lead to misclassification of renal disease.

We report the case of a 42-year-old woman who presented with multiple pulmonary nodules. Surgical resection of 3 nodules revealed differentiated thyroid carcinoma. Thyroid and neck ultrasound was normal. A review of her history revealed that this patient underwent an ovarian cyst resection 15 years ago. Reexamination of pathology samples, with the help of immunohistochemical markers, concluded to a struma ovarii. Pelvic ultrasound was normal; F-18 FDG PET scan was negative. She had total thyroidectomy, with negative histology, followed by first I-131 therapy (3.9 GBq). Thyroglobuline (Tg) was elevated (3230 microg/L in hypothyroidism). The whole-body scan showed multiple foci of pulmonary I-131 uptake, a bone metastasis of third rib, and I-131 uptake in an abdominal para-aortic lymph node. At second I-131 therapy (3.8 GBq), Tg level had decreased to 14 microg/L and there was a decrease in the number of pulmonary nodular I-131 uptake, and resolution of the bone and para-aortic lymph node metastasis. At third I-131 therapy (4.9 GBq), thyroglobuline was undetectable and the whole-body scan showed no I-131 uptake. Struma ovarii is a rare ovarian tumor mostly benign. Metastasis of malignant struma ovarii are rare. Most frequent localizations are liver and peritoneum. Treatment of the malignant struma ovarii implies ovarian surgical resection, total thyroidectomy, and I-131 therapy.