Contextualizing the use of oncologic imaging within treatment phases: imaging trends and modality preferences, 2000-2014.

BACKGROUND: In the present study, we retrospectively evaluated the use of tomographic imaging in adult cancer patients to clarify how recent growth plateaus in the use of tomographic imaging in the United States might have affected oncologic imaging during the same period. METHODS: At a U.S. academic cancer centre, 12,059 patients with dates of death from January 2000 through December 2014 were identified. Imaging was restricted to brain and body computed tomography (ct), brain and body magnetic resonance (mr), and body positron-emission tomography (pet) with and without superimposed ct. Trends during the staging (1 year after diagnosis), monitoring (18-6 months before death), and end-of-life (final 6 months before death) phases were analyzed. RESULTS: Comparing the 2005-2009 with the 2010-2014 period, mean intensity of pet imaging increased 21% during staging (p = 0.0000) and 27% during end of life (p = 0.0019). In the monitoring phase, mean intensity for ct brain, ct body, and mr body imaging decreased by 26% (p = 0.0133), 11% (p = 0.0118), and 26% (p = 0.0008), respectively. Aggregate mean intensity of imaging increased in the 13%-27% range every 3 months from 18 months before death to death, reaching 1.43 images in the final 3 months of life. Patients diagnosed in the final 18 months of life had an average of 1 additional image during both the 3 months after diagnosis (p = 0.0000) and the final 3 months before death (p = 0.0000). CONCLUSIONS: Imaging increased as temporal proximity to death decreased, and patients diagnosed near death received more staging imaging, suggesting that imaging guidelines should consider imaging intensity within the context of treatment phase. Despite the development, by multiple organizations, of appropriateness criteria to reduce imaging utilization, aggregate per-patient imaging showed insignificant changes. Simultaneous fluctuations in the intensity of imaging by modality suggest recent changes in the modalities preferred by providers.

Unsupervised Learning in PET Radiomics.

In this study, we investigated large scale radoimics on 116 breast cancer patients. We are particularly interested in unsupervised learning to bicluster patients and features in order to associate such biclusters with the disease characteristics. The results show that radiomics features with wavelet features have a better biclustering ability. And 172 radiomics features have shown a better classification capability.

Behavioral and neurochemical characterization of TrkB-dependent mechanisms of agomelatine in glucocorticoid receptor-impaired mice.

Growing evidence indicates that impairment of the stress response, in particular the negative feedback regulation mechanism exerted by the hypothalamo-pituitary-adrenal (HPA) axis, might be responsible for the hippocampal atrophy observed in depressed patients. Antidepressants, possibly through the activation of BDNF signaling, may enhance neuroplasticity and restore normal hippocampal functions. In this context, glucocorticoid receptor-impaired (GR-i) mice-a transgenic mouse model of reduced GR-induced negative feedback regulation of the HPA axis-were used to investigate the role of BDNF/TrkB signaling in the behavioral and neurochemical effects of the new generation antidepressant drug, agomelatine. GR-i mice exhibited marked alterations in depressive-like and anxiety-like behaviors, together with a decreased cell proliferation and altered levels of neuroplastic and epigenetic markers in the hippocampus. GR-i mice and their wild-type littermates were treated for 21 days with vehicle, agomelatine (50mg/kg/day; i.p) or the TrkB inhibitor Ana-12 (0.5mg/kg/day, i.p) alone, or in combination with agomelatine. Chronic treatment with agomelatine resulted in antidepressant-like effects in GR-i mice and reversed the deficit in hippocampal cell proliferation and some of the alterations of mRNA plasticity markers in GR-i mice. Ana-12 blocked the effect of agomelatine on motor activity as well as its ability to restore a normal hippocampal cell proliferation and expression of neurotrophic factors. Altogether, our findings indicate that agomelatine requires TrkB signaling to reverse some of the molecular and behavioral alterations caused by HPA axis impairment.

[Cost-effectiveness analysis of vacuum-assisted closure in the surgical wound bed preparation of soft tissue injuries]. / Evaluation coût-efficacité de la thérapie par pression négative dans la préparation chirurgicale des pertes de substance cutanée.

This work proposes, from the point of view of the University Hospital Center of Nantes (acute care), a cost-effectiveness assessment of negative pressure wound therapy (NPWT), in comparison with moist wound therapy, in the surgical preparation of cutaneous defects requiring reconstructive surgery. This retrospective study was realized after data collection from patient files with hospitalization for the management of open-leg fractures with a view to reconstructive surgery by graft or flap (Cauchoix II or III). Effectiveness criteria, after debridement and NWPT initiation, was the time period required for preparing the wound for definitive reconstructive surgery closure by flap or graft. NWPT is compared, over the same 2000 to 2006 period, to the only existing therapeutic alternative, that is to say moist wound therapy. Only direct costs in relation with consumed resources dedicated to each medical strategy were taken into account. A Mann-Whitney U nonparametric test and boostrap technique have been used for statistical and sensitivity analysis. Twenty-five patients were recruited for the two medical strategies. Wound preparation time is significantly shorter for patient treated with NPWT (p=0.026 Mann-Whitney U-test) and is equal to 20 days less on average for time period required for preparing the wound for reconstructive surgery. Hospitalization costs is very significantly lower for patients being treated with NPWT (p=0.02). In absolute value, this cost is reduced on the average by 6000 euro per patient (i.e. by more than 60%). The incremental cost-effectiveness ratio is of the order of 164 euro per day of wound preparation for surgery gained.

Death-associated protein 3 is overexpressed in human thyroid oncocytic tumours.

BACKGROUND: The human death-associated protein 3 (hDAP3) is a GTP-binding constituent of the small subunit of the mitochondrial ribosome with a pro-apoptotic function. METHODS: A search through publicly available microarray data sets showed 337 genes potentially coregulated with the DAP3 gene. The promoter sequences of these 337 genes and 70 out of 85 mitochondrial ribosome genes were analysed in silico with the DAP3 gene promoter sequence. The mitochondrial role of DAP3 was also investigated in the thyroid tumours presenting various mitochondrial contents. RESULTS: The study revealed nine transcription factors presenting enriched motifs for these gene promoters, five of which are implicated in cellular growth (ELK1, ELK4, RUNX1, HOX11-CTF1, TAL1-ternary complex factor 3) and four in mitochondrial biogenesis (nuclear respiratory factor-1 (NRF-1), GABPA, PPARG-RXRA and estrogen-related receptor alpha (ESRRA)). An independent microarray data set showed the overexpression of ELK1, RUNX1 and ESRRA in the thyroid oncocytic tumours. Exploring the thyroid tumours, we found that DAP3 mRNA and protein expression is upregulated in tumours presenting a mitochondrial biogenesis compared with the normal tissue. ELK1 and ESRRA were also showed upregulated with DAP3. CONCLUSION: ELK1 and ESRRA may be considered as potential regulators of the DAP3 gene expression. DAP3 may participate in mitochondrial maintenance and play a role in the balance between mitochondrial homoeostasis and tumourigenesis.

Human thyroid tumours, the puzzling lessons from E7 and RET/PTC3 transgenic mice.

Human rearranged RET/PTC3 (papillary thyroid carcinoma) proto-oncogene and high-risk human papillomavirus (HPV) type 16 E7 oncogene induces in the mouse a neoplastic transformation of thyroid follicular cells. We present a detailed immuno-histological study (170 mouse thyroids: RET/PTC3, E7, wild type, 2- to 10-month-old) with cell cycle proliferation and signalling pathway indicators. The characteristics of both models are different. There is an 'oncogene dependent' cellular signature, maintained at all studied ages in the E7 model, less in the RET/PTC3 model. During tumour development a large heterogeneity occurred in the Tg-RET/PTC3 model within a same tumour or within a same thyroid lobe. The Tg-E7 model was less heterogeneous, with a dominant goitrous pattern. The solid tumour already described in the RET/PTC3 models associated with cribriform patterns, suggested 'PTC spindle cell changes' as in humans PTC rather than the equivalent of the solid human PTC. Proliferation and apoptosis in the two thyroid models are related to the causal oncogene rather than reflect a general tumorigenic process. The thyroids of RET/PTC3 mice appeared as a partial and transient model of human PTCs, whereas the Tg-E7 mice do not belong to the usual PTC type.

Nuclear medicine in the assessment of differentiated thyroid cancer.

Despite modern multi-modality treatment, 10-30% of patients treated for differentiated thyroid cancer (DTC) ultimately develop local recurrence or metastatic disease. These malignancies are frequently slow-growing and secondary surgical resection is often undertaken along with radioactive iodine treatment. Correlation of radiological imaging with nuclear medicine studies is essential for individualized treatment planning, and to optimize this management. Radiologists should be familiar with the interpretation of various nuclear medicine studies used to image differentiated thyroid neoplasms.

Microarray analysis refines classification of non-medullary thyroid tumours of uncertain malignancy.

Conventional histology failed to classify part of non-medullary thyroid lesions as either benign or malignant. The group of tumours of uncertain malignancy (T-UM) concerns either atypical follicular adenomas or the recently called 'tumours of uncertain malignant potential'. To refine this classification we analysed microarray data from 93 follicular thyroid tumours: 10 T-UM, 3 follicular carcinomas, 13 papillary thyroid carcinomas and 67 follicular adenomas, compared to 73 control thyroid tissue samples. The diagnosis potential of 16 selected genes was validated by real-time quantitative RT-PCR on 6 additional T-UM. The gene expression profiles in several groups were examined with reference to the mutational status of the RET/PTC, BRAF and RAS genes. A pathological score (histological and immunohistochemical) was estimate for each of the T-UM involved in the study. The correlation between the T-UM gene profiles and the pathological score allowed a separation of the samples in two groups of benign or malignant tumours. Our analysis confirms the heterogeneity of T-UM and highlighted the molecular similarities between some cases and true carcinomas. We demonstrated the ability of few marker genes to serve as diagnosis tools and the need of a T-UM pathological scoring.

Genome-wide gene expression profiling suggests distinct radiation susceptibilities in sporadic and post-Chernobyl papillary thyroid cancers.

Papillary thyroid cancers (PTCs) incidence dramatically increased in the vicinity of Chernobyl. The cancer-initiating role of radiation elsewhere is debated. Therefore, we searched for a signature distinguishing radio-induced from sporadic cancers. Using microarrays, we compared the expression profiles of PTCs from the Chernobyl Tissue Bank (CTB, n=12) and from French patients with no history of exposure to ionising radiations (n=14). We also compared the transcriptional responses of human lymphocytes to the presumed aetiological agents initiating these tumours, gamma-radiation and H(2)O(2). On a global scale, the transcriptomes of CTB and French tumours are indistinguishable, and the transcriptional responses to gamma-radiation and H(2)O(2) are similar. On a finer scale, a 118 genes signature discriminated the gamma-radiation and H(2)O(2) responses. This signature could be used to classify the tumours as CTB or French with an error of 15-27%. Similar results were obtained with an independent signature of 13 genes involved in homologous recombination. Although sporadic and radio-induced PTCs represent the same disease, they are distinguishable with molecular signatures reflecting specific responses to gamma-radiation and H(2)O(2). These signatures in PTCs could reflect the susceptibility profiles of the patients, suggesting the feasibility of a radiation susceptibility test.

Gene expression and the biological phenotype of papillary thyroid carcinomas.

The purpose of this paper is to correlate the molecular phenotype of papillary thyroid carcinoma (PTC) to their biological pathology. We hybridized 26 PTC on microarrays and showed that nearly 44% of the transcriptome was regulated in these tumors. We then combined our data set with two published PTC microarray studies to produce a platform- and study-independent list of PTC-associated genes. We further confirmed the mRNA regulation of 15 genes from this list by quantitative reverse transcription-PCR. Analysis of this list with statistical tools led to several conclusions: (1) there is a change in cell population with an increased expression of genes involved in the immune response, reflecting lymphocyte infiltration in the tumor compared to the normal tissue. (2) The c-jun N-terminal kinase pathway is activated by overexpression of its components. (3) The activation of ERKK1/2 by genetic alterations is supplemented by activation of the epidermal growth factor but not of the insulin-like growth factor signaling pathway. (4) There is a downregulation of immediate early genes. (5) We observed an overexpression of many proteases in accordance with tumor remodeling, and suggested a probable role of S100 proteins and annexin A2 in this process. (6) Numerous overexpressed genes favor the hypothesis of a collective migration mode of tumor cells.

A time trend analysis of papillary and follicular cancers as a function of tumour size: a study of data from six cancer registries in France (1983-2000).

The incidence of thyroid cancers, and in particular the papillary forms, has been increasing sharply for many years in Western countries. However, the factors explaining this increase have not been clearly established. Some studies mention the effects of radioactive fallout, particularly after the accident in Chernobyl. Another probable cause is related to progress in medical practice, and particularly in diagnosis. In this article, we describe time trends in the incidence of papillary and follicular cancers, taking into account the size of the tumour at the time of diagnosis. The analysis was carried out on cases from six French cancer registries for the period 1983-2000. Anatomopathological reports concerning 3381 cancer cases were systematically recoded and centralised, following ICDO-3 rules. Over the whole period, the annual percent change of the incidence of papillary cancers was +8.13% and +8.98%, respectively in men and in women. For micropapillary carcinomas (< or = 10 mm), this increase was respectively +12.05% and +12.85%. There is no significant effect of period apart from micropapillary carcinomas in women. However, a birth cohort effect exists for some groups. This effect corresponds to an acceleration in the risk for people born after the 1930s. For the most recent period (1998-2000), half the cases of papillary cancer were micropapillary carcinomas, and for one third of these, the tumour was < or = 5 mm. Our description of a time trend of incidence as a function of tumour size supports the hypothesis of the role of medical practice in a context of high prevalence. Obviously, these findings do not exclude the possible role of other factors.

Prognosis of stage II colon cancer by non-neoplastic mucosa gene expression profiling.

We have assessed the possibility to build a prognosis predictor (PP), based on non-neoplastic mucosa microarray gene expression measures, for stage II colon cancer patients. Non-neoplastic colonic mucosa mRNA samples from 24 patients (10 with a metachronous metastasis, 14 with no recurrence) were profiled using the Affymetrix HGU133A GeneChip. Patients were repeatedly and randomly divided into 1000 training sets (TSs) of size 16 and validation sets (VS) of size 8. For each TS/VS split, a 70-gene PP, identified on the TS by selecting the 70 most differentially expressed genes and applying diagonal linear discriminant analysis, was used to predict the prognoses of VS patients. Mean prognosis prediction performances of the 70-gene PP were 81.8% for accuracy, 73.0% for sensitivity and 87.1% for specificity. Informative genes suggested branching signal-transduction pathways with possible extensive networks between individual pathways. They also included genes coding for proteins involved in immune surveillance. In conclusion, our study suggests that one can build an accurate PP for stage II colon cancer patients, based on non-neoplastic mucosa microarray gene expression measures.

Absence of a specific radiation signature in post-Chernobyl thyroid cancers.

Thyroid cancers have been the main medical consequence of the Chernobyl accident. On the basis of their pathological features and of the fact that a large proportion of them demonstrate RET-PTC translocations, these cancers are considered as similar to classical sporadic papillary carcinomas, although molecular alterations differ between both tumours. We analysed gene expression in post-Chernobyl cancers, sporadic papillary carcinomas and compared to autonomous adenomas used as controls. Unsupervised clustering of these data did not distinguish between the cancers, but separates both cancers from adenomas. No gene signature separating sporadic from post-Chernobyl PTC (chPTC) could be found using supervised and unsupervised classification methods although such a signature is demonstrated for cancers and adenomas. Furthermore, we demonstrate that pooled RNA from sporadic and chPTC are as strongly correlated as two independent sporadic PTC pools, one from Europe, one from the US involving patients not exposed to Chernobyl radiations. This result relies on cDNA and Affymetrix microarrays. Thus, platform-specific artifacts are controlled for. Our findings suggest the absence of a radiation fingerprint in the chPTC and support the concept that post-Chernobyl cancer data, for which the cancer-causing event and its date are known, are a unique source of information to study naturally occurring papillary carcinomas.

[The cost of Mohs micrographic surgery for basal cell carcinoma. The Ambroise Paré hospital's experience (Boulogne, France)]. / Coût de la chirurgie micrographique de Mohs dans les carcinomes basocellulaires. L'expérience de l'hôpital Ambroise Paré (Boulogne, France).

OBJECTIVE: Mohs'micrographic surgery is generally considered as the best procedure for the treatment of difficult basal cell carcinomas. It is supposed to be costly, but an economic evaluation, with a cost-outcome analysis, is necessary to estimate the actual contribution of this procedure in skin cancer treatment, in comparison with the reference procedure, i.e. traditional surgical excision. Our aim was to evaluate the actual cost of Mohs'surgery applied on basal cell carcinoma treatment in France. METHODS: The charts of 97 patients treated by Mohs'surgery between january 1997 and july 2001 in a teaching hospital near Paris (Ambroise Paré hospital, Boulogne), where Mohs'surgery is exclusively performed in France, were reviewed. Direct costs were derived from resource utilization of staff and material required for Mohs'surgery, estimated by a micro-costing method. Indirect costs and total costs were then calculated. RESULTS: When adding surgery and pathology facility costs, mean direct and total costs per basal cell carcinoma were 776.0 (range: 538.4-1273.9), and 1014.6 Euros (range: 777-1512.4), respectively. When including costs of diagnosis, the average total cost per procedure was 1084.3 Euros. DISCUSSION: These costs appear higher than those obtained with other methods of valuation of hospital costs used in France, but they are slightly lower than those found in the literature. The next stage will be to estimate, in the same way, the cost of traditional surgical excision for the same type of lesions, and to calculate the incremental cost-effectiveness ratio between the two procedures, with rate of recurrence at five years as the effectiveness outcome.

[Treatment of dermatofibroma protuberans with fixed Mohs' micrographic surgery]. / Dermatofibrosarcome de Darier Ferrand: traitement par chirurgie micrographique de Mohs avec inclusion en paraffine.

INTRODUCTION: Dermatofibrosarcoma protuberans is a tumor of intermediate malignancy characterized by its aggressive local growth due to pseudopodium-like outgrowths and marked propensity to recur after surgical excision. To achieve complete cure with conventional surgery, surgical margins up to 5 cm are required, leading to wide scars. Mohs' micrographic surgery is used for the removal of certain malignant tumors, both ensuring complete excision by examination of all margins as well as minimizing normal tissue loss. However, differentiating minimal residual tumor from normal skin can be difficult on the frozen sections used in Mohs' micrographic surgery. Our aim was to develop a procedure of Mohs' micrographic surgery in conjunction with rush formalin-fixed, paraffin-embedded tangential sections. PATIENTS AND METHODS: Ten consecutive cases have been prospectively treated since 1998. Under local anesthesia, the tumor was first excised including lateral margin of 1 cm and a deep margin including the underlying muscle aponevrosis. A 2 to 3 mm thick horizontal section of the surgical bed was then removed, rush formalin-fixed, paraffin-embedded, tangentially sectioned, hematin-eosin stained, and eventually stained with an anti-CD34 monoclonal antibody. While waiting for pathology results, the surgical bed was not definitively closed. If excision was incomplete, an oriented complementary excision was performed. RESULTS: Excision was complete after the first stage in 7 patients and incomplete only deeply in 3. Lateral surgical margins were reduced to 1.3 cm in all patients, facilitating wound closure: direct suture (5 patients), controlled wound healing (3 patients) or flap coverage (2 patients). No recurrence has been observed after a mean follow-up of 26 months. DISCUSSION: The use of Mohs' micrographic surgery in conjunction with rush formalin-fixed, paraffin-embedded tangential sections reduce surgical margins in dermatofibrosarcoma protuberans. This procedure would be interesting in difficult sites, such as the genitalia, the breast, or the periarticular regions. Other cases, and longer follow-up are however necessary to validate this promising technique.

[Mohs' micrographic surgery: history, principles, critical analysis of its efficacy and indications]. / Historique, principes, analyse critique de l'efficacité et indications de la chirurgie micrographique de Mohs.

OBJECTIVES: To systematically review the literature for studies reporting on the role of Mohs' micrographic (MMS) surgery in the treatment of skin tumors. To show how it is performed in France. DESIGN: We reviewed with a quality grid all studies indexed in MEDLINE before 2003/01/01 and published in English or French. Data were extracted by two independent reviewers. MAIN OUTCOME MEASURES: Quality of clinical studies, recurrence rates, number of patients lost to follow-up. RESULTS: No randomized study was found among the 493 references found. Studies of lower quality, on procedures similar to MMS, or previous systematic reviews were therefore selected. In tumors such as basal (BCC) or spinous (SCC) cell carcinoma, microcystic adnexal carcinoma, dermatofibrosarcoma protuberans, and Merkel cell carcinoma, MMS commonly induced lower recurrence rates than figures reported for conventional treatments and/or reduced surgical margins. Studies on melanoma were of low quality. CONCLUSIONS: Although no evidence-based guidelines could be developed, MMS should be used mainly for larger, morphea, micronodular or infiltrative-type, or recurrent BCCs located in danger zones, but also (sometimes with a slightly modified procedure) in microcystic adnexal carcinomas, dermatofibrosarcoma protuberans, Merkel cell carcinoma, and in aggressive forms of SCC. Randomized, controlled studies should be performed.

Loss of heterozygosity on 10q and mutational status of PTEN and BMPR1A in colorectal primary tumours and metastases.

We investigated the possible role of chromosome 10q losses in colorectal cancer metastasis by carrying out an allelic imbalance study on a series of microsatellite instability-negative (MSI-) primary tumours (n=32) and metastases (n=36) from 49 patients. Our results demonstrate that 10q allelic losses are associated with a significant proportion (25%) of MSI- colorectal tumours, but are not involved in the metastatic process. PTEN and BMPR1A, two genes located in the common deleted region, were screened for mutations in samples with loss of heterozygosity. The absence or low frequency of mutations indicates that the inactivation of these genes by deletion of one allele and mutation of the other one plays only a minor role in MSI- tumours.

Histological validation of diagnoses of thyroid cancer among adults in the registries of Belarus and the Ukraine.

In order to evaluate the diagnostic reliability of the thyroid cancers listed in adult registries from the Ukraine and Belarus, a histological review was organised of 327 randomly selected thyroid carcinoma cases diagnosed between 1980 and 1999. A final diagnosis was reached at a 5-day consensus conference by six pathologists who met around a multiheaded microscope. The study concluded with a comparison between the final diagnosis and the initial diagnosis. The pathologists agreed with the initial diagnosis of malignancy in 286 cases (88%). A final diagnosis of papillary, follicular or medullary thyroid carcinoma was reached in 86, 4, and 6% of the cases respectively. In 2.8% of the cases reviewed, diagnostic discrepancies persisted. The percentage of agreement between the final diagnosis and the initial diagnosis was 93%, with a weighted kappa-statistic of 0.61 (confidence interval 95% (CI(95%)): [0.45-0.77]). In all, 89% of the 286 confirmed cancer cases were in agreement for the type of cancer, with a kappa-statistic of 0.56 (CI(95%): [0.43-0.69]). The level of agreement differed according to cancer categories, with concordance rates of 94, 40 and 33% for papillary, follicular and medullary thyroid carcinomas respectively. The low prevalence of follicular thyroid carcinomas in the adult population studied calls for further exploration. The discrepancies and classification difficulties encountered were analysed.

Correlation between the loss of thyroglobulin iodination and the expression of thyroid-specific proteins involved in iodine metabolism in thyroid carcinomas.

Progress in biotechnology has provided useful tools for tracing proteins involved in thyroid hormone synthesis in vivo. Mono- or polyclonal antibodies are now available to detect on histological sections the Na(+)/I(-) symporter (NIS) at the basolateral pole of the cell, the putative iodide channel (pendrin) at the apical plasma membrane, thyroperoxidase (TPO), and members of the NADPH-oxidase family, thyroid oxidase 1 and 2 (ThOXs), part of the H(2)O(2)-generating system. The aim of this study was to correlate thyroglobulin (Tg) iodination with the presence of these proteins. Tg, T(4)-containing Tg, NIS, pendrin, TPO, ThOXs, and TSH receptor (TSHr) were detected by immunohistochemistry on tissue sections of normal thyroids and various benign and malignant thyroid disorders. Tg was present in all cases. T(4)-containing Tg was found in the adenomas, except in Hurthle cell adenomas. It was never detected in carcinomas. NIS was reduced in all types of carcinomas, whereas it was detected in noncancerous tissues. Pendrin was not expressed in carcinomas, except in follicular carcinomas, where weak staining persisted. TPO expression was present in insular, follicular carcinomas and in follicular variants of papillary carcinomas, but in a reduced percentage of cells. It was below the level of detection in papillary carcinomas. The H(2)O(2)-generating system, ThOXs, was found in all carcinomas and was even increased in papillary carcinomas. Its staining was apical in normal thyroids, whereas it was cytoplasmic in carcinomas. The TSHr was expressed in all cases, but the intensity of the staining was decreased in insular carcinomas. In conclusion, our work shows that all types of carcinomas lose the capacity to synthesize T(4)-rich, iodinated Tg. In follicular carcinomas, this might be due to a defect in iodide transport at the basolateral pole of the cell. In papillary carcinomas, this defect seems to be coupled to an altered apical transport of iodide and probably TPO activity. The TSHr persists in virtually all cases.