Durvalumab plus tremelimumab for the treatment of advanced neuroendocrine neoplasms of gastroenteropancreatic and lung origin.

Single immune checkpoint blockade in advanced neuroendocrine neoplasms (NENs) shows limited efficacy; dual checkpoint blockade may improve treatment activity. Dune (NCT03095274) is a non-randomized controlled multicohort phase II clinical trial evaluating durvalumab plus tremelimumab activity and safety in advanced NENs. This study included 123 patients presenting between 2017 and 2019 with typical/atypical lung carcinoids (Cohort 1), G1/2 gastrointestinal (Cohort 2), G1/2 pancreatic (Cohort 3) and G3 gastroenteropancreatic (GEP) (Cohort 4) NENs; who progressed to standard therapies. Patients received 1500 mg durvalumab and 75 mg tremelimumab for up to 13 and 4 cycles (every 4 weeks), respectively. The primary objective was the 9-month clinical benefit rate (CBR) for cohorts 1-3 and 9-month overall survival (OS) rate for Cohort 4. Secondary endpoints included objective response rate, duration of response, progression-free survival according to irRECIST, overall survival, and safety. Correlation of PD-L1 expression with efficacy was exploratory. The 9-month CBR was 25.9%/35.5%/25% for Cohorts 1, 2, and 3 respectively. The 9-month OS rate for Cohort 4 was 36.1%, surpassing the futility threshold. Benefit in Cohort 4 was observed regardless of differentiation and Ki67 levels. PD-L1 combined scores did not correlate with treatment activity. Safety profile was consistent with that of prior studies. In conclusion, durvalumab plus tremelimumab is safe in NENs and shows modest survival benefit in G3 GEP-NENs; with one-third of these patients experiencing a prolonged OS.

Fusobacterium nucleatum persistence and risk of recurrence after preoperative treatment in locally advanced rectal cancer.

BACKGROUND: Accumulating evidence has identified Fusobacterium as an important pathogenic gut bacterium associated with colorectal cancer. Nevertheless, only limited data exist about the role of this bacterium in locally advanced rectal cancer (LARC). In this study, we quantified Fusobacterium nucleatum in untreated and post-neoadjuvant chemoradiotherapy (nCRT) samples from LARC patients and investigated its association with therapy response and survival. PATIENTS AND METHODS: A total of 254 samples from 143 patients with rectal adenocarcinomas were analyzed for the presence and abundance of F. nucleatum using RNA in situ hybridization and digital image analysis. Assay accuracy was determined using infected cell lines and tumor samples with available quantitative PCR data. We studied the impact of F. nucleatum load on pathologic complete response and relapse-free survival. Treatment-induced changes were evaluated in paired pre- and post-nCRT samples (n = 71). Finally, tumor microenvironment changes during nCRT were assessed in paired samples (n = 45) by immune contexture analysis. RESULTS: F. nucleatum tissue levels by RNA in situ hybridization strongly correlated with quantitative PCR (r = 0.804, P < 0.001). F. nucleatum abundance was higher in untreated [median, 7.4; 95% confidence interval (3.7-16.2)] compared with treated [median, 1.6; 95% confidence interval (1.3-2.4)] tumors (P <0.001) with 58% (73/126) and 26% (22/85) positive tumors, respectively (P < 0.001). Baseline F. nucleatum levels were not associated with pathologic complete response. F. nucleatum positivity after nCRT, but not baseline status, significantly increased risk of relapse [hazard ratio = 7.5, 95% confidence interval (3.0-19.0); P < 0.001]. Tumors that turned F. nucleatum-negative after nCRT had a strong increase in CD8+ T cells post-nCRT (P < 0.001), while those that persisted F. nucleatum-positive after nCRT lacked CD8+ T cells induction in post-nCRT samples compared with baseline (P = 0.69). CONCLUSION: F. nucleatum persistence post-nCRT is associated with high relapse rates in LARC, potentially linked to suppression of immune cytotoxicity.

Esofagitis linfocítica: una causa rara emergente de impactación alimentaria / Lymphocytic oesophagitis: a rare emerging cause of food impaction

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Update of the recommendations for the determination of biomarkers in colorectal carcinoma: National Consensus of the Spanish Society of Medical Oncology and the Spanish Society of Pathology.

In this update of the consensus of the Spanish Society of Medical Oncology (Sociedad Española de Oncología Médica-SEOM) and the Spanish Society of Pathology (Sociedad Española de Anatomía Patológica-SEAP), advances in the analysis of biomarkers in advanced colorectal cancer (CRC) as well as susceptibility markers of hereditary CRC and molecular biomarkers of localized CRC are reviewed. Recently published information on the essential determination of KRAS, NRAS and BRAF mutations and the convenience of determining the amplification of human epidermal growth factor receptor 2 (HER2), the expression of proteins in the DNA repair pathway and the study of NTRK fusions are also evaluated. From the pathological point of view, the importance of analysing the tumour budding and poorly differentiated clusters, and its prognostic value in CRC is reviewed, as well as the impact of molecular lymph node analysis on lymph node staging in CRC. The incorporation of pan-genomic technologies, such as next-generation sequencing (NGS) and liquid biopsy in the clinical management of patients with CRC is also outlined. All these aspects are developed in this guide, which, like the previous one, will remain open to any necessary revision in the future.

Comparison between small bowel manometric patterns and full-thickness biopsy histopathology in severe intestinal dysmotility.

BACKGROUND: Intestinal manometry is the current standard for direct evaluation of small bowel dysmotility. Patients with abnormal motility can either be diagnosed of pseudo-obstruction when there are radiological findings mimicking mechanical intestinal obstruction or of enteric dysmotility when these findings are absent. The aim of the present study was to prospectively compare small bowel manometric abnormalities with histopathological findings in intestinal full-thickness biopsies in patients with severe dysmotility disorders. METHODS: We investigated 38 patients with intestinal manometry and a subsequent full-thickness intestinal biopsy. Manometric recordings were read by 4 investigators and a diagnostic consensus was obtained in 35 patients. Histopathological analysis, including specific immunohistochemical techniques of small bowel biopsies was performed and compared to manometric readings. KEY RESULTS: Patients with abnormal intestinal manometry had abnormal histopathological findings in 73% of cases. However, manometric patterns did not match with the specific neuromuscular abnormalities. Among patients with a neuropathic manometry pattern and abnormal histopathology, only 23% had an enteric neuropathy, whereas 62% had neuromuscular inflammation, and 15% an enteric myopathy. On the other hand, patients with a myopathic manometry pattern all had abnormal histopathology, however, none of them with signs of enteric myopathy. CONCLUSION & INFERENCES: Small bowel dysmotility detected by intestinal manometry is often associated with abnormal neuromuscular findings in full-thickness biopsies. However, there is no correlation between the specific manometric patterns and the histopathological findings.

The effectiveness of electrocautery ablation for the treatment of high-grade anal intraepithelial neoplasia in HIV-infected men who have sex with men.

OBJECTIVES: Electrocautery is one of the main treatment options for high-grade anal intraepithelial neoplasia (HGAIN). However, data regarding its efficacy are scarce. The aim of the study was to evaluate the effectiveness of electrocautery for the treatment of HGAIN. METHODS: An observational study of HIV-infected men who have sex with men (MSM) who underwent screening for anal dysplasia was carried out. The on-treatment effectiveness of electrocautery was evaluated (according to biopsy findings measured 6-8 weeks after treatment) in patients with HGAIN. A complete response was defined as resolution of anal intraepithelial neoplasia (AIN), a partial response as regression to low-grade AIN and recurrence as biopsy-proven HGAIN during follow-up. RESULTS: From May 2009 to November 2014, 21.9% (126 of 576) of patients screened were found to have HGAIN. Electrocautery effectiveness was evaluated in 83 patients. A complete response was observed in 27 patients [32.5%; 95% confidence interval (CI) 23.4-53.2%], a partial response in 28 patients (33.7%; 95% CI 24.5-44.4%) and persistence in 28 patients (33.7%; 95% CI 24.5-44.4%). The patients with the most successful results (81.8%) required two to four sessions of electrocautery. After a mean follow-up of 12.1 months, 14 of 55 patients with a response (25.4%; 95% CI 15.8-38.3%) developed recurrent HGAIN within a mean time of 29.9 months (95% CI 22-37.7 months). No patient progressed to invasive cancer during the study or developed serious adverse events after treatment. No factors associated with poor response or recurrences were observed. CONCLUSIONS: Although electrocautery is the standard treatment for anal dysplasia, almost 50% of patients with HGAIN in our study did not respond or relapsed. New treatment strategies are necessary to optimize the management of anal dysplasia.

Right angular pregnancy at seven weeks' gestation: a case report treated by laparoscopic approach.

Angular pregnancy (AP) or implantation of the embryo in the lateral angle of the uterine cavity close to the internal ostium of the fallopian tube is a very rare event. In fact, angular pregnancy refers to implantation of the embryo just medial to the uterotubal junction, in the lateral angle of the uterine cavity. AP must be distinguished, anatomically, from interstitial pregnancy by its position in relation to the round ligament, which crosses the Müllerian duct at the side of the uterotubal junction. AP is associated with a high rate of complications such as bleeding and ruptured uterus due to delayed diagnosis. The authors present a clinical report of AP at seven weeks' gestation without uterine rupture. They performed directly operative laparoscopy because of acute intra-abdominal hemorrhage. Laparoscopy was useful in the treatment of early angular pregnancy and could avoid the need for invasive surgery or hysterectomy.

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology

Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely (AU)

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Detailed characterization of MLH1 p.D41H and p.N710D variants coexisting in a Lynch syndrome family with conserved MLH1 expression tumors.

Lynch syndrome (LS) is an autosomal dominant cancer-susceptibility disease caused by inactivating germline mutations in mismatch repair (MMR) genes. Variants of unknown significance (VUS) are often detected in mutational analysis of MMR genes. Here we describe a large family fulfilling Amsterdam I criteria carrying two rare VUS in the MLH1 gene: c.121G > C (p.D41H) and c.2128A > G (p.N710D). Collection of clinico-pathological data, multifactorial analysis, in silico predictions, and functional analyses were used to elucidate the clinical significance of the identified MLH1 VUS. Only the c.121G > C variant cosegregated with LS-associated tumors in the family. Diagnosed colorectal tumors were microsatellite unstable although immunohistochemical staining revealed no loss of MMR proteins expression. Multifactorial likelihood analysis classified c.2128A > G as a non-pathogenic variant and c.121G > C as pathogenic. In vitro functional tests revealed impaired MMR activity and diminished expression of c.121G > C. Accordingly, the N710 residue is located in the unconserved MLH1 C-terminal domain, whereas D41 is highly conserved and located in the ATPase domain. The obtained results will enable adequate genetic counseling of c.121G > C and c.2128A > G variant carriers and their families. Furthermore, they exemplify how cumulative data and comprehensive analyses are mandatory to refine the classification of MMR variants.

Updated guidelines for biomarker testing in colorectal carcinoma: a national consensus of the Spanish Society of Pathology and the Spanish Society of Medical Oncology.

Publication of this consensus statement is a joint initiative of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM), intended to revise and update the diagnostic and treatment recommendations published 2 years ago on biomarker use and the management of patients with colorectal carcinoma (CRC), thereby providing an opportunity to improve healthcare efficiency and resource use in these patients. This expert group recommends testing for KRAS and NRAS status in all patients with metastatic CRC being considered for anti-epidermal growth factor receptor (anti-EGFR) therapy, as this type of treatment should only be used in patients not harbouring mutations in these genes. In contrast, testing for BRAF, EGFR, PI3K and PTEN mutation status is not necessary for therapeutic decision making, so does not need to be done routinely.

SPROUTY2 is a ß-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.

SPROUTY2 (SPRY2) is an intracellular regulator of receptor tyrosine kinase signaling involved in cell growth, differentiation and tumorigenesis. Here, we show that SPRY2 is a target gene of the Wnt/ß-catenin pathway that is abnormally activated in more than 90% of colon carcinomas. In human colon cancer cells, SPRY2 expression is induced by ß-catenin in co-operation with the transcription factor FOXO3a instead of lymphoid enhancer factor/T-cell factor proteins. We found binding of ß-catenin to the SPRY2 promoter at FOXO3a response elements. In vivo, cells marked by nuclear ß-catenin and FOXO3a express SPRY2 in proliferative epithelial tissues, such as intestinal mucosa and epidermis. Consistently, inducible ß-catenin deletion in mice reduced Spry2 expression in the small intestine. Moreover, SPRY2 protein expression correlated with nuclear ß-catenin and FOXO3a colocalization in human colon carcinomas. Importantly, the amount of SPRY2 protein correlated with shorter overall survival of colon cancer patients. Our data reveal SPRY2 as a novel Wnt/ß-catenin and FOXO3a target gene indicative of poor prognosis in colon cancer.

Intestinal schistosomiasis as unusual aetiology for acute appendicitis, nowadays a rising disease in Western countries.

Intestinal schistosomiasis as unusual aetiology for acute appendicitis, nowadays a rising disease in western countries. Recent changes in global migration has led to an immigration growth in our scenario, upsurging people coming from endemic areas of schistosomiasis. Schistosomal appendicitis, seldom reported in developed countries, is now an expected incrising entity in our hospitals during the near future. Due to this circumstances, we believe that schistosomiasis should be consider as a rising source for acute appendicitis in western countries. In order to illustrate this point, we present a case of a 45-years-old black man, from Africa, was admitted via A&E because of acute abdominal pain, located in right lower quadrant. Acute appendicitis was suspected, and he underwent laparotomy and appendectomy. Pathological study by microscope revealed a gangrenous appendix with abscesses and parasitic ova into the submucosal layer of the appendix, suggesting Schistosomiasis.

SPROUTY-2 and E-cadherin regulate reciprocally and dictate colon cancer cell tumourigenicity.

SPROUTY-2 (SPRY2) regulates receptor tyrosine kinase signalling and therefore cell growth and differentiation. In this study, we show that SPRY2 expression in colon cancer cells is inhibited by the active vitamin D metabolite 1alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) through E-cadherin-dependent and -independent mechanisms. In turn, SPRY2 represses both basal and 1,25(OH)(2)D(3)-induced E-cadherin expression. In line with this, SPRY2 induces ZEB1 RNA and protein, but not that of other epithelial-to-mesenchymal transition inducers that repress the CDH1/E-cadherin promoter. Consistently, SPRY2 and E-cadherin protein levels inversely correlate in colon cancer cell lines and xenografted tumours. Moreover, SPRY2 knockdown by small hairpin RNA increases CDH1/E-cadherin expression and, reciprocally, CDH1/E-cadherin knockdown increases that of SPRY2. In colon cancer patients, SPRY2 is upregulated in undifferentiated high-grade tumours and at the invasive front of low-grade carcinomas. Quantification of protein expression in 34 tumours confirmed an inverse correlation between SPRY2 and E-cadherin. Our data demonstrate a tumourigenic action of SPRY2 that is based on the repression of E-cadherin, probably by the induction of ZEB1, and a reciprocal regulation of SPRY2 and E-cadherin that dictates cell phenotype. We propose SPRY2 as a candidate novel marker for high-grade tumours and a target of therapeutic intervention in colon cancer.

Lapatinib, a HER2 tyrosine kinase inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity.

Lapatinib is a human epidermal growth factor receptor 2 (HER2) tyrosine kinase inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo, where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.

[Neuroendocrine carcinomas of the colon and rectum. A unit's experience over six years]. / Carcinomas neuroendocrinos de colon y recto. Experiencia de una unidad en seis años.

INTRODUCTION: Neuroendocrine tumours of the colon and rectum are infrequent. They are usually undifferentiated, easy to diagnose for the pathologist and are especially aggressive in their clinical behaviour. Prognosis is usually poor and they have a high tendency to metastase early. MATERIAL AND METHODS: We have reviewed our experience in a Colorectal Unit during a period of six years. Patients with neuroendocrine tumours have been reviewed retrospectively. Carcinoid tumours have not been included in this study. RESULTS: During this period, 2,155 patients have been operated for colorectal cancer and in five patients a neuroendocrine tumour has been found in the specimen. Mean age was 66 years, three male and two female. One tumour was located in the caecum, two in the rectum and two in the sigmoid colon. Two patients had hepatic metastasis at diagnosis. Surgery was performed in all patients and two patients received adjuvant quimiotherapy. A patient died because of post-operative hepatic insufficiency, another at 2 months and another after one year. Two patients are still alive after eight months follow-up. CONCLUSIONS: Neuroendocrine tumours appear to be rare in the colon and rectum. Clinical manifestations are not different from standard adenocarcinoma. When these tumours are diagnosed, they have distance disease, as in two of the five cases, related to a poor prognosis for the patient. Surgery is the treatment that can offer a greater chance of survival to these patients.

Carcinomas neuroendocrinos de colon y recto. Experiencia de una unidad en seis años / No disponible

Introducción: los tumores neuroendocrinos de colon y rectoson poco frecuentes. Suelen ser tumores poco diferenciados,diagnosticados por el patólogo y de especial agresividad en sucomportamiento clínico. El pronóstico suele ser malo, con tendenciaa la rápida metastatización.Material y métodos: se ha revisado la experiencia de unaUnidad de Coloproctología durante un periodo de seis años. Se hanrevisado de manera retrospectiva los pacientes con un tumor de estirpeneuroendocrina. Se han excluido los tumores carcinoides.Resultados: durante este periodo, se han intervenido 2.155pacientes por cáncer de colon y recto y se han hallado cinco pacientescon tumores neuroendocrinos. La edad media fue de 66años, tres varones y dos hembras. Se localizaron uno en ciego,dos en recto y dos en sigma. Dos pacientes presentaban diseminacióndel tumor a distancia. Se realizó cirugía en todos los pacientescon quimioterapia posterior en dos de ellos. Un pacientefalleció por insuficiencia hepática postoperatoria, otro a los dosmeses y otro al año. Dos pacientes siguen vivos con un seguimientomedio de ocho meses.Conclusiones: los tumores neuroendocrinos son unos tumoresde aparición rara en el colon y recto. La clínica de presentaciónno difiere de la que podrían tener los adenocarcinomas. En elmomento del diagnóstico estos tumores suelen presentar enfermedada distancia, como en dos de los cinco casos presentados,relacionándose con un mal pronóstico para el enfermo. El tratamientoquirúrgico y quimioterápico combinado es el que puedealargar más la supervivencia de los pacientes

Introduction: neuroendocrine tumours of the colon and rectumare infrequent. They are usually undifferentiated, easy to diagnosefor the pathologist and are especially aggressive in theirclinical behaviour. Prognosis is usually poor and they have a hightendency to metastase early.Material and methods: we have reviewed our experience ina Colorectal Unit during a period of six years. Patients with neuroendocrinetumours have been reviewed retrospectively. Carcinoidtumours have not been included in this study.Results: during this period, 2,155 patients have been operatedfor colorectal cancer and in five patients a neuroendocrine tumourhas been found in the specimen. Mean age was 66 years,three male and two female. One tumour was located in the caecum,two in the rectum and two in the sigmoid colon. Two patientshad hepatic metastasis at diagnosis. Surgery was performedin all patients and two patients received adjuvant quimiotherapy.A patient died because of post-operative hepatic insufficiency, anotherat 2 months and another after one year. Two patients arestill alive after eight months’ follow-up.Conclusions: neuroendocrine tumours appear to be rare inthe colon and rectum. Clinical manifestations are not differentfrom standard adenocarcinoma. When these tumours are diagnosed,they have distance disease, as in two of the five cases, relatedto a poor prognosis for the patient. Surgery is the treatmentthat can offer a greater chance of survival to these patients (AU)

Expression of somatostatin receptor types 1-5 in 81 cases of gastrointestinal and pancreatic endocrine tumors. A correlative immunohistochemical and reverse-transcriptase polymerase chain reaction analysis.

Somatostatin receptors (SSTRs) have been extensively mapped in human tumors by means of autoradiography, reverse-transcriptase polymerase chain reaction (RT-PCR), in situ hybridization (ISH) and immunohistochemistry (IHC). We analyzed the SSTR type 1-5 expression by means of RT-PCR and/or IHC in a series of 81 functioning and non-functioning gastroenteropancreatic (GEP) endocrine tumors and related normal tissues. Moreover, we compared the results with clinical, pathological and hormonal features. Forty-six cases (13 intestinal and 33 pancreatic) were studied for SSTR 1-5 expression using RT-PCR, IHC with antibodies to SSTR types 2, 3, 5 and ISH for SSTR2 mRNA. The vast majority of tumors expressed SSTR types 1, 2, 3 and 5, while SSTR4 was detected in a small minority. Due to the good correlation between RT-PCR and IHC data on SSTR types 2, 3, and 5, thirty-five additional GEP endocrine tumors were studied with IHC alone. Pancreatic insulinomas had an heterogeneous SSTR expression, while 100% of somatostatinomas expressed SSTR5 and 100% gastrinomas and glucagonomas expressed SSTR2. Pre-operative biopsy material showed an overlapping immunoreactivity with that of surgical specimens, suggesting that the SSTR status can be detected in the diagnostic work-up. It is concluded that SSTRs 1-5 are heterogeneously expressed in GEP endocrine tumors and that IHC is a reliable tool to detect SSTR types 2, 3 and 5 in surgical and biopsy specimens.

Specific haplotypes of the RET proto-oncogene are over-represented in patients with sporadic papillary thyroid carcinoma.

BACKGROUND: Papillary thyroid carcinoma (PTC), which may be sporadic (95%) or familial (5%), has a prevalence adjusted for age in the general population of 1:100 000. Somatic rearrangements of the RET proto-oncogene are present in up to 66% of sporadic tumours, while they are rarely found in familial cases. PURPOSE: In order to determine if some variants of this gene, or a combination of them, might predispose to PTC, we looked for an association of RET haplotype(s) in PTC cases and in controls from four countries matched for sex, age, and population. METHODS: Four single nucleotide polymorphisms (SNPs) across the RET coding sequence were typed and haplotype frequencies were estimated. Genotype and haplotype distributions were compared among these cases and controls. RESULTS: Ten haplotypes were observed, the seven most frequent of which have been previously described in sporadic Hirschsprung patients and controls. The single locus analyses suggested association of exon 2 and exon 13 SNPs with sporadic PTC. The haplotype analysis showed over-representation of one haplotype in French and Italian sporadic PTC, whereas a different haplotype was significantly under-represented in French familial PTC. CONCLUSIONS: Our data suggest that some variants of RET and some specific haplotypes may act as low penetrance alleles in the predisposition to PTC.