Safety and efficacy of sirolimus in recurrent intravenous leiomyomatosis, pulmonary benign metastatic leiomyomatosis, and leiomyomatosis peritonealis disseminata: a pilot study.

BACKGROUND: Intravenous leiomyomatosis (IVL), pulmonary benign metastatic leiomyomatosis (PBML), and leiomyomatosis peritonealis disseminata (LPD) are leiomyomas with special growth patterns and high postoperative recurrence rates. We report the safety and efficacy of a pilot study of sirolimus in the treatment of recurrent IVL, PBML, and recurrent LPD. METHODS: This was a pilot study to evaluate the safety and efficacy of sirolimus in the treatment of leiomyomatosis (ClinicalTrials.gov identifier NCT03500367) conducted in China. Patients received oral sirolimus 2 mg once a day for a maximum of 60 months or until disease progression, intolerable toxicity, withdrawal of consent, or investigator decision to stop. The primary end point of this study was the objective response rate. Secondary end points included safety and tolerability, disease control rate, and progression-free survival. RESULTS: A total of 15 patients with leiomyomatosis were included in the study, including five with recurrent IVL, eight with PBML and two with recurrent LPD. The median follow-up time was 15 months (range 6-54 months), nine patients (60%) had treatment-related adverse events (including all levels), and two patients had treatment-related grade 3 or 4 adverse events. The objective response rate was 20.0% (95% CI, 7.1-45.2%), and the disease control rate was 86.7% (95% CI, 62.1-96.3%). Partial response was achieved in three patients. The median response time in the three partial response patients was 33 months (range 29-36 months), and the sustained remission time of these three patients reached 0, 18, and 25 months, respectively. CONCLUSIONS: Sirolimus was safe and effective in the treatment of recurrent IVL, PBML, and recurrent LPD. TRIAL REGISTRATION: ClinicalTrials.gov identifier NCT03500367. Registered on 18 April 2018.

Diffuse Uerine Leiomyomatosis Complicated with Cerebral Thrombosis After Oral Contraceptive Treatment: A Case Report of a Athletic Patients

We would like to emphasize the differentiations of diagnosis and treatment between general uterine leiomyomas and diffuse uterine leiomyomatosis (DUL), which is a kind of extremely rare disease. Levonorgestrel-releasing intrauterine system (LNG-IUS) is an attainable option provided to treat DUL with cerebral thrombosis, as a feasible novel method. Case report: A 21-year-old female patient with DUL was due to cerebral venous thrombosis caused by oral contraceptives. The patient was persistently vaginal bleeding after decreasing intracranial pressure and anticoagulant therapy for 3 days. Subsequently, a hysteroscopic submucosal myomectomy was performed to restore the normal shape of the uterine cavity, and the placement of Mirena was given after surgery, which aimly played a good role in hemostasis, prevention of severe menorrhagia and reconstruction of endometrial function. Conclusion: This case report shows that, levonorgestrel-releasing intrauterine system (LNG-IUS) is efficient and secure to treat DUL after hysteroscopic surgery, and simultaneously does not increase the risk of venous thromboembolism (VTE). (AU)

The role of estrogen deprivation therapy in premenopausal women with primary unresectable intracardiac leiomyomatosis: a systematic review and meta-analysis.

BACKGROUND: Intracardiac leiomyomatosis (ICLM) is a rare life-threatening form of intravenous leiomyomatosis (IVLM). The incomplete resection and recurrence are associated with high morbidity and mortality. The objective of this study is to identify that whether estrogen deprivation therapies, including bilateral salpingo-oophorectomy (BSO)-based surgery and gonadotrophin releasing hormone agonists (GnRHa) administration, could bring benefits to patients with primary unresectable ICLM. METHODS: PubMed/MEDLINE (Ovid) was searched (up to May 2021) for studies reporting individual patient data on demographics, clinicopathological features, treatment, and follow-up information. Exclusion criteria were patients who may have been included in two or more publications. This study was performed in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. RESULTS: A total of 114 patients from 70 papers were included. Several reports showed that the tumor in the right atrium and inferior vena cava shrank dramatically after BSO-based surgery, or GnRHa administrated preoperatively in premenopausal women. The rate of complete resection was 64.04% in patients with ICLM, which was 85.25% in no/slight adhesion and no pulmonary nodules group, while 22.22% in firm/extensive adhesion and/or pulmonary nodules group (p < 0.0001). Meanwhile, the recurrence rates in patients with complete resection and incomplete resection were 4.29% and 37.84% respectively (p < 0.0001). Furthermore, complete resection with BSO had the lowest recurrence rate of 3.13%, incomplete resection with BSO had a progression rate of 45.45%, while incomplete resection with ovarian preservation had the highest progression rate of 75.00%. CONCLUSIONS: The recurrence rate of ICLM was closely related to firm/extensive adhesion in IVC or above, and/or pulmonary nodules. BSO-based surgery might reduce the recurrence rate no matter ICLM could be completely resected or not. In addition, estrogen deprivation therapies could decrease tumor burden as a primary treatment, and further make a secondary complete resection feasible in premenopausal women with initially unresectable ICLM.

Ovarian Serous Carcinoma With a Novel HSP90AB1 Mutation in a Patient With Synchronous Primary Fallopian Tube Serous Carcinoma.

BACKGROUND/AIM: Ovarian carcinoma is the fifth leading cause of cancer-related deaths in women in the United States. Serous papillary carcinoma is the most common histological type of ovarian carcinoma that often goes undetected until it has spread within the pelvis and abdomen leading to poor prognosis. Translation of next-generation sequencing (NGS) technology into personalized medicine and identification of new potential targets for therapeutic applications may be helpful. CASE REPORT: We report a case of a 59-year-old female who initially presented in the emergency department with increasing abdominal girth, and bloating. Computed tomography showed ascites and omental and pelvic masses. Fine needle biopsy of the omental mass showed high-grade papillary adenocarcinoma consistent with high-grade ovarian serous carcinoma. She was treated with chemotherapy followed by debulking surgery. Primary ovarian serous carcinoma and synchronous primary fallopian tube serous carcinoma with multiple leiomyomas were identified in the surgical specimen. Pleural biopsy was also positive for carcinoma. NGS and programmed death-ligand 1 (PD-L1) expression testing were performed in the ovarian serous carcinoma. The results showed mutations of breast cancer type 1 (BRCA1) and type 2 (BRCA2), tumor protein p53 (TP53) (c.524G>A at pR175H), and heat shock protein 90 alpha family class B member 1 (HSP90AB1) (p.R456C), as well as low RNA expression score of PD-L1. CONCLUSION: Identification of these mutations and PD-L1 abnormality at the diagnosis of ovarian carcinoma may shed light for clinicians to provide targeted therapy with poly (ADP-ribose) polymerase (PARP) inhibitors and immune checkpoint inhibitors for ovarian serous carcinoma. This is the first documented case of ovarian serous carcinoma to have found a HSP90AB1 (p.R456C) mutation.

Hematometra y hematocervix en paciente postmenopáusica: reporte de caso / Hematometry and hematocervix in postmenopausal patient: case repor

El hematometra es la retención de sangre en el útero y comúnmente se presenta en mujeres jóvenes con anomalías mullerianas pero puede aparecer también en mujeres postmenopausicas por causas secundarias como traumas, tumores, terapia de remplazo hormonal, estenosis cervical, entre otras. En esta presentación de caso interesante se describe una mujer postmenopáusica bajo terapia de remplazo hormonal. Dicha mujer inicia con hemorragia uterina anormal por lo que se le realiza ultrasonido evidenciando hematómetra y hematocervix. Como método diagnóstico y terapéutico de la hemorragia postmenopáusica se le realiza histerectomía abdominal en la cual la patología evidencia leiomiomatosis uterina con endometrio secretor

Hematometra is the retention of blood in the uterus and commonly occurs in young women with Mullerian abnormalities but can also appear in postmenopausal women due to secondary causes such as trauma, tumors, hormone replacement therapy, cervical stenosis, among others. In this presentation an interesting case is described a postmenopausal woman under hormone replacement therapy. She said woman began with abnormal uterine bleeding, so an ultrasound was performed showing hematometer and hematocervix. As a method diagnosis and treatment of postmenopausal hemorrhage, abdominal hysterectomy is performed in which the pathology shows uterine leiomyomatosis with secretory endometrium

Novel morphological and genetic features of fumarate hydratase deficient renal cell carcinoma in HLRCC syndrome patients with a tailored therapeutic approach.

The hereditary leiomyomatosis and renal cell carcinoma syndrome (HLRCC) is defined by germline mutations in the fumarate hydratase (FH) gene and associated with leiomyomas and aggressive renal cell carcinomas with FH deficiency. Here, we comprehensively characterize two new patients with HLRCC syndrome on a morphological, immunohistochemical and genetic level. The patients developed aggressive HLRCC syndrome-associated RCCs, uterine leiomyomas and dermal leiomyomas. One HLRCC syndrome-associated RCC exhibited an unusual morphology with accumulation of "colloid-like" cytoplasmic inclusions, which might serve as a novel sentinel feature to trigger further testing. This case showed partially retained FH expression, initially hampering correct diagnosis. Comprehensive next-generation sequencing analyses of HLRCC syndrome-associated RCC and leiomyomas in our patients revealed divergent genetic changes in the FH gene in different tumors from the same patient. While all leiomyomas (uterine and cutaneous) showed a FH loss of heterozygosity (LOH) as a wildtype allele inactivating event, one HLRCC-RCC showed a second, undescribed NM_000143.3; c.947C>T; p.Ala316Val FH mutation accompanying the preexisting splice site mutation c.378+2T>C. In the other HLRCC syndrome-associated RCC, the FH mutation (NM_000143.3; c.462T>G; p.Asn154Lys with a somatic LOH) represents another variant of unknown significance that we link to HLRCC - and thus classify as likely pathogenic. Due to the specific diagnosis of metastatic HLRCC syndrome-associated RCC, both cases were treated in first line with bevacizumab/erlotinib and showed remarkable and long lasting responses. These findings allow new morphological and molecular insights into the biology of the HLRCC syndrome, corroborate the "second hit" hypothesis of tumor formation in HLRCC patients and may promote a distinct therapeutic approach.

Synthetically Lethal Interactions of Heme Oxygenase-1 and Fumarate Hydratase Genes.

Elevated expression of heme oxygenase-1 (HO-1, encoded by HMOX1) is observed in various types of tumors. Hence, it is suggested that HO-1 may serve as a potential target in anticancer therapies. A novel approach to inhibit HO-1 is related to the synthetic lethality of this enzyme and fumarate hydratase (FH). In the current study, we aimed to validate the effect of genetic and pharmacological inhibition of HO-1 in cells isolated from patients suffering from hereditary leiomyomatosis and renal cell carcinoma (HLRCC)-an inherited cancer syndrome, caused by FH deficiency. Initially, we confirmed that UOK 262, UOK 268, and NCCFH1 cell lines are characterized by non-active FH enzyme, high expression of Nrf2 transcription factor-regulated genes, including HMOX1 and attenuated oxidative phosphorylation. Later, we demonstrated that shRNA-mediated genetic inhibition of HMOX1 resulted in diminished viability and proliferation of cancer cells. Chemical inhibition of HO activity using commercially available inhibitors, zinc and tin metalloporphyrins as well as recently described new imidazole-based compounds, especially SLV-11199, led to decreased cancer cell viability and clonogenic potential. In conclusion, the current study points out the possible relevance of HO-1 inhibition as a potential anti-cancer treatment in HLRCC. However, further studies revealing the molecular mechanisms are still needed.

Proteasome inhibition disrupts the metabolism of fumarate hydratase- deficient tumors by downregulating p62 and c-Myc.

Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is characterized by germline mutations of the FH gene that encodes for the TCA cycle enzyme, fumarate hydratase. HLRCC patients are at risk for the development of an aggressive form of type 2 papillary renal cell carcinoma. By studying the mechanism of action of marizomib, a proteasome inhibitor able to cross the blood-brain barrier, we found that it modulates the metabolism of HLRCC cells. Marizomib decreased glycolysis in vitro and in vivo by downregulating p62 and c-Myc. C-Myc downregulation decreased the expression of lactate dehydrogenase A, the enzyme catalyzing the conversion of pyruvate to lactate. In addition, proteasomal inhibition lowered the expression of the glutaminases GLS and GLS2, which support glutamine metabolism and the maintenance of the redox balance. Thus, in HLRCC cells, proteasome inhibition disrupts glucose and glutamine metabolism, restricting nutrients and lowering the cells' anti-oxidant response capacity. Although the cytotoxicity induced by proteasome inhibitors is complex, the understanding of their metabolic effects in HLRCC may lead to the development of effective therapeutic strategies or to the development of markers of efficacy.

[Extra uterine leiomyomatosis: Review of the literature]. / La léiomyomatose extra-utérine : revue de la littérature.

Extra-uterine leiomyomatosis is a rare pathology defined by the presence of benign smooth uterine muscle cells in unusual localizations, including different entities. It mainly affects premenopausal women with a medical history of uterine myoma with or without surgical treatment. Three main types are discribed: intraveinous leiomyomatosis, benign metastatisizing leiomyoma and leiomyomatosis peritonealis disseminata. The diagnosis may be complex with many differential diagnosis, and relies on histology. The treatment depends on multiple factors such as age, localization, size, symptoms and associated comorbidities. It is based on surgical resection and hormonal privation, surgical (adnexectomy) or medical (hormonotherapy). There is a high risk of recurrence. Some malignant evolutions have been reported, mostly leiomyosarcoma following peritoneal disseminated leiomyomatosis. Long term follow-up of these patients is mandatory. A particular manifestation of extra-uterine leiomyomatosis is the hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome. It is an autosomal dominant disorder which confers an increased risk of cutaneous and uterine leiomyomas and renal cell cancer, with a poor prognosis due to the urologic tumor.

Long-term response of metastatic hereditary leiomyomatosis and renal cell carcinoma syndrome associated renal cell carcinoma to bevacizumab plus erlotinib after temsirolimus and axitinib treatment failures.

BACKGROUND: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare hereditary kidney cancer syndrome in which affected individuals are at risk of skin and uterine leiomyomatosis and kidney cancer. HLRCC-associated kidney cancer is a lethal disease with a highly aggressive behavior, and there is no standard treatment option for metastatic disease. CASE PRESENTATION: Here, we report a 29-year-old patient with a locally advanced HLRCC-assiciated RCC. He was administrated temsirolimus initially, then underwent surgical removal of kidney, retroperitoneal lymph nodes, inferior vena cava and tumor thrombi. Unfortunately, multiple liver metastases were confirmed 1 month after surgery, so axitinib was given but failed immediately. We tried bevacizumab plus erlotinib, which achieved long-term good response lasting more than 18 months. He is alive with disease and maintains bevacizumab plus erlotinib treatment. CONCLUSION: The promising results obtained in this patient suggest that combined bevacizumab plus erlotinib may offer a valid treatment option for advanced HLRCC-associated kidney cancer, even after failures of mTOR inhibitor and/or VEGFR TKI based therapies.

Hemopneumotórax recorrente: descrição da síndrome da endometriose torácica / Recurrent hemopneumothorax: thoracic endometriosis syndrome description

A endometriose torácica é uma forma de endometriose extrapélvica encontrada em tecidos pulmonares ou na pleura. Caracteriza- se clinicamente pela presença de pneumotórax catamenial, hemotórax catamenial, hemoptise e nódulos pulmonares. O pneumotórax catamenial é a manifestação mais frequente, sendo caracterizado pelo acúmulo recorrente de ar na cavidade torácica durante o período menstrual. Ocorre, geralmente, no hemitórax direito e possui maior incidência na faixa etária dos 30 aos 40 anos de idade. Nosso objetivo é descrever um caso de derrame pleural hemorrágico recorrente e pneumotórax espontâneo correlacionados ao período menstrual em paciente de 34 anos. (AU)

Thoracic endometriosis is a form of extrapelvic endometriosis found in pulmonary tissue or the pleura. Clinically, it is characterized by the presence of catamenial pneumothorax, catamenial hemothorax, hemoptysis, and pulmonary nodules. The most frequent clinical presentation is catamenial pneumothorax, which is typified by a recurrent collection of air in the thoracic cavity occurring in conjunction with menstrual periods. It occurs more commonly on the right side and its highest incidence is between 30 and 40 years of age. Our objective is to describe a case of recurrent hemorrhagic pleural effusion and spontaneous pneumothorax correlated to the menstrual period in a 34-year-old patient. (AU)

Bevacizumab Plus Erlotinib Combination Therapy for Advanced Hereditary Leiomyomatosis and Renal Cell Carcinoma-Associated Renal Cell Carcinoma: A Multicenter Retrospective Analysis in Korean Patients.

PURPOSE: Hereditary leiomyomatosis and renal cell carcinoma (HLRCC) is a rare genetic syndrome resulting from germline mutations in fumarate hydratase. The combination of bevacizumab plus erlotinib showed promising interim results for HLRCC-associated RCC. Based on these results, we analyzed the outcome of bevacizumab plus erlotinib in Korean patients with HLRCC-associated RCC. MATERIALS AND METHODS: We retrospectively reviewed the efficacy and safety of bevacizumab plus erlotinib in patients with HLRCC-associated RCC who were confirmed to have germline mutations in fumarate hydratase. The primary endpoint was the objective response rate (ORR), while the secondary endpoints were progression-free survival (PFS) and overall survival (OS). RESULT: We identified 10 patients with advanced HLRCC-associated RCC who received bevacizumab plus erlotinib. Median age at diagnosis was 41 years, and five of the patients had received the combination as first- or second-line treatments. The ORR was 50% and the median PFS and OS were 13.3 and 14.1 months, respectively. Most adverse events were predictable and manageable by conventional measures, except for one instance where a patient died of gastrointestinal bleeding. CONCLUSION: This is the first real-world outcome of the treatment of advanced HLRCC-associated RCC. Bevacizumab plus erlotinib therapy showed promising activity with moderate toxicity. We should be increasingly aware of HLRCC-associated RCC and bevacizumab plus erlotinib should be a first-line treatment for this condition, unless other promising data are published.

Ulipristal Acetate for Disseminated Peritoneal Leiomyomatosis.

BACKGROUND: Disseminated peritoneal leiomyomatosis is a rare condition manifesting as hormone-sensitive soft tissue nodules lining the peritoneal cavity. Given the extensiveness of this disease, surgical management is challenging, making hormonal suppression the primary treatment. CASE: A 23-year-old woman presenting with abdominal pain was found to have innumerable abdominopelvic nodules on imaging. Biopsy of these lesions was consistent with disseminated peritoneal leiomyomatosis. Treatment using leuprolide acetate led to satisfactory results but was discontinued owing to vasomotor symptoms. Treatment was changed to cyclic ulipristal acetate, a selective progesterone receptor modulator. Over the past 2 years, the patient has completed five 3-month courses of ulipristal acetate with excellent symptomatic and radiologic response. CONCLUSION: The use of ulipristal acetate may be an effective, novel therapeutic option for the management of disseminated peritoneal leiomyomatosis.

Potential synergism between ulipristal acetate and vitamin D3 in uterine fibroid pharmacotherapy - 2 case studies.

This is a preliminary report of the first cases of successful simultaneous use of ulipristal acetate (UPA) and vitamin D3 in uterine fibroid (UF) oral treatment in humans. We present two cases of 37- and 49-year-old females with clinically symptomatic UFs and vitamin D deficiency. Both patients were treated with a standard 3 months of UPA scheme (5 mg daily) with the additional use of vitamin D3 (7000 IU daily orally). In the 37-year-old female all the symptoms (pain, pressure, frequent urination) decreased, total tumor volume after the treatment changed by 47.8%. In the 49-year-old female most symptoms perished, total tumor volume was reduced by 63.3%. UPA and vitamin D share synergistic anti-fibroid properties. Further studies are necessary to show the exact effect of UPA and vitamin D as co-drugs.

Sonographic and hysteroscopic endometrial examination in women treated with ulipristal acetate: Exploratory findings at a tertiary referral center.

OBJECTIVE: Ulipristal acetate (UPA) is a progesterone receptor modulator (PRM) agent that has shown benefits in women with symptomatic uterine fibroids. However, its effects on the endometrium are complex and not fully understood. We describe exploratory findings on macroscopic observation of the endometrium at transvaginal sonography (TVS) and hysteroscopy. The aim of the study is to characterize endometrial patterns commonly observed after UPA treatment. STUDY DESIGN: We performed a prospective longitudinal study at a tertiary referral center with 100 women with symptomatic uterine fibroids who received a 12-week treatment with UPA (5 mg/day). Patients underwent TVS before and after the treatment, and also a hysteroscopy examination was performed. Main outcome was to compare sonographic and hysteroscopic findings to histology after UPA treatment. RESULTS: Twenty one out of 100 (21%) women showed PAEC confirmed by histology after UPA treatment. Ultrasound findings were normal in most women after UPA treatment, but 18/100 (18%) showed an endometrial pattern suggestive of PRM effects (non-uniform, homogeneous endometrium with regular cystic areas). Endometrial thickness ≥16 mm was detected in 6/100 patients (6%), and all of them also presented sonographic PRM pattern. No patient presented malignancy according to histology in this subgroup, and 100% of them had PAEC pattern at histology. Among total patient population showing PAEC at histology, only 33% of these were identified by hysteroscopy, while 57% were identified by TVS with the PRM suggestive pattern. Of note, visibility of endometrium was improved at TVS after UPA. CONCLUSION: Identification of increased endometrial thickness together with the categorized endometrial PRM pattern at TVS may be correlated to benign lesions and may not be a cause of concern. This study is exploratory and further research is necessary to support these conclusions. Nevertheless, TVS seems to be feasible to plan adequate follow-up protocols by avoiding unnecessary interventional procedures such as hysteroscopy.

Ulipristal acetate for pre-operative management of uterine fibroids: Modeling outcomes and costs.

OBJECTIVES: The aim of this study was to evaluate the pharmacoeconomic profile in Italy of preoperative treatment with ulipristal acetate at the dose of 5 mg/day for 13 weeks in comparison with placebo prior to surgical management of symptomatic uterine fibroids. STUDY DESIGN: The pharmacoeconomic analysis was based on the calculation of incremental cost-effectiveness ratio (ICER). Effectiveness data were derived from the randomized-controlled trial PEARL-1, whilst costs data were retrieved from the published literature. A Markov model was employed to simulate the pattern of costs and two univariate sensitivity analyses tested the robustness of the results. RESULTS: In comparison with placebo, ulipristal acetate 5 mg for presurgical therapy was estimated to be associated with an incremental cost of €351 per patient. Costs per patient were €3836 for ulipristal acetate vs €3485 for placebo. The incremental effectiveness was 0.01931 QALYs per patient (around 7 quality-adjusted days per patient). Hence, the cost effectiveness ratio was calculated to be €18,177 per QALY gained. CONCLUSIONS: Preoperative use of ulipristal acetate 5 mg in patients with uterine fibroids has a favourable pharmacoeconomic profile.

Outcome of patients with uterine fibroids after 3-month ulipristal acetate therapy.

OBJECTIVES: To determine the proportion and the characteristics of patients who did or did not respond after 3 months of ulipristal acetate (UPA) therapy. STUDY DESIGN: In this retrospective cohort study conducted in the University Hospital of Bordeaux (France) and University Medical Center Ljubljana (Slovenia), symptomatic non-menopausal patients with fibroids that qualified for surgery were pretreated by 3 months of oral UPA 5 mg/day. Clinical success was defined by normalization of the bleeding score, and/or regression of pelvic pain, and/or abdominal distension. Imaging success was defined by reduction in fibroid volume ≥ 25%. RESULTS: The clinical and imaging success rates were 54/66 (82%) and 39/66 (59%) respectively. The absence of previous pregnancy (p = 0.004) and the size of the dominant fibroid ≥ 80 mm (p = 0.004) were independent factors associated with clinical failure. Age <35 years (p = 0.02) was the only independent factor associated with imaging failure. CONCLUSION: Young women developing fibroids and/or women with large fibroids may be resistant to ulipristal acetate therapy.