PMID: 19853898
Title: Uterine sarcomas: a review.
Journal: Gynecologic oncology 2010
Authors: Emanuela D'Angelo Jaime Prat
OBJECTIVE: Uterine sarcomas are rare tumors that account for 3% of uterine cancers. Their histopathologic classification was revised by the World Health Organization (WHO) in 2003. A new staging system has been recently designed by the International Federation of Gynecology and Obstetrics (FIGO). Currently, there is no consensus on risk factors for adverse outcome. This review summarizes the available clinicopathological data on uterine sarcomas classified by the WHO diagnostic criteria.
METHODS: Medline was searched between 1976 and 2009 for all publications in English where the studied population included women diagnosed of uterine sarcomas.
RESULTS: Since carcinosarcomas (malignant mixed mesodermal tumors or MMMT) are currently classified as metaplastic carcinomas, leiomyosarcomas remain the most common uterine sarcomas. Exclusion of several histologic variants of leiomyoma, as well as "smooth muscle tumors of uncertain malignant potential," frequently misdiagnosed as sarcomas, has made apparent that leiomyosarcomas are associated with poor prognosis even when seemingly confined to the uterus. Endometrial stromal sarcomas are indolent tumors associated with long-term survival. Undifferentiated endometrial sarcomas exhibiting nuclear pleomorphism behave more aggressively than tumors showing nuclear uniformity. Adenosarcomas have a favorable prognosis except for tumors showing myometrial invasion or sarcomatous overgrowth. Adenofibromas may represent well-differentiated adenosarcomas. The prognosis of carcinosarcomas (which are considered here in a post-script fashion) is usually worse than that of grade 3 endometrial carcinomas. Immunohistochemical expression of Ki67, p53, and p16 is significantly higher in leiomyosarcomas and undifferentiated endometrial sarcomas than in endometrial stromal sarcomas.
CONCLUSIONS: Evaluation of H&E stained sections has been equivocal in the prediction of behavior of uterine sarcomas. Immunohistochemical studies of oncoproteins as well as molecular analysis of non-random translocations will undoubtedly lead to an accurate and prognostically relevant classification of these rare tumors.

PMID: 21849978
Title: Haem oxygenase is synthetically lethal with the tumour suppressor fumarate hydratase.
Journal: Nature 2011
Authors: Christian Frezza Liang Zheng Ori Folger Kartik N Rajagopalan Elaine D MacKenzie Livnat Jerby Massimo Micaroni Barbara Chaneton Julie Adam Ann Hedley Gabriela Kalna Ian P M Tomlinson Patrick J Pollard Dave G Watson Ralph J Deberardinis Tomer Shlomi Eytan Ruppin Eyal Gottlieb
ALL_TEXT: Fumarate hydratase (FH) is an enzyme of the tricarboxylic acid cycle (TCA cycle) that catalyses the hydration of fumarate into malate. Germline mutations of FH are responsible for hereditary leiomyomatosis and renal-cell cancer (HLRCC). It has previously been demonstrated that the absence of FH leads to the accumulation of fumarate, which activates hypoxia-inducible factors (HIFs) at normal oxygen tensions. However, so far no mechanism that explains the ability of cells to survive without a functional TCA cycle has been provided. Here we use newly characterized genetically modified kidney mouse cells in which Fh1 has been deleted, and apply a newly developed computer model of the metabolism of these cells to predict and experimentally validate a linear metabolic pathway beginning with glutamine uptake and ending with bilirubin excretion from Fh1-deficient cells. This pathway, which involves the biosynthesis and degradation of haem, enables Fh1-deficient cells to use the accumulated TCA cycle metabolites and permits partial mitochondrial NADH production. We predicted and confirmed that targeting this pathway would render Fh1-deficient cells non-viable, while sparing wild-type Fh1-containing cells. This work goes beyond identifying a metabolic pathway that is induced in Fh1-deficient cells to demonstrate that inhibition of haem oxygenation is synthetically lethal when combined with Fh1 deficiency, providing a new potential target for treating HLRCC patients.

PMID: 21868628
Title: MED12, the mediator complex subunit 12 gene, is mutated at high frequency in uterine leiomyomas.
Journal: Science (New York, N.Y.) 2011
Authors: Netta Mäkinen Miika Mehine Jaana Tolvanen Eevi Kaasinen Yilong Li Heli J Lehtonen Massimiliano Gentile Jian Yan Martin Enge Minna Taipale Mervi Aavikko Riku Katainen Elina Virolainen Tom Böhling Taru A Koski Virpi Launonen Jari Sjöberg Jussi Taipale Pia Vahteristo Lauri A Aaltonen
ALL_TEXT: Uterine leiomyomas, or fibroids, are benign tumors that affect millions of women worldwide and that can cause considerable morbidity. To study the genetic basis of this tumor type, we examined 18 uterine leiomyomas derived from 17 different patients by exome sequencing and identified tumor-specific mutations in the mediator complex subunit 12 (MED12) gene in 10. Through analysis of 207 additional tumors, we determined that MED12 is altered in 70% (159 of 225) of tumors from a total of 80 patients. The Mediator complex is a 26-subunit transcriptional regulator that bridges DNA regulatory sequences to the RNA polymerase II initiation complex. All mutations resided in exon 2, suggesting that aberrant function of this region of MED12 contributes to tumorigenesis.

PMID: 22244472
Title: The estimated annual cost of uterine leiomyomata in the United States.
Journal: American journal of obstetrics and gynecology 2012
Authors: Eden R Cardozo Andrew D Clark Nicole K Banks Melinda B Henne Barbara J Stegmann James H Segars
OBJECTIVE: The purpose of this study was to estimate the total annual societal cost of uterine fibroid tumors in the United States, based on direct and indirect costs that include associated obstetric complications.
STUDY DESIGN: A systematic review of the literature was conducted to estimate the number of women who seek treatment for symptomatic fibroid tumors annually, the costs of medical and surgical treatment, the amount of work time lost, and obstetric complications that are attributable to fibroid tumors. Total annual costs were converted to 2010 US dollars. A sensitivity analysis was performed.
RESULTS: The estimated annual direct costs (surgery, hospital admissions, outpatient visits, and medications) were $4.1-9.4 billion. Estimated lost work-hour costs ranged from $1.55-17.2 billion annually. Obstetric outcomes that were attributed to fibroid tumors resulted in a cost of $238 million to $7.76 billion annually. Uterine fibroid tumors were estimated to cost the United States $5.9-34.4 billion annually.
CONCLUSION: Obstetric complications that are associated with fibroid tumors contributed significantly to their economic burden. Lost work-hour costs may account for the largest proportion of societal costs because of fibroid tumors.

PMID: 24088094
Title: Uterine fibroids.
Journal: The New England journal of medicine 2013
Authors: Serdar E Bulun

PMID: 25693131
Title: The Mediator complex: a central integrator of transcription.
Journal: Nature reviews. Molecular cell biology 2015
Authors: Benjamin L Allen Dylan J Taatjes
ALL_TEXT: The RNA polymerase II (Pol II) enzyme transcribes all protein-coding and most non-coding RNA genes and is globally regulated by Mediator - a large, conformationally flexible protein complex with a variable subunit composition (for example, a four-subunit cyclin-dependent kinase 8 module can reversibly associate with it). These biochemical characteristics are fundamentally important for Mediator's ability to control various processes that are important for transcription, including the organization of chromatin architecture and the regulation of Pol II pre-initiation, initiation, re-initiation, pausing and elongation. Although Mediator exists in all eukaryotes, a variety of Mediator functions seem to be specific to metazoans, which is indicative of more diverse regulatory requirements.

PMID: 26935559
Title: The 2016 WHO Classification of Tumours of the Urinary System and Male Genital Organs-Part A: Renal, Penile, and Testicular Tumours.
Journal: European urology 2016
Authors: Holger Moch Antonio L Cubilla Peter A Humphrey Victor E Reuter Thomas M Ulbright
UNLABELLED: The fourth edition of the World Health Organization (WHO) classification of urogenital tumours (WHO "blue book"), published in 2016, contains significant revisions. These revisions were performed after consideration by a large international group of pathologists with special expertise in this area. A subgroup of these persons met at the WHO Consensus Conference in Zurich, Switzerland, in 2015 to finalize the revisions. This review summarizes the most significant differences between the newly published classification and the prior version for renal, penile, and testicular tumours. Newly recognized epithelial renal tumours are hereditary leiomyomatosis and renal cell carcinoma (RCC) syndrome-associated RCC, succinate dehydrogenase-deficient RCC, tubulocystic RCC, acquired cystic disease-associated RCC, and clear cell papillary RCC. The WHO/International Society of Urological Pathology renal tumour grading system was recommended, and the definition of renal papillary adenoma was modified. The new WHO classification of penile squamous cell carcinomas is based on the presence of human papillomavirus and defines histologic subtypes accordingly. Germ cell neoplasia in situ (GCNIS) of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours, and testicular germ cell tumours are now separated into two fundamentally different groups: those derived from GCNIS and those unrelated to GCNIS. Spermatocytic seminoma has been designated as a spermatocytic tumour and placed within the group of non-GCNIS-related tumours in the 2016 WHO classification.
PATIENT SUMMARY: The 2016 World Health Organization (WHO) classification contains new renal tumour entities. The classification of penile squamous cell carcinomas is based on the presence of human papillomavirus. Germ cell neoplasia in situ of the testis is the WHO-recommended term for precursor lesions of invasive germ cell tumours.

PMID: 27253694
Title: Cancer treatment and survivorship statistics, 2016.
Journal: CA: a cancer journal for clinicians 2016
Authors: Kimberly D Miller Rebecca L Siegel Chun Chieh Lin Angela B Mariotto Joan L Kramer Julia H Rowland Kevin D Stein Rick Alteri Ahmedin Jemal
ALL_TEXT: The number of cancer survivors continues to increase because of both advances in early detection and treatment and the aging and growth of the population. For the public health community to better serve these survivors, the American Cancer Society and the National Cancer Institute collaborate to estimate the number of current and future cancer survivors using data from the Surveillance, Epidemiology, and End Results cancer registries. In addition, current treatment patterns for the most prevalent cancer types are presented based on information in the National Cancer Data Base and treatment-related side effects are briefly described. More than 15.5 million Americans with a history of cancer were alive on January 1, 2016, and this number is projected to reach more than 20 million by January 1, 2026. The 3 most prevalent cancers are prostate (3,306,760), colon and rectum (724,690), and melanoma (614,460) among males and breast (3,560,570), uterine corpus (757,190), and colon and rectum (727,350) among females. More than one-half (56%) of survivors were diagnosed within the past 10 years, and almost one-half (47%) are aged 70 years or older. People with a history of cancer have unique medical and psychosocial needs that require proactive assessment and management by primary care providers. Although there are a growing number of tools that can assist patients, caregivers, and clinicians in navigating the various phases of cancer survivorship, further evidence-based resources are needed to optimize care. CA Cancer J Clin 2016;66:271-289. (c) 2016 American Cancer Society.

PMID: 28228279
Title: Loss of PTEN Is Associated with Resistance to Anti-PD-1 Checkpoint Blockade Therapy in Metastatic Uterine Leiomyosarcoma.
Journal: Immunity 2017
Authors: Suzanne George Diana Miao George D Demetri Dennis Adeegbe Scott J Rodig Sachet Shukla Mikel Lipschitz Ali Amin-Mansour Chandrajit P Raut Scott L Carter Peter Hammerman Gordon J Freeman Catherine J Wu Patrick A Ott Kwok-Kin Wong Eliezer M Van Allen
ALL_TEXT: Response to immune checkpoint blockade in mesenchymal tumors is poorly characterized, but immunogenomic dissection of these cancers could inform immunotherapy mediators. We identified a treatment-naive patient who has metastatic uterine leiomyosarcoma and has experienced complete tumor remission for >2 years on anti-PD-1 (pembrolizumab) monotherapy. We analyzed the primary tumor, the sole treatment-resistant metastasis, and germline tissue to explore mechanisms of immunotherapy sensitivity and resistance. Both tumors stained diffusely for PD-L2 and showed sparse PD-L1 staining. PD-1+ cell infiltration significantly decreased in the resistant tumor (p = 0.039). Genomically, the treatment-resistant tumor uniquely harbored biallelic PTEN loss and had reduced expression of two neoantigens that demonstrated strong immunoreactivity with patient T cells in vitro, suggesting long-lasting immunological memory. In this near-complete response to PD-1 blockade in a mesenchymal tumor, we identified PTEN mutations and reduced expression of genes encoding neoantigens as potential mediators of resistance to immune checkpoint therapy.

PMID: 29439178
Title: Uterine Neoplasms, Version 1.2018, NCCN Clinical Practice Guidelines in Oncology.
Journal: Journal of the National Comprehensive Cancer Network : JNCCN 2018
Authors: Wui-Jin Koh Nadeem R Abu-Rustum Sarah Bean Kristin Bradley Susana M Campos Kathleen R Cho Hye Sook Chon Christina Chu David Cohn Marta Ann Crispens Shari Damast Oliver Dorigo Patricia J Eifel Christine M Fisher Peter Frederick David K Gaffney Suzanne George Ernest Han Susan Higgins Warner K Huh John R Lurain Andrea Mariani David Mutch Christa Nagel Larissa Nekhlyudov Amanda Nickles Fader Steven W Remmenga R Kevin Reynolds Todd Tillmanns Stefanie Ueda Emily Wyse Catheryn M Yashar Nicole R McMillian Jillian L Scavone
ALL_TEXT: Endometrial carcinoma is a malignant epithelial tumor that forms in the inner lining, or endometrium, of the uterus. Endometrial carcinoma is the most common gynecologic malignancy. Approximately two-thirds of endometrial carcinoma cases are diagnosed with disease confined to the uterus. The complete NCCN Guidelines for Uterine Neoplasms provide recommendations for the diagnosis, evaluation, and treatment of endometrial cancer and uterine sarcoma. This manuscript discusses guiding principles for the diagnosis, staging, and treatment of early-stage endometrial carcinoma as well as evidence for these recommendations.