Haplotype-resolved germline and somatic alterations in renal medullary carcinomas.

BACKGROUND: Renal medullary carcinomas (RMCs) are rare kidney cancers that occur in adolescents and young adults of African ancestry. Although RMC is associated with the sickle cell trait and somatic loss of the tumor suppressor, SMARCB1, the ancestral origins of RMC remain unknown. Further, characterization of structural variants (SVs) involving SMARCB1 in RMC remains limited. METHODS: We used linked-read genome sequencing to reconstruct germline and somatic haplotypes in 15 unrelated patients with RMC registered on the Children's Oncology Group (COG) AREN03B2 study between 2006 and 2017 or from our prior study. We performed fine-mapping of the HBB locus and assessed the germline for cancer predisposition genes. Subsequently, we assessed the tumor samples for mutations outside of SMARCB1 and integrated RNA sequencing to interrogate the structural variants at the SMARCB1 locus. RESULTS: We find that the haplotype of the sickle cell mutation in patients with RMC originated from three geographical regions in Africa. In addition, fine-mapping of the HBB locus identified the sickle cell mutation as the sole candidate variant. We further identify that the SMARCB1 structural variants are characterized by blunt or 1-bp homology events. CONCLUSIONS: Our findings suggest that RMC does not arise from a single founder population and that the HbS allele is a strong candidate germline allele which confers risk for RMC. Furthermore, we find that the SVs that disrupt SMARCB1 function are likely repaired by non-homologous end-joining. These findings highlight how haplotype-based analyses using linked-read genome sequencing can be applied to identify potential risk variants in small and rare disease cohorts and provide nucleotide resolution to structural variants.

Renal Medullary Carcinoma.

Renal medullary carcinoma, also referred to as the seventh sickle cell nephropathy, typically affects young African Americans with sickle cell trait, or, less frequently, patients with sickle cell disease. The existence of renal medullary carcinoma without a concomitant hemoglobinopathy is a topic of controversy. The typical patient is a young male of African or Mediterranean descent, with hematuria and/or flank pain. Most patients have metastatic disease at the time of presentation. The tumor is characteristically a poorly circumscribed mass in the medullary region, commonly showing variable amounts of hemorrhage and necrosis. Microscopically, a characteristic reticular or cribriform pattern with a striking desmoplastic stromal response and a robust mixed inflammatory infiltrate is observed. Collecting duct carcinoma, malignant rhabdoid tumor, urothelial carcinoma, and other subtypes of renal cell carcinoma are in the differential diagnosis. Because of the advanced stage of disease at presentation and the aggressive nature of this malignant neoplasm, survival is poor even with chemotherapy; however, isolated reports of prolonged survival have been documented.

Platinum plus bortezomib for the treatment of pediatric renal medullary carcinoma: Two cases.

Renal medullary carcinoma (RMC) was first described over two decades ago as the seventh sickle nephropathy. Survival after diagnosis with metastatic disease still rarely extends beyond 1 year, with recent reports of median overall survival in patients treated with platinum therapy being just 10 months. We describe our experience using platinum-based chemotherapy plus the proteasome inhibitor bortezomib to treat metastatic RMC in two pediatric patients who had complete responses. One patient passed away 7 years after diagnosis, while another remains disease free nearly 2 years from diagnosis.

Passive Smoking and Breast Cancer - a Suspicious Link.

BACKGROUND: Breast cancer is the most common malignancy of women in the world. The disease is caused by infectious and non-infectious, environmental and lifestyle factors. Tobacco smoke has been one of the most widely studied environmental factors with possible relevance to breast cancer. The purpose of this study was to assess the impact of tobacco smoking in breast cancer patients in a hospital based cohort and to establish prognostic implications if any. MATERIALS AND METHODS: A retrospective audit of 100 women with pathological diagnosis of invasive breast cancer was included in this study. The verbal questionnaire elicited information on current and previous history of exposure to smoking in addition to active smoking. All analyses were adjusted for potential confounders, including stage at presentation, alcohol intake, hormonal replacement therapy, oral contraceptive intake, obesity and menopausal status. RESULTS: The mean age at presentation of breast cancer was 51.4 ± 10.86 years. Mean age of presentation was 53.1±11.5 and 45.7±11.9 years in never smokers and passive smokers, respectively. Age at presentation varied widely in patients exposed to tobacco smoke for >10 years in childhood from 40.3± 12.0 years to 47.7± 13.9 in patients exposed for > 20 years as adults. Among passive smokers, 60.9% were premenopausal and 39.1% of patients were postmenopausal. In never smokers, 71.4% were post menopausal. Expression of receptors in non-smokers vs passive smokers was comparable with no significant differences. Metastatic potential in lung parenchyma was slightly elevated in passive smokers as compared to never smokers although statistically non-significant. CONCLUSIONS: An inverse relationship exists between the intensity and duration of smoking and the age at presentation and poor prognostic factors. The results strongly suggest efforts should be taken to prevent smoking, encourage quitting and restrict exposure to second hand smoke in India.

Diagnostic radiography exposure increases the risk for thyroid microcarcinoma: a population-based case-control study.

Thyroid cancer incidence and diagnostic radiography exposures, particularly computed tomography (CT) scanning and nuclear medicine examinations, have increased substantially in the USA. However, very few epidemiologic studies have directly investigated their associations. A population-based case-control study was conducted in Connecticut in 2010-2011, including 462 histologically confirmed incident thyroid cancer cases and 498 population-based controls. Multivariate unconditional logistic regression models were used to estimate the associations between diagnostic radiography and the risk of thyroid cancer, controlling for potential confounding factors. Exposure to any form of diagnostic radiography was associated with an increased risk of well-differentiated thyroid microcarcinoma [tumor size≤10 mm, odds ratio (OR)=2.76, 95% confidence interval (CI): 1.31-5.81]. The highest risk increase occurred with nuclear medicine examinations (excluding cardiology tests and thyroid uptake studies; OR=5.47, 95% CI: 2.10-14.23), followed by chest CT scanning (OR=4.30, 95% CI: 1.66-11.14), head and neck CT scanning (OR=3.88, 95% CI: 1.75-8.63), upper gastrointestinal series (OR=3.56, 95% CI: 1.54-8.21), lower gastrointestinal series (OR=3.29, 95% CI: 1.41-7.66), kidney radiography involving dye injection into a vein or artery (OR=3.21, 95% CI: 1.20-8.54), mammography (OR=2.95, 95% CI: 1.14-7.61), chest radiography (OR=2.93, 95% CI: 1.37-6.29), and abdomen CT scanning (OR=2.54, 95% CI: 1.02-6.30). No significant associations were found between these imaging modalities and thyroid tumors larger than 10 mm. This study provides the first direct evidence that CT scanning and nuclear medicine examinations are associated with an increased risk of thyroid cancer. The novel finding that an array of diagnostic radiography procedures are associated with thyroid microcarcinomas warrants further investigation.

The rising trend of papillary carcinoma in thyroidectomies: 14-years of experience in a referral center of Turkey.

BACKGROUND: During the past 25 years, the incidence of thyroid papillary carcinoma (TPC), especially the micropapillary subtype, has been increasing in different countries worldwide. The rise in the rate of thyroid malignancies were also determined in Turkey in the last two decades. This fact was attributed to the Chernobyl accident because Turkey is one of the affected countries by the radioactive fallout. The aim of this study was to assess the changes in the parameters of the thyroid and put forth the reasons in a 14-year period. METHODS: The patient records, demographic and malignancy characteristics, and operations of 1,585 patients who had a thyroidectomy from 1996 to 2009 were reviewed retrospectively. The study was divided in two equal time periods for comparison of data. RESULTS: A total of 216 thyroid carcinomas (13.6%) were diagnosed in the study period. There was a significant increase in the frequency of papillary (P <0.023) and micropapillary (P <0.001) carcinomas when the two different time periods were compared. The rate of follicular, medullary and other types of malignancies did not change. In the second period (2003 to 2009) of analysis, the rate of micropapillary carcinoma (P = 0.001) and within male (P = 0.031) and female (P <0.001) genders, application of total thyroidectomy (p = 0.029), and multicentric disease (P = 0.015) increased significantly. A slight decrease in the mean age of the whole number of patients and patients with papillary and micropapillary carcinomas (P >0.05) was observed. The increased number of TPC >10 mm was insignificant. Geographic region and age specific malignancy increase was not determined. CONCLUSIONS: Micropapillary carcinoma has become a dominant type of thyroid malignancy in Turkey. The main reasons of this transition were mandatory iodization and much higher application of total thyroidectomy in surgery. Improvement in healthcare and diagnostic techniques are the complementary factors. Due to its lack of molecular and genetic basis from the perspective of thyroid cancer, the Chernobyl disaster has lost its importance in Turkey.

Transient partial response to sorafenib treatment in an adolescent patient with MEN2B syndrome and end-stage medullary thyroid carcinoma.

Metastatic medullary thyroid carcinoma (MTC) is an aggressive malignancy with an extremely poor prognosis. Currently no effective conventional systemic therapies exist to treat pediatric MTC. We describe an adolescent female with newly diagnosed MEN2B syndrome who presented with advanced stage metastatic MTC and demonstrated a partial transient response to sorafenib monotherapy. This clinical result supports further research into the use of sorafenib in the treatment of pediatric MTC.

Kidney abnormalities in sickle cell disease.

Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nefrología difussion.

Afectación renal en la enfermedad falciforme / Kidney abnormalities in sickle cell disease

La enfermedad falciforme (EF) es la hemoglobinopatía estructural más frecuente en el mundo. Su afectación renal clínicamente significativa ocurre más frecuentemente en los individuos homocigotos que en los heterocigotos o con hemoglobinopatías mixtas, con la excepción del carcinoma medular renal, que es más frecuente en los portadores del rasgo falciforme. Como en otras manifestaciones de la EF, los fenómenos vasooculsivos son el principal mecanismo etiopatogénico. Sus manifestaciones más frecuentes son la hematuria macroscópica asintomática, las alteraciones funcionales tubulares y la necrosis papilar. Menos frecuentes, pero de peor pronóstico, son la glomerulopatía que conduce a enfermedad renal crónica y el carcinoma medular renal. Debido a la alta tasa de inmigración en España y a una mayor supervivencia de estos pacientes se espera una prevalencia creciente en nuestro país. En 2009, la Asociación Española de Hematología y Hemoterapia elaboró las Guías de manejo de la enfermedad falciforme. Este artículo reproduce el capítulo sobre afectación renal actualizado para su difusión en NEFROLOGÍA (AU)

Patients with sickle cell disease exhibits numerous kidney structural and functional abnormalities, changes that are seen along the entire length of the nephron. Changes are most marked in patients with homozygous sickle cell anemia, but are also seen in those with compound heterozygous states and the sickle cell trait. The renal features of sickle cell disease include some of the most common reasons for referral to nephrologists, such as hematuria, proteinuria, tubular disturbances and chronic kidney disease. Therapy of these conditions requires specialized knowledge of their distinct pathogenic mechanisms. Spanish Haemathology and Hemotherapy Association has recently publicated their Clinical Practice Guidelines of SCD management. Renal chapter is reproduced in this article for Nephrology difussion (AU)

Does percutaneous thyroid laser ablation induce mixed papillary and medullary thyroid carcinoma?

Mixed medullary-papillary carcinomas are very rare and still not listed in the WHO classification (1988). The rarity of the co-existence of medullary and papillary carcinoma suggests that these cases represent mere coincidence. Some studies have shown that radiation exposure has induced neoplasia in the two cell types in rats. But we still have limited information about the carcinogenetic effect of laser ablation on the thyroid gland. This report describes the first case of thyroid carcinoma that demonstrated both medullary carcinoma and papillary components in the thyroid, which might occur due to percutaneous thyroid laser ablation.

Papillary thyroid cancer incidence in the volcanic area of Sicily.

BACKGROUND: The steadily increasing incidence of thyroid cancer has been attributed mostly to more sensitive thyroid nodule screening. However, various environmental factors, such as those associated with volcanic areas, cannot be excluded as risk factors. We evaluated thyroid cancer incidence in Sicily, which has a homogenous population and a province (Catania) that includes the Mt Etna volcanic area. METHODS: In a register-based epidemiological survey, we collected all incident thyroid cancers in Sicily from January 1, 2002, through December 31, 2004. The age-standardized incidence rate for the world population (ASR(w)) was calculated and expressed as the number of thyroid cancer diagnoses per 100 000 residents per year. The association of thyroid cancer incidence rate with sex, age, tumor histotype, and various environmental factors was evaluated by modeling the variation of the ASR(w). All statistical tests were two-sided. RESULTS: In 2002-2004, 1950 incident thyroid cancers were identified in Sicily (among women, ASR(w) = 17.8, 95% confidence interval [CI] = 16.9 to 18.7; and among men, ASR(w) = 3.7, 95% CI = 3.3 to 4.1). Although the percentage of thyroid cancers that were microcarcinomas (ie, < or = 10 mm) and ratio of men to women with thyroid cancer were similar in all nine Sicilian provinces, thyroid cancer incidence was statistically significantly higher in the province of Catania (among women, ASR(w) = 31.7, 95% CI = 29.1 to 34.3; and among men, ASR(w) = 6.4, 95% CI = 5.2 to 7.5) than in the rest of Sicily (among women, ASR(w) = 14.1, 95% CI = 13.2 to 15.0; and among men, ASR(w) = 3.0, 95% CI = 2.6 to 3.4) (all P values < .001). Incidence of papillary, but not follicular or medullary, cancers was statistically significantly increased in Catania province, and papillary tumors from patients in Catania more frequently carried the BRAF V600E gene mutation (55 [52%] of 106 tumors) than tumors from patients elsewhere in Sicily (68 [33%] of 205 tumors) (relative risk = 1.7, 95% CI = 1.0 to 2.8, P = .02). Cancer incidence was statistically significantly lower in rural areas than in urban areas of Sicily (P = .003). No association with mild iodine deficiency or industrial installations was found. Levels of many elements (including boron, iron, manganese, and vanadium) in the drinking water of Catania province often exceeded maximum admissible concentrations, in contrast to water in the rest of Sicily. CONCLUSION: Residents of Catania province with its volcanic region appear to have a higher incidence of papillary thyroid cancer than elsewhere in Sicily.

Medullary thyroid cancer: management guidelines of the American Thyroid Association.

BACKGROUND: Inherited and sporadic medullary thyroid cancer (MTC) is an uncommon and challenging malignancy. The American Thyroid association (ATA) chose to create specific MTC Clinical Guidelines that would bring together and update the diverse MTC literature and combine it with evidence-based medicine and the knowledge and experience of a panel of expert clinicians. METHODS: Relevant articles were identified using a systematic PubMed search and supplemented with additional published materials. Evidence-based recommendations were created and then categorized using criteria adapted from the United States Preventive Services Task Force, Agency for Healthcare Research and Quality. RESULTS: Clinical topics addressed in this scholarly dialog included: initial diagnosis and therapy of preclinical disease (including RET oncogene testing and the timing of prophylactic thyroidectomy), initial diagnosis and therapy of clinically apparent disease (including preoperative testing and imaging, extent of surgery, and handling of devascularized parathyroid glands), initial evaluation and treatment of postoperative patients (including the role of completion thyroidectomy), management of persistent or recurrent MTC (including the role of tumor marker doubling times, and treatment of patients with distant metastases and hormonally active metastases), long-term follow-up and management (including the frequency of follow-up and imaging), and directions for future research. CONCLUSIONS: One hundred twenty-two evidence-based recommendations were created to assist in the clinical care of MTC patients and to share what we believe is current, rational, and optimal medical practice.

Prevalence of hypercalcitoninemia in patients on maintenance dialysis referred to kidney transplantation.

AIMS: Elevated calcitonin concentrations in dialysis patients had led to thyroidectomy for a benign C-cell hyperplasia in dozens of patients in the past decade. The prevalence of hypercalcitoninemia, however, has not been examined in a large cohort of dialysis patients. METHODS: We, therefore, measured calcitonin concentrations in 283 dialysis patients. We used different reference intervals: according to the threshold to perform further stimulation tests (i.e. > 10 pg/ml) and new reference intervals for the currently used assay (i.e. serum calcitonin concentration < 11.5 pg/ml in men and < 4.6 pg/ml in women). RESULTS: Median calcitonin concentrations of men and women were 12 (1; 290) pg/ml vs 2 pg/ml (1; 45), respectively, (p < 0.0001). The prevalence of hypercalcitoninemia was 10% in women and 58% in men using a cut-off of 10 pg/ml. Applying the new reference intervals 31% of women and 54% of men presented with hypercalcitoninemia. All patients with basal calcitonin concentrations above 50 pg/ml were men (highest calcitonin concentration was 290 pg/ml). Two of them underwent thyroidectomy and had C-cell hyperplasia. CONCLUSION: The prevalence of hypercalcitoninemia in dialysis patients amounts to 46%. It is more common in male than in female dialysis patients.

Complications associated with sickle cell trait: a brief narrative review.

Sickle cell trait occurs in approximately 300 million people worldwide, with the highest prevalence of approximately 30% to 40% in sub-Saharan Africa. Long considered a benign carrier state with relative protection against severe malaria, sickle cell trait occasionally can be associated with significant morbidity and mortality. Sickle cell trait is exclusively associated with rare but often fatal renal medullary cancer. Current cumulative evidence is convincing for associations with hematuria, renal papillary necrosis, hyposthenuria, splenic infarction, exertional rhabdomyolysis, and exercise-related sudden death. Sickle cell trait is probably associated with complicated hyphema, venous thromboembolic events, fetal loss, neonatal deaths, and preeclampsia, and possibly associated with acute chest syndrome, asymptomatic bacteriuria, and anemia in pregnancy. There is insufficient evidence to suggest an independent association with retinopathy, cholelithiasis, priapism, leg ulcers, liver necrosis, avascular necrosis of the femoral head, and stroke. Despite these associations, the average life span of individuals with sickle cell trait is similar to that of the general population. Nonetheless, given the large number of people with sickle cell trait, it is important that physicians be aware of these associations.

New therapeutic advances in the management of progressive thyroid cancer.

The spectrum of thyroid cancers ranges from one of the most indolent to one of the most aggressive solid tumors identified. Conventional therapies for thyroid cancers are based on the histologic type of thyroid cancers such as papillary or follicular thyroid cancer (differentiated thyroid cancer (DTC)), medullary thyroid cancer (MTC), or anaplastic thyroid cancer (ATC). While surgery is one of the key treatments for all such types of thyroid cancers, additional therapies vary. Effective targeted therapy for DTC is a decades-old practice with systemic therapies of thyroid stimulating hormone suppression and radioactive iodine therapy. However, for the iodine-refractory DTC, MTC, and ATC there is no effective systemic standard of care treatment. Recent advances in understanding pathogenesis of DTC and development of molecular targeted therapy have dramatically transformed the field of clinical research in thyroid cancer. Over the last five years, incredible progress has been made and phases I-III clinical trials have been conducted in various types of thyroid cancers with some remarkable results that has made an impact on lives of patients with thyroid cancer. Such history-making events have boosted enthusiasm and interest among researchers, clinicians, patients, and sponsors and we anticipate ongoing efforts to develop more effective and safe therapies for thyroid cancer.

Clinical and oncological features of children and young adults with multiple endocrine neoplasia type 2A.

BACKGROUND: RET genotype analysis allows identification of asymptomatic carriers at risk of developing medullary thyroid carcinoma (MTC). However, there is still controversy regarding the ideal timing and extent of prophylactic thyroidectomy due to the wide spectrum of clinical presentation. Surveillance of a large number of young patients is crucial to advance our understanding of the natural course of the disease. This study aimed to describe the clinical presentation, oncological features, and treatment outcome of children and young adults harboring RET mutations followed at our institution from 1997 to 2007. METHODS: Forty-one individuals aged < or =25 years from 17 independent multiple endocrine neoplasia type 2A kindred were studied. Twenty-one individuals presented with thyroid nodules at diagnosis, and 20 were disease free at physical examination. RESULTS: Preoperative basal calcitonin levels were elevated in 85.7% of patients with clinical disease and in 54.5% of asymptomatic carriers. Thyroid ultrasonography (US) showed one or more nodules in 69.0% of the patients. A positive correlation between age at surgery and tumor-node-metastasis (TNM) stages was observed (p < 0.001). None of the patients under 15 years of age presented lymph node or distant metastasis. After a follow-up of 4.4 +/- 1.4 years all asymptomatic patients were disease free based on physical examination, cervical US, and undetectable serum calcitonin levels. In the group of patients with clinical disease, 47.6% have persistent disease (follow-up of 12.0 +/- 5.9 years). Indeed, palpable thyroid nodule at diagnosis was significantly associated with persistent disease (p < 0.001, odds ratio [OR] 1.9, 95% confidence interval [CI 95%] 1.27-2.87). Of note, none of the patients who presented lymph node metastasis at diagnosis were cured by surgical intervention (p < 0.001, OR 5.0, CI 95% 1.45-17.0). CONCLUSION: Our data show a time-dependent MTC progression. The presence of a palpable thyroid nodule and lymph node metastasis at diagnosis was associated with persistent or recurrent disease after surgical procedure.