Other Primary Malignancies Among Women With Adult-Type Ovarian Granulosa Cell Tumors

Objective: The aim of this study was to determine the incidence of new primary malignancies after adult-type granulosa cell tumor (AGCT) and the incidence of AGCT after breast and uterine cancer using nationwide population-based registry data. Methods: We used the Finnish Cancer Registry to identify all patients diagnosed with AGCT in 1968 to 2013 (n = 986). The number of subsequent primary malignancies among women with AGCT and the number of AGCTs in women with previous breast or uterine cancer were compared with the expected number of cases and expressed as standardized incidence ratios (SIRs). Results: There were 122 cases of subsequent cancers diagnosed at least 6 months after the primary diagnosis of AGCT (SIR, 1.09; 95% confidence interval [CI], 0.91-1.3). In particular, the observed number of cancers of the soft tissue (SIR, 4.13; 95% CI, 1.33-12.8), thyroid (SIR, 3.42; 95% CI, 1.54-7.62), and leukemia (SIR, 2.67; 95% CI, 0.98-5.82) exceeded the number of expected cases. The SIR for breast cancers after AGCT was 1.26 (95% CI, 0.92-1.73), and the SIR for AGCT after breast cancer was 1.59 (95% CI, 1.04-2.29). The risk for subsequent AGCT was more than 2-fold in breast cancer patients younger than 50 years, and over 15 years after primary diagnosis. Conclusions: There is an increased risk for thyroid and soft tissue cancer as well as leukemia after AGCT, which may be associated with late effects of carcinogenic treatments and possibly shared risk factors. After breast cancer, the risk for AGCT was higher, which may indicate a shared hormonal etiology.Peer reviewe

Downregulation of transcription factor GATA4 sensitizes human hepatoblastoma cells to doxorubicin-induced apoptosis

Hepatoblastoma, the most common type of pediatric liver cancer, is treated with a combination of surgery and chemotherapy. An essential drug in the treatment of hepatoblastoma is doxorubicin, which in high doses is cardiotoxic. This adverse effect is due to downregulation of cardiac expression of transcription factor GATA4, leading in turn to diminished levels of anti-apoptotic BCL2 (B-cell lymphoma 2) protein family members. GATA4 is also expressed in early fetal liver, but absent from normal postnatal hepatocytes. However, GATA4 is highly expressed in hepatoblastoma tissue. In this study, we assessed the role of GATA4 in doxorubicin-induced apoptosis of hepatoblastoma cells. Herein, we demonstrate that doxorubicin decreases GATA4 expression and alters the expression pattern of BCL2 family members, most profoundly that of BCL2 and BAK, in the HUH6 hepatoblastoma cell line. Silencing of GATA4 by siRNA prior to doxorubicin treatment sensitizes HUH6 cells to the apoptotic effect of this drug by further shifting the balance of BCL2 family members to the pro-apoptotic direction. Specifically, expression levels of anti-apoptotic BCL2 were decreased and pro-apoptotic BID were increased after GATA4 silencing. On the whole, our results indicate that since high endogenous levels of transcription factor GATA4 likely protect hepatoblastoma cells from doxorubicin-induced apoptosis, these cells can be rendered more sensitive to the drug by downregulation of GATA4.Peer reviewe

HER2 and GATA4 are new prognostic factors for early-stage ovarian granulosa cell tumor-a long-term follow-up study

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Circulating levels of TNF-related apoptosis inducing-ligand are decreased in patients with large adult-type granulosa cell tumors-implications for therapeutic potential

Targeted treatments are needed for advanced adult-type granulosa cell tumors (AGCTs). We set out to assess tumor tissue and circulating levels of TNF-related apoptosis-inducing ligand (TRAIL), a promising anti-cancer cytokine, in patients affected by AGCT. We analyzed tissue expression of TRAIL in 127 AGCTs using immunohistochemistry or RT-PCR. Soluble TRAIL was measured by means of ELISA from 141 AGCT patient serum samples, as well as the conditioned media of 15 AGCT patient-derived primary cell cultures, and the KGN cell line. Tissue and serum TRAIL levels were analyzed in relationship with clinical parameters, and serum estradiol, FSH, and LH levels. We found that AGCT samples expressed TRAIL mRNA and protein at levels comparable to normal granulosa cells. AGCT cells did not release soluble TRAIL. TRAIL protein levels were decreased in tumors over 10 cm in diameter (p = 0.04). Consistently, circulating TRAIL levels correlated negatively to tumor dimension (p = 0.01). Circulating TRAIL levels negatively associated with serum estradiol levels. In multiple regression analysis, tumor size was an independent factor contributing to the decreased levels of soluble TRAIL in AGCT patients. AGCTs associate with significantly decreased tumor tissue and serum TRAIL levels in patients with a large tumor mass. These findings encourage further study of agonistic TRAIL treatments in patients with advanced or recurrent AGCT.Peer reviewe

Late gadolinium enhancement (LGE) progresses with right ventricle volume in children after repair of tetralogy of fallot

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Characteristics and outcome of recurrence in molecularly defined adult-type ovarian granulosa cell tumors

Objective. Adult-type ovarian granulosa cell tumors (AGCTs) have an unpredictable tendency to relapse. In a carefully validated patient cohort, we evaluated the prognostic factors related to AGCT recurrence. Methods. We identified all patients diagnosed with AGCT during 1956-2014 in Helsinki University Hospital, with a minimum follow-up of one year (n = 240). After a histological review supplemented with FOXL2 (402C G) mutation status analysis, we analyzed the clinical data for association with relapse. Results. The final cohort included 164 (68%) molecularly defined AGCTs (MD-AGCTs). The majority of the women were postmenopausal (63%), and 92% of tumors were stage I. The median follow-up time was 15.5 years. Fifty-two (32%) patients developed tumor recurrence, of whom 55% had successive recurrences. Multiple-site recurrences were common, and nearly half of the recurrences were asymptomatic. The median time to the first relapse was 7.4 years, and 75% of relapses occurred within ten years after primary diagnosis. The median disease-free survival was 11.3 years. Premenopausal status at initial diagnosis, FIGO stage Ic versus la, and tumor rupture associated with relapse. However, tumor rupture was the only independent predictive factor. Of the relapsed patients, 48% died of AGO' in a median time of 153 years. Conclusion. Tumor rupture is the strongest predictive factor for recurrence, and these patients might benefit from a more aggressive initial treatment approach. AGCT requires active follow up for 10 to 15 years after primary diagnosis, since recurrences may develop late, asymptomatically and in multiple anatomical locations. (C) 2016 Elsevier Inc. All rights reserved.Peer reviewe

Transcription factors GATA-4 and GATA-6 in normal and neoplastic human gastrointestinal mucosa

Background Human gastrointestinal mucosa regenerates vigorously throughout life, but the factors controlling cell fate in mature mucosa are poorly understood. GATA transcription factors direct cell proliferation and differentiation in many organs, and are implicated in tumorigenesis. GATA-4 and GATA-6 are considered crucial for the formation of murine gastrointestinal mucosa, but their role in human gastrointestinal tract remains unexplored. We studied in detail the expression patterns of these two GATA factors and a GATA-6 down-stream target, Indian hedgehog (Ihh), in normal human gastrointestinal mucosa. Since these factors are considered important for proliferation and differentiation, we also explored the possible alterations in their expression in gastrointestinal neoplasias. The expression of the carcinogenesis-related protein Indian hedgehog was also investigated in comparison to GATA factors. Methods Samples of normal and neoplastic gastrointestinal tract from children and adults were subjected to RNA in situ hybridization with 33P labelled probes and immunohistochemistry, using an avidin-biotin immunoperoxidase system. The pathological tissues examined included samples of chronic and atrophic gastritis as well as adenomas and adenocarcinomas of the colon and rectum. Results GATA-4 was abundant in the differentiated epithelial cells of the proximal parts of the gastrointestinal tract but was absent from the distal parts. In contrast, GATA-6 was expressed throughout the gastrointestinal epithelium, and in the distal gut its expression was most intense at the bottom of the crypts, i.e. cells with proliferative capacity. Both factors were also present in Barrett's esophagus and metaplasia of the stomach. GATA-6 expression was reduced in colon carcinoma. Ihh expression overlapped with that of GATA-6 especially in benign gastrointestinal neoplasias. Conclusion The results suggest differential but overlapping functions for GATA-4 and GATA-6 in the normal gastrointestinal mucosa. Furthermore, GATA-4, GATA-6 and Ihh expression is altered in premalignant dysplastic lesions and reduced in overt cancer.BioMed Central Open acces

Type 1 tyrosinemia in Finland: a nationwide study

Background Introduction of nitisinone and newborn screening (NBS) have transformed the treatment of type 1 tyrosinemia, but the effects of these changes on the long-term outcomes remain obscure. Also, the predictors for later complications, the significance of drug levels and the normalization of laboratory and imaging findings are poorly known. We investigated these issues in a nationwide study. Results Type 1 tyrosinemia was diagnosed in 22 children in 1978-2019 in Finland. Incidence was 1/90,102, with a significant enrichment in South Ostrobothnia (1/9990). Median age at diagnosis was 5 (range 0.5-36) months, 55% were girls and 13 had homozygotic Trp262X mutation. Four patients were detected through screening and 18 clinically, their main findings being liver failure (50% vs. 100%, respectively, p = 0.026), ascites (0% vs. 53%, p = 0.104), renal tubulopathy (0% vs. 65%, p = 0.035), rickets (25% vs. 65%, p = 0.272), growth failure (0% vs. 66%, p = 0.029), thrombocytopenia (25% vs. 88%, p = 0.028) and anaemia (0% vs. 47%, p = 0.131). One patient was treated with diet, seven with transplantation and 14 with nitisinone. Three late-diagnosed (6-33 months) nitisinone treated patients needed transplantation later. Kidney dysfunction (86% vs. 7%, p = 0.001), hypertension (57% vs. 7%, p = 0.025) and osteopenia/osteoporosis (71% vs. 14%, p = 0.017) were more frequent in transplanted than nitisinone-treated patients. Blood/serum alpha-fetoprotein decreased rapidly on nitisinone in all but one patient, who later developed intrahepatic hepatocellular carcinoma. Liver values normalized in 31 months and other laboratory values except thrombocytopenia within 18 months. Imaging findings normalized in 3-56 months excluding five patients with liver or splenic abnormalities. Low mean nitisinone concentration was associated with higher risk of severe complications (r = 0.758, p = 0.003) despite undetectable urine succinylacetone. Conclusions Prognosis of type 1 tyrosinemia has improved in the era of nitisinone, and NBS seems to provide further benefits. Nevertheless, the long-term risk for complications remains, particularly in the case of late diagnosis and/or insufficient nitisinone levels.Peer reviewe