Enrique Prats

Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations

In order to search for sequence variants conferring risk of thyroid cancer we conducted a genome-wide association study in 192 and 37,196 Icelandic cases and controls, respectively, followed by a replication study in individuals of European descent. Here we show that two common variants, located on 9q22.33 and 14q13.3, are associated with the disease. Overall, the strongest association signals were observed for rs965513 on 9q22.33 (OR = 1.75; P = 1.7 × 10−27) and rs944289 on 14q13.3 (OR = 1.37; P = 2.0 × 10−9). The gene nearest to the 9q22.33 locus is FOXE1 (TTF2) and NKX2-1 (TTF1) is among the genes located at the 14q13.3 locus. Both variants contribute to an increased risk of both papillary and follicular thyroid cancer. Approximately 3.7% of individuals are homozygous for both variants, and their estimated risk of thyroid cancer is 5.7-fold greater than that of noncarriers. In a study on a large sample set from the general population, both risk alleles are associated with low concentrations of thyroid stimulating hormone (TSH), and the 9q22.33 allele is associated with low concentration of thyroxin (T4) and high concentration of triiodothyronine (T3).

Discovery of common variants associated with low TSH levels and thyroid cancer risk

To search for sequence variants conferring risk of nonmedullary thyroid cancer, we focused our analysis on 22 SNPs with a P < 5 × 10−8 in a genome-wide association study on levels of thyroid stimulating hormone (TSH) in 27,758 Icelanders. Of those, rs965513 has previously been shown to associate with thyroid cancer. The remaining 21 SNPs were genotyped in 561 Icelandic individuals with thyroid cancer (cases) and up to 40,013 controls. Variants suggestively associated with thyroid cancer (P < 0.05) were genotyped in an additional 595 non-Icelandic cases and 2,604 controls. After combining the results, three variants were shown to associate with thyroid cancer: rs966423 on 2q35 (OR = 1.34; Pcombined = 1.3 × 10−9), rs2439302 on 8p12 (OR = 1.36; Pcombined = 2.0 × 10−9) and rs116909374 on 14q13.3 (OR = 2.09; Pcombined = 4.6 × 10−11), a region previously reported to contain an uncorrelated variant conferring risk of thyroid cancer. A strong association (P = 9.1 × 10−91) was observed between rs2439302 on 8p12 and expression of NRG1, which encodes the signaling protein neuregulin 1, in blood.

A genome-wide association study yields five novel thyroid cancer risk loci

The great majority of thyroid cancers are of the non-medullary type. Here we report findings from a genome-wide association study of non-medullary thyroid cancer, including in total 3,001 patients and 287,550 controls from five study groups of European descent. Our results yield five novel loci (all with Pcombined<3 × 10−8): 1q42.2 (rs12129938 in PCNXL2), 3q26.2 (rs6793295 a missense mutation in LRCC34 near TERC), 5q22.1 (rs73227498 between NREP and EPB41L4A), 10q24.33 (rs7902587 near OBFC1), and two independently associated variants at 15q22.33 (rs2289261 and rs56062135; both in SMAD3). We also confirm recently published association results from a Chinese study of a variant on 5p15.33 (rs2736100 near the TERT gene) and present a stronger association result for a moderately correlated variant (rs10069690; OR=1.20, P=3.2 × 10−7) based on our study of individuals of European ancestry. In combination, these results raise several opportunities for future studies of the pathogenesis of thyroid cancer.

Lymphoscintigraphic SPECT/CT Localization of a Sentinel Node in an Unusual Position: Rotterʼs Node

A 57-year-old woman with infiltrating ductal carcinoma of the right breast underwent lymph node scintigraphy with Tc-99m-nanocolloid for preoperative sentinel node localization. On planar images, an unusual pattern of lymphatic drainage was observed. We performed a chest SPECT/CT, revealing an interpectoral sentinel node, ie, Rotters node. The patient underwent radioguided surgery and the sentinel node was located intraoperatively, and found to be disease-free. SPECT/CT fusion techniques have enhanced precision in locating sentinel nodes, enabling the surgeon to shorten surgical times.

Rescue Radioguided Laparoscopy Surgery for Meckelʼs Diverticulum: Technical Notes

Abstract The extirpation of Meckels diverticulum (MD) via conventional or laparoscopic surgery is the definitive treatment. However, certain circumstances may modify or alter this situation and require the application of exceptional measures. We report a case under our observation who previously had an exploratory abdominal laparotomy for a suspected MD; however, the findings were negative. At that time, the diagnosis was established based on low-level gastrointestinal bleeding and isotopic tests that confirmed the existence of the diverticulum. Given the findings of gamma-graphic exploration and the previous negative surgical exploration, a decision was made to remove the lesion by laparoscopic radioguided surgery. The patient underwent bilateral laparoscopic radioguided surgery using a gamma radiation detection probe. The exploration of the abdominal cavity noted the existence of the diverticulum about 60 to 70 cm from the ileocecal valve. In this way, it was possible to proceed with the resection of the bowel loop and perform an intracorporeal anastomosis termino lateral. The postoperative course was uneventful, and the patient was discharged on the fifth postoperative day. We believe that the combination of radioguided surgery and single photon emission computed tomography/computed tomography could be useful for treating lesions in locations that are surgically difficult because of the characteristics of the lesion itself or the peculiarities of an individual patient.

Radioguided Adrenal Surgery: Access in Complex Situations: Technical Notes.

AbstractThe laparoscopic adrenalectomy is considered as the procedure of choice for the treatment of adrenal hyperplasia and tumor lesions. However, some special situations may limit the use of this method due to the difficulty to locate the gland and perform the lesion excision.We analyze 2 patients of a left adrenal tumor, explaining how they have overcome the difficulties in both situations. The first case was a patient with a history of intra-abdominal surgery and the other patient suffered from severe obesity.We performed with the use of the gamma probe, and the 2 cases, was of great help to access and glandular localization. The help of gamma probe test was achieved in the surgical bed, that removal was complete.The use of the portable gamma probe facilitated the access to the left adrenal gland as well as conducting the glandular excision without delay, despite the difficulties due to the intra abdominal surgery caused by the previous surgery, and in the case of severe obesity.

Results of RT-PCR for tyrosinase mRNA in sentinel lymph nodes from patients with localized melanoma

AbstractBackground. Significant activity (50% objective responses) plus a small fraction of long term survivors have been reported in pilot trials of chemoimmunotherapy (CT-IT) for disseminated melanoma. Requirement for hospitalization is a major inconvenience. Aims. To assess the feasibility of fully ambulatory CT-IT with single-day cisplatine+dacarbacine (DTIC) combined with subcutaneous interleukin-2 +interferon-α for patients with metastatic melanoma in a multicenter phase II trial. Patients and methods. Courses, to be repeated every 21 days, included cisplatin 80 mg/m2 and DTIC 800 mg/m2, both i.v. on day one, plus subcutaneous injections of interleukin-2, 9 million/m2 IU, day two to 5 and interferon-α, 5 million m2 IU day one to 5. No corticosteroids were allowed except for 20 mg dexamethasone before cisplatine on day one for antiemesis. After 6 courses patients without progression received 6 additional courses of IT alone. Results. Forty four patients with metastasic melanoma have been treated. Male/female: 30/14. Median age: 47 years. Performance status (ECOG): 1 (0–2). Full doses of therapy have been delivered in 224 courses. Toxicity was acceptable: grade 3 toxicity included nausea (6% of courses), vomiting (10%), fever (1%), neutropenia (1%), anemia (0.8%), asthenia (2%), elevation of transaminases (0.8%) and elevation of serum creatinine (0.8%). Response (39 patients evaluable after three or more courses; rest too early): complete response 4 patients (10.2%); partial response 13 patients (33%); stable disease 8 patients (20.5%); progression 14 patients (35.8%). With median follow-up of 20 months or to death, median survival was 11.6 months. Conclusions. The activity and limited toxicity of this regimen allow its ambulatory use. The superiority of CT-IT over each modality alone remains to be confirmed.ResumenFundamento. Se ha descrito una importante actividad (50% de respuestas objetivas) con un pequeño número de supervivientes en los ensayos clínicos de quimioinmunoterapia (QIT) para el melanoma diseminado. En la mayoría la hospitalización era un requerimiento habitual. Objetivos. Valorar la posibilidad de administración ambulatoria completa de la QIT dentro de un ensayo fase II multicéntrico con cisplatino+dacarbacina en un día, combinado con la administración subcutánea de interleukina-2+interferon-α en pacientes con melanoma metastásico. Pacientes y métodos. Los ciclos, administrados cada 21 días, incluían cisplatino 80 mg/m2 y DTIC 800 mg/m2 intravenosos el día uno, con inyecciones subcutáneas de interleukina-2 9 millones UI/m2 del día dos al 5 e interferón-α 5 millones IU/m2 del día uno al 5. No se permitió la utilización de corticoides salvo los 20 mg de dexametasona previo al cisplatino del día uno como antiemético. Tras 6 ciclos, los pacientes sin progresión recibieron otros 6 ciclos de inmunoterapia sola. Resultados. Se han tratado 44 pacientes con melanoma metastásico. Hombres/mujeres: 30/14. Edad mediana: 47. Mediana de estado funcional (ECOG): 0 (0–2). Se han administrado 224 ciclos completos. La toxicidad fue aceptable: la toxicidad grado 3 incluyó náuseas (6% de los ciclos), vómitos (10%), fiebre (1%), neutropenia (1%), anemia (0.8%), astenia (2%), elevación de las transaminasas (0.8%) y elevación de la creatinina sérica (0.8%). La respuesta (39 pacientes evaluables tras tres o más ciclos; resto demasiado pronto): respuesta completa en 4 pacientes (10,2%); respuesta parcial en 13 (33,3%); enfermedad estable en 8 (20,5%); progresión en 14 (35,8%). Tras una mediana de seguimiento de 20 meses o hasta la muerte, la mediana de la supervivencia fue de 11,6 meses. Conclusiones. La actividad y limitada toxicidad de este régimen permite su uso ambulatorio. La superioridad de la QIT sobre cada una de las modalidades de tratamiento aisladas todavía ha de ser confirmada.