Potential Costs and Benefits of Incorporating PGT-A Across Age Groups: A Canadian Clinic Perspective.

OBJECTIVE: To assess the potential costs and benefits of preimplantation genetic testing for aneuploidy (PGT-A) across age groups, considering financial costs, total euploidy rates and the potential for morphology grading to predict a euploid embryo. METHODS: This study is a blinded retrospective chart review of patients who incorporated PGT-A as part of their in vitro fertilization (IVF) treatment cycle at a university-affiliated fertility clinic. Patients between 25-44 years of age undergoing IVF with intracytoplasmic sperm injection and PGT-A with autologous oocytes (n = 220) were included in this study. Number of blastocysts achieved, euploidy rates and PGT-A costs were compared between 3 age groups: <35 years, 35-37, and ≥38. Additionally, agreement on the top-quality embryo based on morphology assessment alone versus PGT-A selection was analyzed and further compared based on the number of blastocysts achieved. RESULTS: A significant negative correlation between patient age and number of embryos produced, PGT-A costs, and euploidy rates (P < 0.001) was observed. Additionally, morphology alone ratings were able to predict the top-quality euploid embryo 78% of the time in the <35 age group, but only 32% of the time in the ≥38 age group (P < 0.05), with a trend toward even lower agreement when 3 or fewer blastocysts were produced. CONCLUSION: Based on our cost analysis, it may be advantageous to incorporate PGT-A when maternal age is ≥38, given the lower financial costs associated with each cycle and the low likelihood of transferring a euploid embryo on the first attempt for this age group. Nevertheless, we acknowledge that PGT-A remains a complex decision influenced by a multitude of factors.

Impact of Protocol Adjustments Due to the COVID-19 Pandemic on Infertility Treatment Outcomes.

As a result of the COVID-19 pandemic, our centre made adjustments that reduced the number of patient visits, ultrasound scans, laboratory investigations, and face-to face instructions. The objective of this study was to evaluate whether these changes had any effect on the pregnancy rate for patients undergoing infertility treatment. The primary outcome was clinical pregnancy rates from intrauterine insemination and frozen embryo transfer. Clinical pregnancy rates were not statistically different between patients who underwent either procedure before and after the protocols were put in place. It is reassuring to know our pandemic protocol adjustments did not have a negative impact on infertility treatment outcomes.

Assessment of denosumab treatment effects and imaging response in patients with giant cell tumor of bone.

BACKGROUND: Denosumab has been shown to reduce tumor size and progression, reform mineralized bone, and increase intralesional bone density in patients with giant cell tumor of bone (GCTB); however, radiologic assessment of tumors in bone is challenging. The study objective was to assess tumor response to denosumab using three different imaging parameters in a prespecified analysis in patients with GCTB from two phase 2 studies. METHODS: The studies enrolled adults and adolescents (skeletally mature and at least 12 years of age) with radiographically measurable GCTB that were given denosumab 120 mg every 4 weeks, with additional doses on days 8 and 15 of cycle 1. The proportion of patients with an objective tumor response was assessed using either Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST), European Organisation for Research and Treatment of Cancer response criteria (positron emission tomography [PET] scan criteria), or inverse Choi density/size (ICDS) criteria. Target lesions were measured by computed tomography or magnetic resonance imaging (both studies), PET (study 2 only), or plain film radiograph (study 2 only). RESULTS: Most patients (71.6%) had an objective tumor response by at least one response criteria. Per RECIST, 25.1% of patients had a response; per PET scan criteria, 96.2% had a response; per ICDS, 76.1% had a response. 68.5% had an objective tumor response ≥ 24 weeks. Using any criteria, crude incidence of response ranged from 56% (vertebrae/skull) to 91% (lung/soft tissue), and 98.2% had tumor control ≥ 24 weeks. Reduced PET avidity appeared to be an early sign of response to denosumab treatment. CONCLUSION: Modified PET scan criteria and ICDS criteria indicate that most patients show responses and higher benefit rates than modified RECIST, and therefore may be useful for early assessment of response to denosumab. TRIAL REGISTRATION: ClinicalTrials.gov Clinical Trials Registry NCT00396279 (retrospectively registered November 6, 2006) and NCT00680992 (retrospectively registered May 20, 2008).

DNA methylation, but not microRNA expression, is affected by in vitro THC exposure in bovine granulosa cells.

BACKGROUND: A global increase in cannabis use has led to questions about its effects on fertility. The rise in consumption amongst women of reproductive age is a growing concern, as this group is vulnerable in terms of reproductive health. Ample evidence suggests that the psychoactive component of cannabis, Δ9-Tetrahydrocannabinol (THC), interacts with the endocannabinoid system (ECS), that helps regulate mammalian reproduction. This study aimed to research the epigenetic effects of THC in bovine granulosa cells (GCs) by (1) investigating global DNA methylation via measuring 5-mC and 5-hmC levels; (2) measuring key methylation regulators, including the methylating enzymes DNMT1, DNMT3a, DNMT3b and the demethylases TDG and TET1/2/3; and (3) assessing fertility-associated miRNAs key in developmental competency, including miR-21, -155, -33b, -324 and -346. METHODS: Bovine GCs were used as a translational model for reproductive toxicity in humans. To determine THC effects, GCs were isolated from Cumulus-Oocyte-Complexes (COCs) from bovine ovaries, cultured in vitro for 7 days, or until confluent, and cryopreserved at passage 1 (P1). For experimentation, cells were thawed, cultured until passage 2 (P2), serum restricted for 24-h and treated for 24-h in one of five groups: control, vehicle (1:1:18 ethanol: tween: saline) and three clinically relevant THC doses (0.032, 0.32 and 3.2 µM). Global methylation was assessed by measuring 5-mC and 5-hmC levels with flow cytometry. To assess mRNA and protein expression of methylation regulators and miRNA profiles, qPCR and Western Blotting were utilized. Shapiro-Wilk test was used to determine normality within datasets. One-way ANOVA was applied to determine statistical significance using GraphPad Prism 6.0.0. RESULTS: Results indicate a significant decrease (p = 0.0435) in 5-mC levels following low THC exposure, while no changes were observed in 5-hmC levels. A significant increase in DNMT1 following high THC exposure at the RNA level (p < 0.05) and a significant increase following low THC exposure at the protein level (p = 0.0048) were also observed. No significant differences were observed in DNMT3a/3b, TDG, TET1/2/3 mRNAs or in any of the miRNAs analyzed. CONCLUSIONS: This research suggests that THC mainly affects DNA methylation, but not miRNA profiles, ultimately altering gene expression and likely impairing oocyte competence, maturation, and fertilization potential.

Genetic and Epigenetic Profiles of Polycystic Ovarian Syndrome and In Vitro Bisphenol Exposure in a Human Granulosa Cell Model.

Higher levels of bisphenols are found in granulosa cells of women with polycystic ovary syndrome (PCOS), posing the question: Is bisphenol exposure linked to PCOS pathophysiology? Human granulosa cells were obtained from women with and without PCOS, and genes and microRNAs associated with PCOS were investigated. The first phase compared healthy women and those with PCOS, revealing distinct patterns: PCOS subjects had lower 11ß-HSD1 (p = 0.0217) and CYP11A1 (p = 0.0114) levels and elevated miR-21 expression (p = 0.02535), elucidating the molecular landscape of PCOS, and emphasizing key players in its pathogenesis. The second phase focused on healthy women, examining the impact of bisphenols (BPA, BPS, BPF) on the same genes. Results revealed alterations in gene expression profiles, with BPS exposure increasing 11ß-HSD1 (p = 0.02821) and miR-21 (p = 0.01515) expression, with the latest mirroring patterns in women with PCOS. BPA exposure led to elevated androgen receptor (AR) expression (p = 0.0298), while BPF exposure was associated with higher levels of miR-155. Of particular interest was the parallel epigenetic expression profile between BPS and PCOS, suggesting a potential link. These results contribute valuable insights into the nuanced impact of bisphenol exposure on granulosa cell genes, allowing the study to speculate potential shared mechanisms with the pathophysiology of PCOS.

Sperm capacitation and transcripts levels are altered by in vitro THC exposure.

BACKGROUND: Delta-9-tetrahydrocannabinol (THC) is the primary phytocannabinoid responsible for the psychoactive properties of cannabis and is known to interact with the endocannabinoid system, which is functionally present in the male reproductive system. Since cannabis consumption is the highest among reproductive aged males, the current study aimed to further investigate the effects of THC exposure to phenotypical, physiological, and molecular parameters in sperm. Bull sperm of known fertility were used as a translational model for human sperm and subjected to in vitro treatment with physiologically relevant experimental doses of THC. Sperm parameters, capacitation, apoptosis, and transcript levels were evaluated following treatment. RESULTS: Motility, morphology, and viability of bovine sperm was unaltered from THC exposure. However, 0.32µM of THC caused an increased proportion of capacitating sperm (p < 0.05) compared to control and vehicle group sperm. Transcriptome analysis revealed that 39 genes were found to be differentially expressed by 0.032µM THC exposure, 196 genes were differentially expressed by 0.32µM THC exposure, and 33 genes were differentially expressed by 3.2µM THC. Secondary analysis reveals pathways involving development, nucleosomes, ribosomes and translation, and cellular metabolism to be significantly enriched. CONCLUSION: Phytocannabinoid exposure to sperm may adversely affect sperm function by stimulating premature capacitation. These findings also show for the first time that spermatozoal transcripts may be altered by THC exposure. These results add to previous research demonstrating the molecular effects of cannabinoids on sperm and warrant further research into the effects of cannabis on male fertility.

Brain-derived neurotrophic factor expression in granulosa lutein cells.

Brain-derived neurotrophic factor (BDNF) is thought to play a role in follicle activation and oocyte maturation. It is postulated that BDNF and its receptor, tyrosine kinase receptor B (TrkB), may also play a role in maintaining the corpus luteum. Therefore,human granulosa lutein cells (GLC) were obtained from women undergoing ovulation induction and treated with increasing concentrations of cAMP (0, 125, 500 and 1000 µmol/l). BDNF and progesterone concentrations were quantified by enzyme-linked immunosorbent assay. cAMP treatment significantly increased progesterone output but had no effect on BDNF concentration in the spent media. However, the BDNF concentration was significantly increased in GLC lysates. To assess the expression of BDNF and TrkB in active versus regressing corpora lutea, ovaries from adult female BALBc mice (n = 4) from each day of the oestrous cycle were processed for immunohistochemistry. Two markers of luteal activity were used (3b-hydroxysteroid dehydrogenase and tenascin-X). There was a trend towards higher BDNF and TrkB H-scores in active versus regressing corpus lutea. In conclusion, intracellular BNDF concentrations were dose-dependently increased by cAMP but treatments had no effect on BDNF output. It is speculated that BDNF contributes in an autocrine manner to GLC survival in the active corpus luteum.

Radiologists and Clinical Trials: Part 2: Practical Statistical Methods for Understanding and Monitoring Independent Reader Performance.

Though many clinical trials rely on medical image evaluations for primary or key secondary endpoints, the methods to monitor reader performance are all too often mired in the legacy use of adjudication rates. If misused, this simple metric can be misleading and sometimes entirely contradictory. Furthermore, attempts to overcome the limitations of adjudication rates using de novo or ad hoc methods often ignore well-established research conducted over the last half-century and can lead to inaccurate conclusions or variable interpretations. Underperforming readers can be missed, expert readers retrained, or worse, replaced. This paper aims to standardize reader performance evaluations using proven statistical methods. Additionally, these methods will describe how to discriminate between scenarios of concern and normal medical interpretation variability. Statistical methods are provided for inter-reader and intra-reader variability and bias, including the adjudicator's bias. Finally, we have compiled guidelines for calculating correct sample sizes, considerations for intra-reader memory recall, and applying alternative designs for independent readers.

Aryl hydrocarbon receptor antagonists attenuate the deleterious effects of benzo[a]pyrene on isolated rat follicle development.

It has been shown that benzo[a]pyrene, a key component of cigarette smoke and an aryl hydrocarbon receptor (AhR) ligand, reduced growth of isolated rat follicles in vitro. However, the mechanism underlying the induced changes in folliculogenesis is unknown. This study proposed that the reported adverse effects of benzo[a]pyrene on follicle growth are mediated through AhR activation. The objective was to investigate the effect of benzo[a]pyrene with and without AhR antagonists (resveratrol or 3',4'-dimethoxyflavone (3,4-DMF)) on follicle growth, oestradiol output, anti-Müllerian hormone (AMH) concentration and cell proliferation in isolated rat follicles cultured in vitro. Benzo[a]pyrene treatment significantly inhibited follicle growth and cell proliferation at concentrations of 1.5 ng/ml and higher (P < 0.05), an effect attenuated by co-incubation with benzo[a]pyrene and resveratrol or 3,4-DMF. A significant decrease in oestradiol (P < 0.05) and AMH output (P < 0.001) by cultured follicles was induced by benzo[a]pyrene treatment, an effect attenuated by co-incubation with 3,4-DMF. The results suggest that the adverse effects of benzo[a]pyrene on follicle growth, steroidogenesis and AMH output are mediated through activation of the AhR. Moreover, AhR antagonists such as resveratrol and 3,4-DMF may have therapeutic benefit in protecting the ovary against the adverse effects of AhR ligands, including benzo[a]pyrene.

Transfers of lower quality embryos based on morphological appearance result in appreciable live birth rates: a Canadian center's experience.

OBJECTIVE: To determine the reproductive outcomes resulting from transfer of lower-grade blastocysts to support the practice of cryopreserving and transferring lower-grade embryos. DESIGN: Retrospective chart review. SETTING: Single infertility center. PATIENTS: Women who have undergone a fresh (n = 570) or frozen (n = 885) transfer of a single blastocyst embryo between December 2013 and December 2018. INTERVENTIONS: None. MAIN OUTCOME MEASURES: The primary outcome was live birth rate. The secondary outcomes included implantation rate, ongoing pregnancy rate, associations with inner cell mass (ICM) and trophectoderm epithelium (TE) grades determined by morphological assessment, and antenatal/perinatal complications. RESULTS: Reproductive outcomes directly correlated with embryo quality. Transfers of AA embryos resulted in a 41.4% live birth rate compared to 31.1% for BB embryos and 13.3% for CC embryos. The TE grade was significantly associated with the live birth rate. Embryos with a TE grade of "B" had an odds ratio of 0.677 and embryos with a TE grade of "C" had an odds ratio of 0.394 compared to embryos with a TE grade of "A" for live birth. CONCLUSION: Embryos with a TE "C" grade should be considered for transfer and cryopreservation, as they are shown to result in appreciable live birth rates. Such treatment should involve a thorough discussion with patients, however, as these live birth rates are significantly lower than those associated with higher-grade embryos.

From natural disaster to pandemic: A health-system pharmacy rises to the challenge.

PURPOSE: This report describes a health-system pharmacy's response to a natural disaster while staff members simultaneously prepared for the coronavirus disease 2019 (COVID-19) pandemic. By detailing our experience, we hope to help other institutions that are current facing or could encounter similar crises. SUMMARY: In early March 2020, a tornado destroyed the health system's warehouse for storage of most clinical supplies, including personal protective equipment and fluids. The pharmacy purchasing team collaborated with suppliers and manufacturers to recover losses and establish alternative storage areas. Days later, the pharmacy department was forced to address the impending COVID-19 pandemic. Key elements of the COVID-19 response included reducing the potential for virus exposure for patients and staff; overcoming challenges in sourcing of staff, personal protective equipment, and medications; and changing care delivery practices to maintain high-quality patient care while maximizing social distancing. The pharmacy department also created distance learning opportunities for 70 pharmacy students on rotations. After an initial plan, ongoing needs include adjustment in patient care activities if significant staff losses occur, when and how to resume clinical activities, and how to best utilize the resources accumulated. Elements of practice changes implemented to reduce COVID-19 threats to patients and pharmacy personnel have proven beneficial and will be further evaluated for potential continuation. CONCLUSION: The pharmacy department's efforts to respond to a natural disaster and unprecedented pandemic have proven successful to this point and have illuminated several lessons, including the necessity of cohesive department communication, staff flexibility, prioritization of teamwork, and external collaboration.

Collaborative multidisciplinary team approach to fertility issues among adolescent and young adult cancer patients.

Cancer treatment and the field of reproductive technology have each made impressive advancements in the last decade. Improved cancer treatment and survival rates have increased the number of cancer survivors, who might benefit from an array of fertility preservation strategies provided by emerging and advanced assisted conception technology. The challenge becomes bridging the gap between these two separate disciplines to ultimately improve the quality of life for cancer survivors. This paper discusses the issues and process involved with bringing these two teams of health-care professionals together. This model provides a framework for coordinating efforts in providing fertility preservation options to patients undergoing treatment for cancer. Effective multidisciplinary teams that include: oncologists, nurses in the specialties of oncology and infertility, social workers, reproductive endocrinology and infertility specialists, andrologists, and embryologists are required to work together in order to achieve success. The result of this unique team approach is not only a cancer survivor, but one whose quality of life might be enhanced by being able to have a child of his or her own in the future.

Environmental contaminants and human infertility: hypothesis or cause for concern?

Throughout the 1980s and 1990s the crude human birth rate (live births per 1000 population) declined, indicating reduced fertility and suggesting a potential decline in fecundity (the potential to conceive). Detection of environmental contaminants in human tissues, together with reports of a global decline in semen quality, further fueled speculation that human infertility rates are increasing and environmental toxicants are potentially important causal agents associated with this change. However, there is little compelling evidence to suggest that infertility rates amongst the general population have changed over time. Moreover, recent studies suggest a rise in the fertility rates. While several studies documented increased time to pregnancy (TTP) in exposed study populations, other investigators were not able to replicate these findings. Nevertheless, studies involving occupational exposure together with results from animal experiments lend support to the conclusion that environmental contaminants potentially adversely affect fertility. Consequently, the impact of exposure to environmental contaminants on human fertility remains controversial. To test the hypothesis that environmental contaminant exposure was associated with enhanced risk of infertility, data concerning trends in fertility and infertility rates were examined to assess the impact of exposure of developing gametes to environmental contaminants. The relationship between exposure and reproductive outcomes was then examined to illustrate the range of adverse effects for reproductive toxicants with data sets of divergent depth and reliability. Data showed that only a weak association between exposure to environmental contaminants and adverse effects on human fertility exists. However, it is postulated that evidence of chemical exposure and potential health consequences of these exposures highlight the need for further research in this area.

Quantification of benzo[a]pyrene and other PAHs in the serum and follicular fluid of smokers versus non-smokers.

Cigarette smoking is a well-established reproductive hazard that has been linked with decreased fertility in both smokers and those exposed to second hand smoke. The chemical components responsible for the reproductive toxic effects of cigarette smoke are unknown. Moreover, exposure of reproductive tissues to the chemical constituents of cigarette smoke is largely unknown. Therefore, we measured the levels of benzo[a]pyrene (B[a]P), and other polycyclic aromatic hydrocarbons (PAH) present in cigarette smoke, in the serum and follicular fluid of women exposed to mainstream (n=19) and side stream smoke (n=7) compared to non-smokers (n=10). Women exposed to mainstream smoke had significantly higher levels of B[a]P (1.32+/-0.68ng/ml) in their follicular fluid compared to side stream exposed (0.05+/-0.01ng/ml) or their non-smoking (0.03+/-0.01ng/ml) counterparts. More importantly we found significantly higher (p<0.001) levels of B[a]P in the follicular fluid of women who did not conceive (1.79+/-0.03ng/ml) compared to those that achieved a pregnancy (0.08+/-0.03ng/ml). Other PAHs known to be present in cigarette smoke were also detectable in both serum and follicular fluid of study subjects studied but with lower frequency compared to B[a]P and no differences in serum or follicular fluid levels between the groups could be demonstrated. The important finding that B[a]P reaches the follicular fluid and the fact that it is found at much higher levels in women who smoke provides further evidence that of the many toxicants present in cigarette smoke, B[a]P may be a key compound that is central to the documented adverse effects of cigarette smoke on follicular development and subsequent fertility.

Bisphenol A concentration-dependently increases human granulosa-lutein cell matrix metalloproteinase-9 (MMP-9) enzyme output.

Bisphenol A (BPA) is an estrogenic contaminant that has been quantified at higher levels in the follicular fluid of women with polycystic ovarian syndrome (PCOS) compared to healthy fertile controls. However, the effect of BPA on granulosa cell function is unknown. Therefore, the objective of the present study was to quantify the effect of BPA on granulosa cell progesterone (P4) output and matrix metalloproteinase (MMP)-2, and -9 output and activity. Granulosa-lutein cells (GLCs) were collected from women undergoing oocyte retrieval in an academic in vitro fertilization (IVF) program. Granulosa-lutein cells were treated with increasing log concentrations of BPA (1-10,000 ng/ml) or 17beta-estradiol (E2, 272 pg/ml or 1.0 nM) and treatment effects on MMP-2 and -9 activity and output, cell viability and cell proliferation were measured by commercial gelatin zymography, MMP-ELISA, MTS and BrdU incorporation assays, respectively. Granulosa-lutein cells in culture secrete MMP-2 and MMP-9. Bisphenol A treatment concentration-dependently increased MMP-9 output by GLCs with a maximal effect observed at 1000 ng/ml. Cell viability/proliferation was unaffected by BPA treatment at concentrations

Granulosa cell aromatase activity in women undergoing IVF: a comparison of good and poor responders.

OBJECTIVE: We wished to investigate the aromatase activity (AA) of granulosa cells (GCs) in women undergoing ovarian follicular stimulation for in vitro fertilization (IVF). METHODS: Granulosa cells were harvested from follicular fluid aspirated at the time of oocyte retrieval in women undergoing IVF. Data related to the follicular stimulation and IVF were collected by chart review. We conducted a retrospective analysis of the relation between the response to stimulation and the AA of GCs obtained from IVF patients. We assessed the response to stimulation by calculation of the area under the curve (AUC) of the monitored serum estradiol levels, and divided patients into "poor responders" and "good responders." RESULTS: There was no difference in AA between women with a poor response to stimulation and women with a good response. Implantation rates and pregnancy rates were significantly lower in poor responders (5.3% and 9.1% respectively) than in good responders (19.7% and 54.8% respectively), even though embryo quality was similar in each group. CONCLUSIONS: Women who have a poor response to ovarian follicular stimulation preceding IVF have lower pregnancy rates than women with a good response. The lower pregnancy rates do not appear to be a consequence of an abnormal follicular environment, because AA and the ratio of serum estradiol AUC to oocytes retrieved was similar in both groups of women.

Predictors of pneumonia on routine chest radiographs in patients with COPD: a post hoc analysis of two 1-year randomized controlled trials.

Background: Patients with COPD are at risk for life-threatening pneumonia. Although anatomical abnormalities in the thorax may predispose to pneumonia, those abnormalities identified on routine chest X-rays (CXRs) in patients with COPD have not been studied to better understand pneumonia risk. Methods: We conducted a post hoc exploratory analysis of data from two replicate year-long clinical trials assessing the impact of fluticasone furoate-vilanterol versus vilanterol alone on COPD exacerbations (GSK studies: HZC102871/NCT01009463 and HZC102970/NCT01017952). Abnormalities on baseline CXRs from 179 patients who developed pneumonia and 50 randomly selected patients who did not were identified by blinded consensus readings conducted by two radiologists. Positive and negative likelihood ratios and diagnostic odds ratios (ORs) were calculated to evaluate the markers for subsequent pneumonia development during the 1-year study period. Results: Baseline characteristics distinguishing the pneumonia and non-pneumonia groups included a lower body mass index (24.9 vs 27.5 kg/m2, P=0.008), more severe airflow obstruction (mean post-bronchodilator forced expiratory volume in 1 second [FEV1]/forced vital capacity ratio: 42.3% vs 47.6%, P=0.003), and prior pneumonia (36% vs 20%, P=0.030). Baseline CXR findings with the highest diagnostic ORs were: elevated hemi-diaphragm (OR: 6.87; 95% CI: 0.90, 52.26), thick tracheal-esophageal stripe (OR: 4.39 [0.25, 78.22]), narrow cardiac silhouette (OR: 2.91 [0.85, 9.99]), calcified pleural plaque/mid-chest pleural thickening (OR: 2.82 [0.15, 53.76]), and large/prominent pulmonary artery shadow (OR: 1.94 [0.95, 3.97]). The presence of a narrow cardiac silhouette at baseline was associated with a statistically significant lower mean pre-bronchodilator FEV1 (P=0.040). There was also a trend for a lower mean pre-bronchodilator FEV1 in patients with a large/prominent pulmonary artery shadow at baseline (P=0.095). Conclusion: Findings on routine CXR that relate to pathophysiological mechanisms of pneumonia could help determine pneumonia risk in patients with COPD.

Phase III HEAT Study Adding Lyso-Thermosensitive Liposomal Doxorubicin to Radiofrequency Ablation in Patients with Unresectable Hepatocellular Carcinoma Lesions.

Purpose: Lyso-thermosensitive liposomal doxorubicin (LTLD) consists of doxorubicin contained within a heat-sensitive liposome. When heated to ≥40°C, LTLD locally releases a high concentration of doxorubicin. We aimed to determine whether adding LTLD improves the efficacy of radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) lesions with a maximum diameter (dmax) of 3 to 7 cm.Experimental Design: The HEAT Study was a randomized, double-blind, dummy-controlled trial of RFA ± LTLD. The 701 enrolled patients had to have ≤4 unresectable HCC lesions, at least one of which had a dmax of 3 to 7 cm. The primary endpoint was progression-free survival (PFS) and a key secondary endpoint was overall survival (OS). Post hoc subset analyses investigated whether RFA duration was associated with efficacy.Results: The primary endpoint was not met; in intention-to-treat analysis, the PFS HR of RFA + LTLD versus RFA alone was 0.96 [95% confidence interval (CI), 0.79-1.18; P = 0.71], and the OS HR ratio was 0.95 (95% CI, 0.76-1.20; P = 0.67). Among 285 patients with a solitary HCC lesion who received ≥45 minutes RFA dwell time, the OS HR was 0.63 (95% CI, 0.41-0.96; P < 0.05) in favor of combination therapy. RFA + LTLD had reversible myelosuppression similar to free doxorubicin.Conclusions: Adding LTLD to RFA was safe but did not increase PFS or OS in the overall study population. However, consistent with LTLD's heat-based mechanism of action, subgroup analysis suggested that RFA + LTLD efficacy is improved when RFA dwell time for a solitary lesion ≥45 minutes. Clin Cancer Res; 24(1); 73-83. ©2017 AACR.

Controlled Ovarian Hyperstimulation with Intrauterine Insemination Is More Successful After r-hCG Administration Than Spontaneous LH Surge.

BACKGROUND: The purpose of this study was to evaluate whether clinical pregnancy rate is affected by timing intrauterine insemination (IUI) according to serum LH surge, r-hCG trigger, or a combination of LH surge and r-hCG trigger in controlled ovarian hyperstimulation (COH) cycles for patients with a variety of infertility etiologies. METHODS: The last 365 consecutive COH-IUI cycles performed at ONE Fertility Burlington in 2014 were reviewed and categorized according to method of IUI timing. Associations between categorical variables were analyzed using a combination of Chi-square and Fisher's Exact tests, and between continuous variables using independent sample t-tests and logistic regression to a level of significance of p<0.05. RESULTS: The overall clinical pregnancy rate in this sample was 18.1% (66/365). Administration of r-hCG prior to IUI resulted in a higher clinical pregnancy rate compared with spontaneous serum LH surge: 18.2% vs. 5.8%, p=0.012. Patients in whom r-hCG was administered concomitantly with a serum LH surge had a higher clinical pregnancy than the r-hCG trigger group (30.8% vs. 18.2%, p=0.004) and LH surge group (30.8% vs. 5.8%, p<0.001). A sub-group analysis revealed that patients receiving r-FSH, rather than clomiphene or letrozole, had a significantly higher clinical pregnancy rate after r-hCG trigger as compared to the LH surge group (21.7% vs. 2.1%, p=0.01). CONCLUSION: In subfertile couples undergoing COH-IUI, r-hCG administration was associated with an increased clinical pregnancy rate compared with spontaneous serum LH surge. When r-hCG was administered concomitantly with a serum LH surge, this benefit was amplified. The effect appears to be of particular importance in r-FSH-medicated cycles.