Search

Cellular components of the tumor microenvironment, including myeloid cells, play important roles in the progression of lung adenocarcinoma (LUAD) and its response to therapy. Here, we characterize the function of the ubiquitin ligases Siah1a/2 in regulating the differentiation and activity of alveolar macrophages (AMs) and assess the implication of Siah1a/2 control of AMs for carcinogen-induced LUAD. Macrophage-specific genetic ablation of Siah1a/2 promoted accumulation of AMs with an immature phenotype and increased expression of pro-tumorigenic and pro-inflammatory Stat3 and β-catenin gene signatures. Administration of urethane to wild-type mice promoted enrichment of immature-like AMs and lung tumor development, which was enhanced by macrophage-specific Siah1a/2 ablation. The pro-fibrotic gene signature seen in Siah1a/2-ablated immature-like macrophages was associated with increased tumor infiltration of CD14+ myeloid cells and poorer survival of LUAD patients. Single-cell RNA-seq confirmed the presence of a cluster of immature-like AMs expressing a pro-fibrotic signature in lungs of LUAD patients, a signature enhanced in smokers. These findings identify Siah1a/2 in alveolar macrophages as gatekeepers of lung cancer development.

MicroRNAs (miRNAs/miRs) are small, endogenous noncoding RNAs that are important post-transcriptional regulators with clear roles in the development of the immune system and immune responses. Using miRNA microarray profiling, we characterized the expression profile of naive and in vivo generated murine effector antiviral CD8+ T cells. We observed that out of 362 measurable mature miRNAs, 120 were differentially expressed by at least 2-fold in influenza-specific effector CD8+ CTLs compared with naive CD8+ T cells. One miRNA found to be highly downregulated on both strands in effector CTLs was miR-139. Because previous studies have indicated a role for miR-139–mediated regulation of CTL effector responses, we hypothesized that deletion of miR-139 would enhance antiviral CTL responses during influenza virus infection. We generated miR-139−/− mice or overexpressed miR-139 in T cells to assess the functional contribution of miR-139 expression in CD8+ T cell responses. Our study demonstrates that the development of naive T cells and generation or differentiation of effector or memory CD8+ T cell responses to influenza virus infection are not impacted by miR-139 deficiency or overexpression; yet, miR-139−/− CD8+ T cells are outcompeted by wild-type CD8+ T cells in a competition setting and demonstrate reduced responses to Listeria monocytogenes. Using an in vitro model of T cell exhaustion, we confirmed that miR-139 expression similarly does not impact the development of T cell exhaustion. We conclude that despite significant downregulation of miR-139 following in vivo and in vitro activation, miR-139 expression is dispensable for influenza-specific CTL responses.

To develop a consensus statement of recommended terminology to use for describing different aspects of hysteroscopic procedures that can be uniformly used in clinical practice and research.Open forum discussion followed by online video meetings.International community of hysteroscopy experts PATIENTS: Not applicable.Series of online video meetings to complete a previously established agenda until a final agreement for standardized nomenclature was obtained.The adoption and implementation of a common terminology to standardize reporting of hysteroscopic procedures was proposed to cover five domains: pain management, healthcare setting, model of care, type of hysteroscopic procedure and the hysteroscopic approach to the uterine cavity. A final agreement was obtained after 3 online video meetings.Hysteroscopy is the gold standard technique for the evaluation and management of uterine disorders. A clear definition and understanding of the terminology used to describe hysteroscopic procedures is lacking. The production of this international consensus statement for terminology to describe hysteroscopic procedures, covering pain management, setting, model of care, type of procedure and hysteroscopic approach, has the potential to enable more effective communication for both clinical and research purposes with the ultimate aim of improving patient care and clinical outcomes.

Tumor microenvironment components, including T and myeloid cells, play important roles in lung adenocarcinoma (LADC) progression and response to therapy. Here, we identify a role for Siah1a/2 ubiquitin ligases in controlling alveolar macrophage (AM) differentiation and urethane-induced LADC. Genetic ablation of Siah1a/2 in AMs enriched their immature state, coinciding with increased pro-tumorigenic and inflammatory gene signatures and abundance of Siah1a/2 substrates NRF2 and β-catenin. Urethane administration to mice enriched the population of monocytic and immature-like AMs, which were more prevalent in the lungs of mice carrying Siah1a/2-ablated macrophages. While resembling transitional profibrotic macrophages often seen in lung fibrosis, enrichment of immature AMs coincided with the development of more frequent and larger lung tumors in urethane-treated mice harboring Siah1a/2 ablated macrophages compared with controls. Gene expression signature of Siah1a/2 ablated immature-like AMs is associated with increased infiltration of CD14+ immune cells and worse survival of LADC patients. Our findings identify Siah1a/2 as gatekeepers of cancer development by controlling AM differentiation and profibrotic phenotypes contributing to carcinogen-induced lung cancer.

Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss with an acceptable safety profile in women with uterine leiomyomas., OBJECTIVE: To investigate the safety and efficacy of elagolix, an oral gonadotropin-releasing hormone antagonist, with hormonal add-back therapy for up to 12 months in women with heavy menstrual bleeding associated with uterine leiomyomas. METHODS: Elaris UF-EXTEND was a phase 3 extension study that evaluated an additional 6 months (up to 12 months total) of elagolix 300 mg twice daily with hormonal add-back therapy (estradiol 1 mg and norethindrone acetate 0.5 mg once daily) in women who completed an initial 6 months of the same treatment in one of two preceding phase 3 studies. The primary endpoint was the percentage of women with both less than 80 mL menstrual blood loss during final month and a 50% or greater reduction in menstrual blood loss from baseline to final month. Safety evaluations included adverse events and bone mineral density changes. The planned sample size of UF-EXTEND was based on estimated rollover and discontinuation rates in the two preceding studies. RESULTS: From September 2016 to March 2019, 433 women were enrolled in UF-EXTEND. Of these women, 218 received up to 12 months of elagolix with add-back therapy; the mean±SD age of this group was 42.4±5.4 years and 67.3% were black. The percentage of women who met the primary endpoint in this elagolix with add-back group was 87.9% (95% CI [83.4–92.3]). The most frequently reported adverse events with up to 12 months of elagolix plus add-back therapy were hot flush (6.9%), night sweats (3.2%), headache (5.5%), and nausea (4.1%). Mean percent decreases in bone mineral density from baseline to extension month 6 were significantly less with elagolix plus add-back therapy than with elagolix alone {between-group difference in lumbar spine: −3.3 (95% CI [−4.1 to −2.5])}. CONCLUSION: Up to 12 months of elagolix with add-back therapy provided sustained reduction in menstrual blood loss in women with uterine leiomyomas, with the addition of add-back therapy attenuating the hypoestrogenic effects of elagolix alone. No new or unexpected safety concerns were associated with an additional 6 months of elagolix with addback therapy. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02925494. FUNDING SOURCE: AbbVie Inc funded this study.

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. In this study, we showed that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identified p53 as a key regulator of immune evasion and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

Summary/AbstractWe previously identified the adhesion molecule PSGL-1 as a T cell intrinsic immune checkpoint regulator of T cell exhaustion. Here we show that the ability of PSGL-1 to restrain TCR sginaling correlates with decreased expression of the Zap70 inhibitor Ubash3b (Sts-1) in PSGL-1-deficient T cells. PSGL-1-deficency in T cells supports antitumor responses to a PD-1 blockade resistant melanoma wherein tumor-specific CD8+ T cells sustain an enhanced metabolic state, with an elevated metabolic gene signature that promotes increased glycolysis and glucose uptake to support effector functions. In models of chronic virus infection and cancer, this outcome was associated with CD8+ T cell stemness, as PSGL-1 deficient CD8+ T cells displayed increased TCF-1 and decreased TOX expression, a phenotype shown to be crucial for responsiveness to checkpoint inhibition. Further, we demonstrate that PSGL-1 signaling promotes development of exhaustion in human CD8+ T cells. Finally, pharmacologic blockade of PSGL-1 was sufficient to curtail T cell exhaustion and enhance functionality both with melanoma tumors and chronic LCMV infection, demonstrating that PSGL-1 represents a therapeutic target for immunotherapy for PD-1/PD-L1 resistant tumors.

There is an unmet need for more effective treatment strategies for diffuse intrinsic pontine glioma (DIPG), a devastating brain tumour arising in children and young adults. While immunotherapy is emerging as a powerful approach to treatment of other cancers, clinical trials with immune checkpoint inhibitors have failed to show a survival benefit for DIPG patients. In this study, we analysed the expression of immune checkpoint molecules on the surface of human and murine DIPG cells by flow cytometry and identified CD155 and B7-H3 as the most highly expressed checkpoint molecules, with minimal expression of PD-L1, PD-L2, Galectin-9, CEACAM-1, CD86, CD252 and CD137. These findings were confirmed in primary patient samples from pediatric brain tumours, including high-grade gliomas, medulloblastomas and ependymomas. To test whether CD155 inhibition increases susceptibility to CD8+ T cell killing in vitro, we cultured DIPG cells expressing ovalbumin (OVA) with CD8+ T cells from OT-I mice, which express T cell receptors specific for OVA. Addition of CD155 blocking antibodies to these cultures increased expression of T cell activation markers (CD25, CD44 and CD69) as well as T cell-mediated tumour killing, supporting the notion that CD155 can function as an immune checkpoint in DIPG. In addition to its effects on T cells, CD155 also exerted direct effects on tumour cells: treatment with anti-CD155 antibodies led to impaired cell viability, and shRNA-mediated knockdown of CD155 resulted in reduced cell proliferation in vitro. Strikingly, knockdown of CD155 also led to reduced growth of DIPG cells in vivo, and mice transplanted with the CD155-deficient cells had a clear survival benefit compared to mice transplanted with wild type cells. These studies demonstrate that CD155 functions as an immune checkpoint and as a regulator of tumor growth in DIPG, and suggest that targeting CD155 could be a valuable therapeutic strategy for this devastating disease.

Many immunotherapies act by enhancing the ability of cytotoxic T cells to kill tumor cells. Killing depends on T cell recognition of antigens presented by class I major histocompatibility complex (MHC-I) proteins on tumor cells. Here we show that medulloblastomas lacking the p53 tumor suppressor do not express surface MHC-I, and are therefore resistant to immune rejection. Mechanistically, this is because p53 regulates expression of the peptide transporter Tap1 and the aminopeptidase Erap1, which are required for MHC-I trafficking to the cell surface. In vitro, tumor necrosis factor (TNF) or lymphotoxin-β receptor agonist (LTβRag) can rescue expression of Erap1, Tap1 and MHC-I on p53-mutant tumor cells. In vivo, low doses of TNF prolong survival and synergize with immune checkpoint inhibitors to promote tumor rejection. These studies identify p53 as a key regulator of immune evasion, and suggest that TNF could be used to enhance sensitivity of tumors to immunotherapy.

Despite an estimated 10% prevalence of endometriosis among reproductive-age women, surgical population-based data are limited.We sought to investigate racial and ethnic disparities in surgical interventions and complications among patients undergoing endometriosis surgery across the United States.We performed a retrospective cohort study of American College of Surgeons National Surgical Quality Improvement Program data from 2010 to 2018 identifying International Classification of Diseases, Ninth/Tenth Revision codes for endometriosis We compared procedures, surgical routes (laparoscopy vs laparotomy), and 30-day postoperative complications by race and ethnicity.We identified 11,936 patients who underwent surgery for endometriosis (65% White, 8.2% Hispanic, 7.3% Black or African American, 6.2% Asian, 1.0% Native Hawaiian or Pacific Islander, 0.6% American Indian or Alaska Native, and 11.5% of unknown race). Perioperative complications occurred in 9.6% of cases. After adjusting for confounders, being Hispanic (adjusted odds ratio, 1.31; 95% confidence interval, 1.06-1.64), Black or African American (adjusted odds ratio, 1.71; confidence interval, 1.39-2.10), Native Hawaiian or Pacific Islander (adjusted odds ratio, 2.08; confidence interval, 1.28-3.37), or American Indian or Alaska Native (adjusted odds ratio, 2.34; confidence interval, 1.32-4.17) was associated with surgical complications. Hysterectomies among Hispanic (adjusted odds ratio, 1.68; confidence interval, 1.38-2.06), Black or African American (adjusted odds ratio, 1.77; confidence interval, 1.43-2.18), Asian (adjusted odds ratio, 1.87; confidence interval, 1.43-2.46), Native Hawaiian or Pacific Islander (adjusted odds ratio, 4.16; confidence interval, 2.14-8.10), and patients of unknown race or ethnicity (adjusted odds ratio, 2.07; confidence interval, 1.75-2.47) were more likely to be open. Being Hispanic (adjusted odds ratio, 1.64; confidence interval, 1.16-2.30) or Black or African American (adjusted odds ratio, 2.64; confidence interval, 1.95-3.58) was also associated with receipt of laparotomy for nonhysterectomy procedures. The likelihood of undergoing oophorectomy was increased for Hispanic and Black women (adjusted odds ratio, 2.57; confidence interval, 1.96-3.37 and adjusted odds ratio, 2.06; confidence interval, 1.51-2.80, respectively), especially at younger ages.Race and ethnicity were independently associated with surgical care for endometriosis, with elevated complication rates experienced by Hispanic, Black or African American, Native Hawaiian or Pacific Islander, and American Indian or Alaska Native patients.

Objective: To assess outcomes of women with uterine fibroids (UFs) and heavy menstrual bleeding (HMB) treated with 300 mg elagolix twice daily plus add-back therapy (E2 1 mg/NETA 0.5 mg once daily)...

Background: The disease and treatment burden of uterine fibroids (UF) in Black women is substantially greater compared with other racial groups, with higher rates of complications and poorer outcom...

MicroRNAs (miRNAs/miRs) are small, endogenous noncoding RNAs that are important post-transcriptional regulators with clear roles in the development of the immune system and immune responses. Using miRNA microarray profiling, we characterized the expression profile of naive and in vivo generated murine effector antiviral CD8(+) T cells. We observed that out of 362 measurable mature miRNAs, 120 were differentially expressed by at least 2-fold in influenza-specific effector CD8(+) CTLs compared with naive CD8(+) T cells. One miRNA found to be highly downregulated on both strands in effector CTLs was miR-139. Because previous studies have indicated a role for miR-139–mediated regulation of CTL effector responses, we hypothesized that deletion of miR-139 would enhance antiviral CTL responses during influenza virus infection. We generated miR-139(2/2) mice or overexpressed miR-139 in T cells to assess the functional contribution of miR-139 expression in CD8(+) T cell responses. Our study demonstrates that the development of naive T cells and generation or differentiation of effector or memory CD8(+) T cell responses to influenza virus infection are not impacted by miR-139 deficiency or overexpression; yet, miR-139(2/2) CD8(+) T cells are outcompeted by wild-type CD8(+) T cells in a competition setting and demonstrate reduced responses to Listeria monocytogenes. Using an in vitro model of T cell exhaustion, we confirmed that miR-139 expression similarly does not impact the development of T cell exhaustion. We conclude that despite significant downregulation of miR-139 following in vivo and in vitro activation, miR-139 expression is dispensable for influenza-specific CTL responses.

BACKGROUND: Uterine fibroids are one of the most common neoplasms found among women globally, with a prevalence of approximately 11 million women in the United States alone. The morbidity of this common disease is significant because it is the leading cause of hysterectomy and causes significant functional impairment for women of reproductive age. Factors including age, body mass index, race, ethnicity, menstrual blood loss, fibroid location, and uterine and fibroid volume influence the incidence of fibroids and severity of symptoms. Elagolix is an oral gonadotropin-releasing hormone receptor antagonist that competitively inhibits pituitary gonadotropin-releasing hormone receptor activity and suppresses the release of gonadotropins from the pituitary gland, resulting in dose-dependent suppression of ovarian sex hormones, follicular growth, and ovulation. In Elaris Uterine Fibroids 1 and Uterine Fibroids 2, 2 replicate multicenter, double-blind, randomized, placebo-controlled, phase 3 studies, treatment of premenopausal women with elagolix with hormonal add-back therapy demonstrated reduction in heavy menstrual bleeding associated with uterine fibroids. OBJECTIVE: This analysis aimed to evaluate the safety and efficacy of elagolix (300 mg twice a day) with add-back therapy (1 mg estradiol/0.5 mg norethindrone acetate once a day) in reducing heavy menstrual bleeding associated with uterine fibroids in various subgroups of women over 6 months of treatment. STUDY DESIGN: Data were pooled from Elaris Uterine Fibroid-1 and Uterine Fibroid-2 studies, which evaluated premenopausal women (18–51 years) with heavy menstrual bleeding (>80 mL menstrual blood loss per cycle, alkaline hematin methodology) and ultrasound-confirmed uterine fibroid diagnosis. Subgroups analyzed included age, body mass index, race, ethnicity, baseline menstrual blood loss, fibroid location, and uterine and primary fibroid volume (largest fibroid identified by ultrasound). The primary endpoint was the proportion of women with

Objective To describe the role of hysteroscopy in diagnosis and subsequent follow-up of uterine enhanced myometrial vascularity (EMV). Uterine EMV, previously known as arteriovenous malformation (AVM), is a rare but cannot-miss finding often associated with prior pregnancy or uterine surgery and is typically suspected when a vascular mass is found on ultrasound. Color Doppler imaging will demonstrate high-velocity, low-impedance flow, with more significant shunts demonstrating higher peak systolic velocity (PSV). If not already diagnosed by ultrasound, accurate recognition during hysteroscopy is mandatory prior to any uterine instrumentation, as biopsy or curettage can lead to unanticipated massive hemorrhage. While many cases of EMV may resolve spontaneously, actively bleeding patients may require treatment with embolization, a procedure that may decrease ovarian reserve and impair fertility, though favorable reproductive outcomes have been reported. Others have reported success with hysteroscopic management using a bipolar electrosurgical loop. Design Case report. Setting Academic hospital system. Patient(s) We describe a 22-year-old G2P1011 who presented to the emergency department with heavy vaginal bleeding and a negative urine human chorionic gonadotropin 9 weeks following a first-trimester termination of pregnancy. Her ultrasound demonstrated a heterogeneous 2.6×2.3×2.6 cm vascular mass in the endometrial canal that was initially interpreted as retained products of conception. Unfortunately, PSV in the lesion was not measured. During observation, bleeding continued, and her hemoglobin dropped from 8.3 g/dL to 6.9 g/dL the next morning. She was transfused 2 units of blood and taken to the operating room for hysteroscopic evaluation and possible uterine curettage. Intervention(s) Hysteroscopy revealed a large pulsating 2cm bluish vascular mass that was recognized as a uterine EMV and the procedure was terminated with the plan for embolization. Given fertility concerns, the diagnosis was confirmed with MRI/MRA, which identified a 2.7cm mass-like process with early post-contrast enhancement in the arterial phase. An angiogram demonstrated bilaterally enlarged tortuous uterine arteries perfusing a hypervascular EMV that was treated with selective bilateral uterine artery embolization. Main Outcome Measure(s) Further bleeding or evidence of EMV. Result(s) Follow-up office hysteroscopy at 2 weeks demonstrated a 2 cm raised area of tissue without pulsations. At 6 weeks post-procedure, bleeding had ceased, and office hysteroscopy revealed only a small 0.5 cm calcified nodule with a circumferential pseudo-decidual reaction. Conclusion(s) Hysteroscopy may be used to diagnose EMV when ultrasound is not conclusive. Recognition of the pulsating vascular appearance of EMV on hysteroscopy is critical in preventing hemorrhage from inappropriate curettage. Resolution of the lesion following embolization can be readily demonstrated with office hysteroscopy.

To evaluate elagolix, an oral gonadotropin-releasing hormone receptor antagonist, alone or with add-back therapy, in premenopausal women with heavy menstrual bleeding (greater than 80 mL per month) associated with uterine leiomyomas.This double-blind, randomized, placebo-controlled, parallel-group study evaluated efficacy and safety of elagolix in cohorts 1 (300 mg twice daily) and 2 (600 mg daily) with four arms per cohort: placebo, elagolix alone, elagolix with 0.5 mg estradiol/0.1 norethindrone acetate, and elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate. A sample size of 65 per group was planned to compare elagolix with add-back to placebo on the primary end point: the percentage of women who had less than 80 mL menstrual blood loss and 50% or greater reduction in menstrual blood loss from baseline to the last 28 days of treatment. Safety assessments included changes in bone mineral density.From April 8, 2013, to December 8, 2015, 571 women were enrolled, 567 were randomized and treated (cohort 1=259; cohort 2=308), and 80% and 75% completed treatment, respectively. Participants had a mean±SD age of 43±5 years (cohort 2, 42±5 years), and 70% were black (cohort 2, 74%). Primary end point responder rates in cohort 1 (cohort 2) were 92% (90%) for elagolix alone, 85% (73%) for elagolix with 0.5 mg estradiol/0.1 mg norethindrone acetate, 79% (82%) for elagolix with 1.0 mg estradiol/0.5 mg norethindrone acetate, and 27% (32%) for placebo (all P.001 vs placebo). Elagolix groups had significant decreases compared with placebo in lumbar spine bone mineral density, which was attenuated by adding 1.0 mg estradiol/0.5 mg norethindrone acetate.Elagolix with and without add-back significantly reduced menstrual blood loss in women with uterine leiomyomas. Add-back therapy reduced hypoestrogenic effects on bone mineral density.ClinicalTrials.gov, NCT01817530; EU Clinical Trial Register, 2013-000082-37.

Uterine fibroids, also known as leiomyomas, are the most common benign tumor in women of reproductive age. When symptomatic, these patients can present with bleeding and/or bulk-related symptoms. Treatment options for symptomatic uterine leiomyomas include medical management, minimally invasive treatment such as uterine artery embolization, and surgical options, such as myomectomy. It is important to understand the role of these treatment options in various clinical scenarios so that appropriate consultation is performed. Furthermore, patients should be presented with the outcomes and complications of each of these treatment options. A summary of the data and clinical trials of the treatment options for symptomatic uterine leiomyomas is outlined in this article. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Immune responses to SARS-CoV-2 reveal regulation and dynamics of lymphocytes

PurposeA pilot systematic evidence review to establish methodology utility in rare genetic diseases, support clinical recommendations, and identify important knowledge gaps.MethodsBroad-based published/gray-literature searches through December 2015 for studies of males with confirmed mucopolysaccharidosis type II (any age, phenotype, genotype, family history) treated with enzyme replacement therapy or hematopoietic stem cell transplantation. Preset inclusion criteria employed for abstract and full document selection, and standardized methods for data extraction and assessment of quality and strength of evidence.ResultsTwelve outcomes reported included benefits of urinary glycosaminoglycan and liver/spleen volume reductions and harms of immunoglobulin G/neutralizing antibody development (moderate strength of evidence). Less clear were benefits of improved 6-minute walk tests, height, early treatment, and harms of other adverse reactions (low strength of evidence). Benefits and harms of other outcomes were unclear (insufficient strength of evidence). Current benefits and harms of hematopoietic stem cell transplantation are unclear, based on dated, low-quality studies. A critical knowledge gap is long-term outcomes. Consensus on selection of critical outcomes and measures is needed to definitively evaluate treatment safety and effectiveness.ConclusionMinor methodology modifications and a focus on critical evidence can reduce review time and resources. Summarized evidence was sufficient to support guidance development and highlight important knowledge gaps.

Operative hysteroscopy is a safe and effective minimally invasive treatment option for submucosal and intramural leiomyomas. We discuss preoperative evaluation, fluid management, postoperative complications, preventative measures, and hysteroscopic outcomes. Technical instructions and tips for successful hysteroscopy, as well as the various equipment options most commonly utilized in the United States, are also reviewed.

Study Objective Heavy menstrual bleeding (HMB) associated with uterine fibroids (UF) often leads to anemia, which may cause fatigue and weakness in affected women. This analysis evaluated clinical improvements in menstrual blood loss (MBL), anemia, and quality of life (QoL) in elagolix-treated women who had HMB, UF, and severe or mild anemia at the time of Elaris UF-1 or UF-2 study entry. Design Pooled subgroup analysis of UF-1 and UF-2, two replicate double-blind, randomized, placebo-controlled, 6-month phase 3 studies. Setting Outpatient. Patients or Participants Subgroup of premenopausal women with HMB (>80mL alkaline hematin-measured MBL/cycle), ultrasound-confirmed UF, and severe (hemoglobin [Hgb] Interventions Elagolix 300mg BID with add-back therapy (estradiol 1mg/norethindrone acetate 0.5mg QD) (elagolix+E2/NETA), compared with placebo. Measurements and Main Results In UF-1 and UF-2, a total of 426/591 (72%) women who received elagolix+E2/NETA or placebo had severe (n=189) or mild anemia (n=237) at study entry. Women with severe anemia had a numerically greater mean baseline MBL (301.6±204.1mL) than women with mild anemia (225.8±128.2mL). Of the elagolix+E2/NETA-treated women with severe anemia at study entry, 74.1% met the study's primary endpoint (had both 2g/dL from baseline to month 6, and 51.1% achieved Hgb≥12g/dL at month 6 (P Conclusion Women with HMB, UF, and severe or mild anemia at study entry demonstrated clinical improvements in MBL, anemia, and QoL with elagolix+E2/NETA treatment.

SUMMARY Growing evidence supports the importance of gut microbiota in the control of tumor growth and response to therapy. Here, we select prebiotics that can enrich bacterial taxa that promote anti-tumor immunity. Addition of the prebiotics inulin or mucin to the diet of C57BL/6 mice induces anti-tumor immune responses and inhibition of BRAF mutant melanoma growth in a subcutaneously implanted syngeneic mouse model. Mucin fails to inhibit tumor growth in germ-free mice, indicating that the gut microbiota is required for the activation of the anti-tumor immune response. Inulin and mucin drive distinct changes in the microbiota, as inulin, but not mucin, limits tumor growth in syngeneic mouse models of colon cancer and NRAS mutant melanoma and enhances the efficacy of a MEK inhibitor against melanoma while delaying the emergence of drug resistance. We highlight the importance of gut microbiota in anti-tumor immunity and the potential therapeutic role for prebiotics in this process., Graphical Abstract, In Brief Li et al. show that the gut microbiota effect on anti-tumor immunity is affected by inulin or mucin, prebiotics that inhibit melanoma and colon cancer growth in syngeneic models and attenuate melanoma resistance to MEKi. These studies highlight a potential therapeutic role for prebiotics in shaping the microbiota composition to promote anti-tumor immunity.

Understanding the mechanisms underlying anti-tumor immunity is pivotal for improving immune-based cancer therapies. Here, we report that growth of BRAF-mutant melanoma cells is inhibited, up to complete rejection, in Siah2−/− mice. Growth-inhibited tumors exhibit increased numbers of intra-tumoral activated T cells and decreased expression of Ccl17, Ccl22, and Foxp3. Marked reduction in Treg proliferation and tumor infiltration coincide with G1 arrest in tumor infiltrated Siah2−/− Tregs in vivo or following T cell stimulation in culture, attributed to elevated expression of the cyclin-dependent kinase inhibitor p27, a Siah2 substrate. Growth of anti-PD-1 therapy resistant melanoma is effectively inhibited in Siah2−/− mice subjected to PD-1 blockade, indicating synergy between PD-1 blockade and Siah2 loss. Low SIAH2 and FOXP3 expression is identified in immune responsive human melanoma tumors. Overall, Siah2 regulation of Treg recruitment and cell cycle progression effectively controls melanoma development and Siah2 loss in the host sensitizes melanoma to anti-PD-1 therapy., The ubiquitin ligase Siah2 has been implicated in immune responses. Here, the authors show that Siah2 null immune cells have an increased inflammatory response to inoculated melanoma cells, along with a reduced number of infiltrating immunosuppressive regulatory T cells, resulting in inhibition of tumour growth.

The immune system, and in particular, cytotoxic CD8+ T cells (CTLs), plays a vital part in the prevention and elimination of tumors. In many patients, however, CTL-mediated tumor killing ultimately fails in the clearance of cancer cells resulting in disease progression, in large part due to the progression of effector CTL into exhausted CTL. While there have been major breakthroughs in the development of CTL-mediated “reinvigoration”-driven immunotherapies such as checkpoint blockade therapy, there remains a need to better understand the drivers behind the development of T cell exhaustion. Our study highlights the unique differences in T cell exhaustion development in tumor-specific CTL which arises over time in a mouse model of mesothelioma. Importantly, we also show that peripheral tumor-specific T cells have a unique expression profile compared to exhausted tumor-infiltrating CTL at a late-stage of tumor progression in mice. Together, these data suggest that greater emphasis should be placed on understanding contributions of individual microenvironments in the development of T cell exhaustion.

Background: Radiofrequency ablation (RFA) has emerged as a safe and effective treatment option for women with symptomatic uterine fibroids and can be delivered by laparoscopic, transvaginal, or transcervical approaches. The evidence regarding typical patient outcomes with RFA has not previously been examined in a comprehensive fashion. Materials and Methods: We performed a systematic review of prospective studies for treatment of uterine fibroids with RFA. Main outcomes were procedure time, patient recovery metrics, change in fibroid volume, symptom severity score (SSS), health-related quality of life (HRQL), and reinterventions. Data were analyzed with random effects meta-analysis and metaregression. Results: We identified 32 articles of 1283 unique patients (median age: 42 years) treated with laparoscopic RFA (19 articles), transvaginal RFA (8 articles), or transcervical fibroid ablation (5 articles). Mean procedure time was 49 minutes, time to discharge was 8.2 hours, time to normal activities was 5.2 days, and time to return to work was 5.1 days. At 12 months follow-up, fibroid volume decreased by 66%, HRQL increased by 39 points, and SSS decreased by 42 points (all P

Summary Repetitive elements (REs) compose ∼50% of the human genome and are normally transcriptionally silenced, although the mechanism has remained elusive. Through an RNAi screen, we identified FBXO44 as an essential repressor of REs in cancer cells. FBXO44 bound H3K9me3-modified nucleosomes at the replication fork and recruited SUV39H1, CRL4, and Mi-2/NuRD to transcriptionally silence REs post-DNA replication. FBXO44/SUV39H1 inhibition reactivated REs, leading to DNA replication stress and stimulation of MAVS/STING antiviral pathways and interferon (IFN) signaling in cancer cells to promote decreased tumorigenicity, increased immunogenicity, and enhanced immunotherapy response. FBXO44 expression inversely correlated with replication stress, antiviral pathways, IFN signaling, and cytotoxic T cell infiltration in human cancers, while a FBXO44-immune gene signature correlated with improved immunotherapy response in cancer patients. FBXO44/SUV39H1 were dispensable in normal cells. Collectively, FBXO44/SUV39H1 are crucial repressors of RE transcription, and their inhibition selectively induces DNA replication stress and viral mimicry in cancer cells.

Numerous independent studies link gut microbiota composition and disease and imply a causal role of select commensal microbes in disease etiology. In the gut, commensal microbiota or pathobionts secrete metabolites that underlie pathological conditions, often impacting proximal tissues and gaining access to the bloodstream. Here we focus on extrinsic and intrinsic factors affecting composition of gut microbiota and their impact on the immune system, as a key driver of anti-tumor immunity. In discussing exciting advances relevant to microbiome-tumor interaction, we note existing knowledge gaps that need to be filled to advance basic and clinical research initiatives.

Many immunotherapies act by enhancing the ability of T cells to kill tumor cells. But T cell killing depends on recognition of antigens presented by Class I MHC (MHC-I) on the tumor cell surface; if a tumor lacks MHC-I, it cannot be recognized by T cells. To study the efficacy of immunotherapy for Group 3 medulloblastoma, we have used mouse models driven by overexpression of Myc and dominant negative p53 (“MP tumors”), or by overexpression of Myc and Gfi1 (“MG tumors”). While MP tumors grow in immunocompetent mice, MG tumors don’t grow, due to T-cell rejection. To understand this difference, we analyzed expression of immunoregulatory molecules, and found that MP tumors completely lack surface MHC-I. Mechanistically, this is because two key proteins required for MHC-I trafficking – TAP1 and ERAP1 – are targets of p53; since MP tumors lack functional p53, they also lack TAP1 and ERAP1, and surface MHC-I. These studies suggest that p53 plays a critical role in determining immunogenicity, and that p53-mutant tumors are resistant to immune attack. To overcome this resistance, we treated tumor cells with agents that regulate MHC-1. We found that low doses of tumor necrosis factor alpha (TNF) can rescue expression of ERAP, TAP and MHC-I on MP tumor cells. In vivo, TNF prolongs survival of tumor-bearing mice, and markedly augments the efficacy of immune checkpoint inhibitors. These results raise the possibility that TNF could be used prior to immunotherapy to render tumors more sensitive to T cell attack.