The effect of methyltestosterone on in vitro fertilization outcomes: A randomized clinical trial on patients with low ovarian response.

OBJECTIVE: The aim of this study was to compare the outcomes of in vitro fertilization (IVF) in patients with a poor ovarian response who used methyltestosterone, versus those using a placebo, in an infertility clinic setting. METHODS: This clinical trial included 120 women who had undergone IVF with intracytoplasmic sperm injection due to poor ovarian reserve and infertility. The study took place at the Yas Infertility Center in Tehran, Iran, between January 1, 2018 and January 1, 2019. In the intervention group, 25 mg of methyltestosterone was administered daily for 2 months prior to the initiation of assisted reproductive treatment. The control group was given placebo tablets for the same duration before starting their cycle. Each group was randomly assigned 60 patients. All analyses were performed using SPSS ver. 23 (IBM Corp.). RESULTS: The endometrial thickness in the intervention group was 7.57±1.22 mm, whereas in the control group, it was 7.11±1.02 (p=0.028). The gonadotropin number was significantly higher in the control group (64.7±13.48 vs. 57.9±9.25, p=0.001). However, there was no significant difference between the two groups in the antral follicular count. The chemical and clinical pregnancy rates in the intervention group were 18.33% and 15% respectively, compared to 8.33% and 6.67% in the control group. The rate of definitive pregnancy was marginally higher in the intervention group (13.3% vs. 3.3%, p=0.05). CONCLUSION: The findings of this study suggest that pretreatment with methyltestosterone significantly increases endometrium thickness and is associated with an increase in the definitive pregnancy rate.

Follicular challenge test to predict suboptimal response to gonadotropin releasing hormone agonist trigger in elective oocyte cryopreservation cycles.

This prospective study aimed to test the ability of follicular GnRH agonist challenge test (FACT) to predict suboptimal response to GnRH agonist trigger, assessed by LH levels post ovulation trigger in non-medical oocyte cryopreservation program. The study included 91 women that underwent non-medical fertility preservation. On day two to menstrual cycle, blood tests were drawn (basal Estradiol, basal FSH, basal LH, Progesterone) and ultrasound (US) was performed. On that evening, the women were instructed to inject 0.2 mg GnRH agonist (FACT) and arrive for repeated blood workup 10-12 h later in the next morning, followed by a flexible antagonist protocol. LH levels on the morning after ovulation trigger were compared to FACT LH levels. The results demonstrated that LH levels following agonist ovulation trigger below 15IU/L occurred in 1.09% of cycles and were predicted by FACT, r = 0.57, p < 0.001. ROC analysis demonstrated that FACT LH > 42.70 IU/L would predict LH post trigger of more than 30 IU/L with 75% sensitivity and 70% specificity, AUC = 0.81. LH levels post trigger also displayed significant positive correlation to basal FSH (r = 0.35, p = 0.002) and basal LH (r = 0.54, p < 0.001). LH levels post ovulation trigger were not associated with total oocytes number or maturity rate. The strongest correlation to the number of frozen oocytes was progesterone levels post agonist trigger (r = 0.746, p < 0.001). We concluded that suboptimal response to agonist trigger, as assessed by post trigger LH levels was a rare event. FACT could serve as an adjunct pre-trigger, intracycle tool to predict adequate LH levels elevation after agonist ovulation trigger. Future studies should focus on optimization of agonist trigger efficacy assessment and prediction, especially in high responders.

No association between LH levels and ovarian response in oocyte donors triggered with gonadotropin-releasing hormone agonist: A prospective study.

OBJECTIVE: Are circulating luteinizing hormone (LH) levels predictive of ovarian response in oocyte donors triggered with gonadotropin-releasing hormone (GnRH) agonists? STUDY DESIGN: A prospective cohort study with 224 oocyte donation cycles between 2021 and 2022 at a single center, examined the relationship between circulating luteinizing hormone (LH) levels and ovarian response. Oocyte donors underwent GnRH antagonist downregulation followed by GnRH agonist trigger. LH, estradiol, and progesterone levels were measured on day one of stimulation, trigger-day and 12 h post-trigger. Oocyte retrieval and maturity rates were analyzed using univariate and multivariate analyses, and the correlation between post-trigger LH levels and outcomes was assessed by Pearson's correlation test. A significance level of p < 0.05 was used. RESULTS: Mean age was 26 ± 4.3 years, mean body mass index (BMI, kg/m2) was 22.6 ± 3.2 and mean antral follicle count (AFC) was 21.7 ± 8.2. Post-trigger LH levels averaged 51.3 IU/L (SD 34.8), and oocyte retrieval rate and maturity rates were 112,7% (+/-48,1%) and 77,8% (+/- 17,2%), respectively. No significant differences were found in these outcomes for donors with post-trigger LH values below and above 15 IU/L (Mann Whitney's p > 0.05). However, exploratory analyses revealed that post-trigger LH values < 22 IU/L and basal LH levels < 4 IU/L were associated with significantly lower oocyte retrieval rate (90 % vs 110 %, p = 0.019 and 100 % vs 110 %, p = 0.019, respectively). CONCLUSIONS: This study, a first in exclusively focusing on oocyte donors, did not support the previously reported LH value of 15 IU/L as predictive of suboptimal ovarian response. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Identifier: NCT05109403.

Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study / Respuesta subóptima a los antagonistas del factor de necrosis tumoral en la enfermedad inflamatoria intestinal en Latinoamérica: Estudio EXPLORE LATAM

Objective Data on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. Patients and methods We performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. Results We included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2–60.1) in UC, and 50.0 months (40.9–60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. Conclusions SOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM (AU)

Objetivo Los datos sobre tratamiento con antagonistas del factor de necrosis tumoral (anti-TNF) y su respuesta subóptima (RSO) en las enfermedades inflamatorias intestinales (EII) en América Latina (LATAM) son escasos. Se evaluaron la incidencia e indicadores de RSO a anti-TNF en pacientes con colitis ulcerosa (CU) y enfermedad de Crohn (EC) de Argentina, Colombia y México. Pacientes y métodos Se realizó un análisis retrospectivo de datos del estudio EXPLORE LATAM (NCT03090139), incluyendo pacientes adultos con EII que iniciaron anti-TNF entre marzo de 2010 a marzo de 2015. Se evaluó la incidencia acumulada de RSO a los anti-TNF en primera línea. Además, se realizó una encuesta a especialistas sobre las barreras del tratamiento con anti-TNF. Resultados Se incluyeron 185 pacientes con EII (CU/EC: 99/86) tratados con anti-TNF en primera línea de Argentina (38 CU; 40 EC), Colombia (21 CU; 25 EC) y México (40 CU; 21 EC); 36,4% de los pacientes con CU y 46,5% de los pacientes con EC experimentaron RSO a anti-TNF durante la mediana (intervalo intercuartílico) de 49 meses (37,2-60,1) en CU y 50 meses (40,9-60,1) en EC. El indicador más común de RSO fue el aumento del tratamiento no biológico (CU: 41,7%; EC: 35,0%). La accesibilidad y la derivación tardía a centros especializados fueron las barreras más comunes para el tratamiento con anti-TNF. Conclusiones La RSO a anti-TNF fue frecuente en pacientes con EII de LATAM, el aumento del tratamiento no biológico representó el indicador más frecuente de RSO. Nuestros hallazgos contribuyen a la evidencia actual sobre las necesidades insatisfechas asociadas a los anti-TNF en LATAM (AU)

Suboptimal response to tumor necrosis factor antagonists in inflammatory bowel disease in Latin America: EXPLORE LATAM study.

OBJECTIVE: Data on anti-tumor necrosis factor (anti-TNF) treatment and suboptimal response (SOR) among patients with inflammatory bowel diseases (IBD) in Latin America (LATAM) are scarce. This study evaluated the incidence and indicators of SOR to anti-TNF therapy in patients with ulcerative colitis (UC) and Crohn's disease (CD) from Argentina, Colombia and Mexico. PATIENTS AND METHODS: We performed retrospective analysis of data from LATAM patients of the EXPLORE study (NCT03090139) including adult patients with IBD who initiated anti-TNF therapy between March 2010 to March 2015. The cumulative incidence of SOR to first-line anti-TNF therapy was assessed. A physician survey to assess barriers to anti-TNF therapies was also carried out. RESULTS: We included 185 IBD patients (UC/CD: 99/86) treated with first-line anti-TNF from Argentina (38 UC; 40 CD), Colombia (21 UC; 25 CD) and Mexico (40 UC; 21 CD). 36.4% of patients with UC and 46.5% of patients with CD experienced SOR to anti-TNF therapy during the median (interquartile range) observational period: 49.0 months (37.2-60.1) in UC, and 50.0 months (40.9-60.1) in CD. The most common indicator of SOR among patients was augmentation of non-biologic therapy (UC: 41.7%; CD: 35.0%). Affordability and late referral to IBD specialist care centers were the most common barriers to anti-TNF therapies. CONCLUSIONS: SOR to anti-TNF therapy was common in LATAM IBD patients, where augmentation with non-biologic therapy represented the most frequent indicator of SOR across indications. Our findings contribute to the current evidence on the unmet needs associated with anti-TNF in LATAM.

Efficacy and safety of tenofovir alafenamide in patients with chronic hepatitis B exhibiting suboptimal response to entecavir.

BACKGROUND: Entecavir (ETV) is a potent and safe antiviral agent for patients with chronic hepatitis B (CHB); however, some patients may exhibit suboptimal response or resistance to ETV. Tenofovir alafenamide (TAF) is a novel tenofovir prodrug with improved pharmacokinetics and reduced renal and bone toxicity compared with tenofovir disoproxil fumarate. AIM: To evaluate the efficacy and safety of switching from ETV to TAF in patients with CHB exhibiting suboptimal response to ETV. METHODS: A total of 60 patients with CHB who had been treated with ETV for at least 12 mo and had persistent or recurrent viremia [Hepatitis B virus (HBV) DNA ≥ 20 IU/mL] or partial virologic response (HBV DNA < 20 IU/mL, but detectable) were enrolled in the study. The patients were randomly assigned to either continue ETV (0.5 mg) daily or switch to TAF (25 mg) daily for 48 wk. The primary endpoint was the proportion of patients who achieved a virologic response (HBV DNA level < 20 IU/mL) at week 48. Secondary endpoints included changes in serum alanine aminotransferase (ALT), hepatitis B surface antigen (HBsAg), hepatitis B e antigen (HBeAg), and anti-HBe levels, and renal and bone safety parameters. RESULTS: At week 48, the proportion of patients who achieved a virologic response was significantly higher in the TAF group than in the ETV group (93.3% vs 66.7%, P = 0.012). The mean reduction in HBV DNA from baseline was also significantly greater in the TAF group than in the ETV group (-3.8 vs -2.4 Log10 IU/mL, P < 0.001). The rates of ALT normalization, HBeAg loss, HBeAg seroconversion, and HBsAg loss were not found to significantly differ between the two groups. None of the patients developed genotypic resistance to ETV or TAF. Both drugs were well tolerated, with no serious adverse events or discontinuations caused by adverse events. No significant changes were observed in the estimated glomerular filtration rate, serum creatinine level, or urine protein-to-creatinine ratio in either group. The TAF group had a significantly lower decrease in bone mineral density at the lumbar spine and hip than the ETV group (-0.8% vs -2.1%, P = 0.004; -0.6% vs -1.8%, P = 0.007, respectively). CONCLUSION: Switching from ETV to TAF is effective and safe for patients with CHB exhibiting a suboptimal response to ETV and may prevent further viral resistance and reduce renal and bone toxicity.

Micheliolide exerts effects in myeloproliferative neoplasms through inhibiting STAT3/5 phosphorylation via covalent binding to STAT3/5 proteins.

Ruxolitinib is a cornerstone of management for some subsets of myeloproliferative neoplasms (MPNs); however, a considerable number of patients respond suboptimally. Here, we evaluated the efficacy of micheliolide (MCL), a natural guaianolide sesquiterpene lactone, alone or in combination with ruxolitinib in samples from patients with MPNs, JAK2V617F-mutated MPN cell lines, and a Jak2V617F knock-in mouse model. MCL effectively suppressed colony formation of hematopoietic progenitors in samples from patients with MPNs and inhibited cell growth and survival of MPN cell lines in vitro. Co-treatment with MCL and ruxolitinib resulted in greater inhibitory effects compared with treatment with ruxolitinib alone. Moreover, dimethylaminomicheliolide (DMAMCL), an orally available derivative of MCL, significantly increased the efficacy of ruxolitinib in reducing splenomegaly and cytokine production in Jak2V617F knock-in mice without evident effects on normal hematopoiesis. Importantly, MCL could target the Jak2V617F clone and reduce mutant allele burden in vivo. Mechanistically, MCL can form a stable covalent bond with cysteine residues of STAT3/5 to suppress their phosphorylation, thus inhibiting JAK/STAT signaling. Overall, these findings suggest that MCL is a promising drug in combination with ruxolitinib in the setting of suboptimal response to ruxolitinib.

BCR::ABL1 kinase domain mutation testing and clinical outcome in a nationwide chronic myeloid leukemia patient population.

OBJECTIVES: Acquired missense mutations in the BCR::ABL1 kinase domain (KD) may cause tyrosine kinase inhibitor (TKI) treatment failure. Based on mutation-specific in vitro derived IC50-values, alternative TKI may be selected. We assessed clinical practice of BCR::ABL1 KD mutation testing, clinical response in relation to IC50-values, and clinical outcome of tested patients. METHODS: Patients from six Dutch CML reference centers and a national registry were included once a mutational analysis was performed. Reasons for testing were categorized as suboptimal TKI response, and primary or secondary TKI resistance. RESULTS: Four hundred twenty analyses were performed in 275 patients. Sixty-nine patients harbored at least one mutation. Most analyses were performed because of suboptimal TKI response but with low mutation incidence (4%), while most mutations were found in primary and secondary resistant patients (21% and 51%, respectively). Harboring a BCR::ABL1 mutation was associated with inferior overall survival (HR 3.2 [95% CI, 1.7-6.1; p < .001]). Clinically observed responses to TKI usually corresponded with the predicted TKI sensitivity based on the IC50-values, but a high IC50-value did not preclude a good clinical response per se. CONCLUSIONS: We recommend BCR::ABL1 KD mutation testing in particular in the context of primary or secondary resistance. IC50-values can direct the TKI choice for CML patients, but clinical efficacy can be seen despite adverse in vitro resistance.

Efficacy of Autologous Stem Cell Transplantation for Myeloma Patients with Suboptimal Response: A Multicenter Retrospective Analysis.

Autologous stem cell transplantation (ASCT) is the standard of care for myeloma patients who achieve partial response (PR) or better after induction therapy. However, its clinical significance in patients with suboptimal response (SR) before ASCT, including stable disease (SD) and progressive disease (PD), has not been established. Additionally, functional high-risk, including SR and early PD within 12 months, was a poor prognostic factor up to now. This study aimed to evaluate the efficacy of ASCT in myeloma patients with SR in the novel agent era. This multicenter retrospective study was conducted using the Transplant Registry Unified Management Program database of the Japanese Society of Transplantation and Cellular Therapy and included 3898 transplantation-eligible patients with newly diagnosed multiple myeloma who underwent ASCT between 2007 and 2020 and were followed up until 2021. The SR rate was 4.7%, including 1.7% with PD. In survival time analysis for overall cases, a significant difference in PFS between the very good partial response (VGPR) and PR groups was observed, whereas there was no significant difference in overall survival (OS) between the VGPR and PR groups. Additionally, there was no significant difference in OS or PFS between the PR and SD groups. Therefore, we focused on the PR, SD, and PD groups, as the purpose of this retrospective study was to investigate the clinical significance of ASCT in patients with SR compared with those with PR. The median patient age was 60 years (range, 30 to 77 years). In total, 1605 (97.4%) patients received bortezomib, 561 (38.2%) received an immunomodulatory drug (ImiD), and 512 (34.9%) received both bortezomib and an ImiD. A total of 558 patients (38.0%) received reinduction therapy. There were 229 patients (37.7%) with high-risk cytogenetics (HRCA). With a median follow-up of 31.7 months, there was a significant difference in 30-month OS rates among the PR, SD, and PD groups (86.3%, 78.5%, and 39.4%, respectively; P <.001). OS was significantly shorter in the SD group compared to the PR group among the patients with HRCA (P < .001) and patients treated with reinduction therapy (P = .013). In the PD group, the 30-month OS and PFS rates were 39.4% and 17.9%, respectively. Finally, early PD within 12 months after ASCT was predictive of short OS, whereas OS without early PD even in the PD group was similar to that in the SD and PR groups. In conclusion, OS in the SR group was not always short, but SR in the HRCA and the reinduction therapy groups was predictive of short OS, so that therapeutic alternatives to ASCT are needed. OS in the PD group was significantly short, but ASCT improved clinical outcomes when early PD did not occur even in the PD group.

High-Dose Ambroxol Therapy in Type 1 Gaucher Disease Focusing on Patients with Poor Response to Enzyme Replacement Therapy or Substrate Reduction Therapy.

Ambroxol hydrochloride (ABX), an oral mucolytic drug available over the counter for many years, acts as a pharmacological chaperone for mutant glucocerebrosidase, albeit at higher doses. Proof-of-concept reports have been published over the past decade on all three types of Gaucher disease (GD). Here, we assess the safety and efficacy of 12 months of 600 mg ambroxol per day in three groups of Type 1 GD patients with a suboptimal response to enzyme replacement therapy (ERT) or substrate reduction therapy (SRT), defined as platelet count < 100 × 103/L, lumbar spine bone density T-score < -2.0, and/or LysoGb1 > 200 ng/mL, and for a group of naïve patients who had abnormal values in two of these three parameters. We enrolled 40 patients: 28 ERT- or SRT-treated, and 12 naïve. There were no severe adverse effects (AEs). There were 24 dropouts, mostly due to AEs (n = 12), all transient, and COVID-19 (n = 7). Among the 16 completers, 5 (31.2%) had a >20% increase in platelet count, 6 (37.5%) had a >0.2 increase in T-score, and 3 (18.7%) had a >20% decrease in Lyso-Gb1. This study expands the number of patients exposed to high-dose ABX, showing good safety and satisfactory efficacy, and provides an additional rationale for adding off-label ABX to the arsenal of therapies that could be offered to patients with GD1 and a suboptimal response or those unable to receive ERT or SRT.

Supplemental Pioglitazone to Patients of CML with Suboptimal TKI Response: A Pragmatic Pilot Study.

Tyrosine kinase inhibitors (TKIs) have improved outcomes of chronic myeloid leukemia (CML). However, 20-30% of patients require second-line TKIs following suboptimal response. The cost and adverse events limit their use in resource-constraint settings. We conducted a pilot study to ascertain the benefit of adding pioglitazone to TKIs with suboptimal response in real-world resource-constraint settings. In this pragmatic pilot study from 01 Jan 2017 to 31 July 2021, CML patients from a tertiary care center in North India with sub-optimal response to TKIs were additionally given pioglitazone after ruling out imatinib resistance mutation (n - 31). Pioglitazone was stopped if there was disease progression on follow-up, and second-line TKI was started. The data were analyzed with the intention-to-treat principle using JMP Ver.15.1.1. The median age of the study population was 54y (27-82), who were followed up for a median duration of 1023.5d (59-1117). Pioglitazone showed the benefit of one-log reduction in BCR-ABL in 89.7% of the study participants. 1y, 2y and 3y-PFS were 92.57%, 76.5%, and 68.3% respectively. During follow-up period, the disease progressed in 38.7%, of which two succumbed. No adverse events to Pioglitazone were documented. This study proved that adding Pioglitazone to the existing TKI regime in CML with sub-optimal response can benefit. The addition of Pioglitazone was well tolerated. Supplementary Information: The online version contains supplementary material available at 10.1007/s12288-022-01561-x.

GnRH-Agonist Ovulation Trigger in Patients Undergoing Controlled Ovarian Hyperstimulation for IVF with Stop GnRH-Agonist Combined with Multidose GnRH-Antagonist Protocol.

OBJECTIVE: This study aimed to characterize those patients undergoing the stop gonadotropin-releasing hormone (GnRH)-agonist combined with multidose GnRH-antagonist protocol, with suboptimal response to GnRH-agonist trigger in in vitro fertilization (IVF) cycles. DESIGN: This is a cohort study. SETTING: The study was conducted in a university hospital. PATIENTS: All consecutive women admitted to our IVF unit from February 2020 through November 2020 who reached the ovum pick-up stage were reviewed. INTERVENTIONS: Triggering final oocyte maturation by GnRH-ag alone (GnRH-ag trigger group), or combined with hCG (dual trigger group), in patients undergoing the stop GnRH-agonist combined with multidose GnRH-antagonist protocol was performed. MAIN OUTCOME MEASURE: The main outcome measure was LH level 12 h after the trigger. RESULTS: Five out of the 32 patients (15.6%) demonstrated suboptimal response as reflected by LH levels <15 IU/L 12 h after GnRH-agonist trigger. Moreover, while no differences were observed in oocyte recovery rate, maturity, or embryo quality between the different study groups (GnRH-ag trigger and dual trigger groups), those achieving a suboptimal response to the GnRH-agonist trigger (post-trigger LH <15 mIU/mL) demonstrated significantly higher number of follicles and peak estradiol levels at the day of trigger, compared to those with optimal response (post-trigger LH >15 mIU/mL). CONCLUSIONS: The stop GnRH-agonist combined with GnRH-antagonist protocol enables the substitution of hCG with GnRH-ag for final oocyte maturation. However, caution should be taken in high responders, where the dual trigger with small doses of hCG (1,000-1,500 IU) should be considered, aiming to avoid suboptimal response (post-trigger LH levels <15 IU/L).

Suboptimal Response to Tenofovir Alafenamide in Two Patients With HBeAg-Positive Hepatitis B: A Case Report.

Tenofovir alafenamide (TAF) is one of the most potent first-line nucleot(s)ide analogs for treating chronic hepatitis B virus (HBV) infections. To date, no cases of TAF drug resistance and/or suboptimal response have been reported. To our knowledge, this is the first report of two adult male patients presenting a suboptimal response response to TAF monotherapy. Our study indicates long-term observations and extensive data are needed to further evaluate the efficacy and safety of TAF, and highlights the need for the development of robust novel direct-acting antivirals and immune therapies for HBV.

Real-World Incidence of Suboptimal Response to Anti-Tumor Necrosis Factor Therapy for Ulcerative Colitis: A Nationwide Population-Based Study.

Background/Aims: Although anti-tumor necrosis factor (TNF) agents have been widely used to treat ulcerative colitis (UC), the real-world incidence of suboptimal response to anti-TNF agents has not been thoroughly investigated, especially among Asians. Methods: Using the Korean National Health Insurance database, we collected data on UC patients who initiated anti-TNF agents between July 1, 2014, and June 30, 2017. We assessed suboptimal responses, including anti-TNF discontinuation or dose escalation, switching to other biologics, augmentation with a non-biologic therapy, and the requirement for colectomy. Results: A total of 1,268 patients were included as new anti-TNF users (infliximab 713, adalimumab 433, golimumab 122). The proportion of patients who experienced at least one suboptimal response within 1 year among all patients was 63.5%, including 59.1%, 69.5%, and 68.0% of patients treated with infliximab, adalimumab, and golimumab, respectively. The cumulative incidences of at least one suboptimal response over time were 41.5%, 63.7%, 80.5%, and 87.1% at 6, 12, 24, and 36 months, respectively. Cox proportional hazards modeling revealed that adalimumab was associated with a higher risk of at least one suboptimal response (hazard ratio [HR], 1.29; 95% confidence interval [CI], 1.13 to 1.48), dose escalation (HR, 4.35; 95% CI, 2.97 to 6.38) and discontinuation (HR, 1.25; 95% CI, 1.03 to 1.52) than infliximab. Golimumab was associated with a higher risk of switching to other biologics than infliximab (HR, 1.78; 95% CI, 1.21 to 2.60). Conclusions: More than half of Korean UC patients had suboptimal responses to anti-TNF agents within 1 year. UC patients treated with infliximab might be less prone to suboptimal responses than those treated with adalimumab or golimumab.

Efficacy of fingolimod after switching from interferon ß-1a in an adolescent with multiple sclerosis: case report.

Pediatric-onset multiple sclerosis (POMS) accounts for approximately 2-10% of all cases of multiple sclerosis (MS) and is associated with higher levels of disease activity than adult-onset MS, including higher rates of clinical relapse and a greater incidence of new T2 lesions on magnetic resonance imaging (MRI). First-line therapy for POMS usually includes interferon ß or glatiramer acetate; however, there is limited evidence from randomized trials regarding the safety and efficacy of these disease-modifying drugs in pediatric patients. Fingolimod represents a second-line therapy option for relapsing-remitting MS in pediatric patients. Here, we report the case of a 14-year-old girl with a diagnosis of POMS who started interferon ß-1a as first-line therapy and then switched to fingolimod after 12 months due to radiologic progression and clinical relapse. The patient subsequently experienced clinical stability and showed minimal radiologic activity on follow-up MRI. Our case demonstrates the real-world clinical effectiveness and safety of fingolimod in pediatric MS and is in line with the results of previous randomized and observational studies.

Serum IL-21 levels predict HBeAg decline during rescue therapy in patients with partial response to nucleos(t)ide analogues.

To investigate whether IL-21 levels predict treatment outcomes of salvage therapy among patients with suboptimal response (SOR) to nucleos(t)ide analogues (NAs), serum IL-21 levels were measured in a prospective cohort of hepatitis B e antigen (HBeAg)-positive patients with SOR to antiviral therapy. The patients switched therapy to entecavir (ETV) with or without adefovir (ADV) for 104 weeks. IL-21 levels at treatment week 12 in patients who achieved HBeAg loss with undetectable levels of hepatitis B virus (HBV)-DNA at week 104 were the primary endpoint and the results were compared with those of corresponding patients without such an endpoint. Furthermore, IL-21 levels at treatment week 12 in patients who achieved an HBeAg-level decline at week 104 were assessed as the secondary endpoint. Among 24 enrolled patients with SOR to ADV (n=21), telbivudine (n=2) or ETV (n=1), the median (10-90th percentile) levels of HBeAg, HBV-DNA and ALT at baseline were 2.7 (0.2-3.1) log10 S/CO, 5.2 (3.5-7.5) log10 IU/ml and 0.9 (0.5-3.1) upper limit of normal, respectively. Comparison of the patients with and without HBeAg loss at week 104 indicated that their mean IL-21 levels did not significantly differ at week 12 (63.0±14.4 vs. 55.9±10.5 pg/ml; P=0.26). In the secondary endpoint analyses of patients with and without HBeAg level decline, the elevated levels of IL-21 at the first 12 weeks were significantly higher in the decline group (15.6±8.3 vs. 3.1±13.2 pg/ml; P=0.03). Following adjustment for confounding factors, the elevated levels of IL-21 from baseline to week 12 independently predicted an HBeAg level decline at week 104 (odds ratio=1.137, R2=0.23; P=0.047). In conclusion, the serum IL-21 levels at the first 12 weeks during the salvage therapy independently predicted HBeAg level decline at treatment week 104 in patients with SOR to NAs (ClinicalTrials.gov identifier: NCT01829685; date of registration, April 2013).

Does the interval between the last GnRH antagonist dose and the GnRH agonist trigger affect oocyte recovery and maturation rates?

RESEARCH QUESTION: Does the time interval between the last gonadotrophin-releasing hormone (GnRH) antagonist dose and the GnRH agonist trigger affect the efficacy of the trigger in IVF treatments? DESIGN: This retrospective cohort study involved 53 normogonadotrophic patients undergoing GnRH antagonist-based IVF cycles, in a single academic centre between June 2019 and February 2020, in whom a GnRH agonist was used for final ovulation triggering. RESULTS: The mean time interval between the last GnRH antagonist dose and GnRH agonist triggering was 4.6 ± 2.7 h (range 1-12 h). There was no correlation between the antagonist-agonist interval and the oocyte recovery rate (Spearman's correlation coefficient [CC] 0.02, P = 0.89) or metaphase II oocyte rate (CC 0.006, P = 0.96). On multivariate analysis, the antagonist-agonist interval was not associated with treatment outcomes, after adjusting for the women's age and body mass index. CONCLUSIONS: This is the first study assessing the efficacy of the GnRH agonist trigger in relation to the time interval between the last GnRH antagonist dose and the agonist trigger within the first half-life of the GnRH antagonist and in less than 12 h. In normogonadotrophic patients, a GnRH agonist trigger can successfully induce an effective LH surge and oocyte maturation and release, irrespective of the time interval between the last antagonist dose and the agonist trigger. Once confirmed by randomized clinical trials, these finding may simplify treatment, improve patients' convenience and promote patient adherence to treatment.

Hepatitis B virus X gene mutants emerge during antiviral therapy and increase cccDNA levels to compensate for replication suppression.

BACKGROUND: Hepatitis B virus (HBV) X gene (HBx) mutants can develop during the natural course of chronic HBV infection. However, little is known about whether the emergence of HBx mutants during long-term antiviral therapy is an adaptation of HBV to antiviral stress. This study was to identify HBx mutants that emerged in patients experiencing Lamivudine resistance or suboptimal treatment. METHODS: Forty-six Lamivudine-resistant patients and 46 patients with suboptimal treatment responses to Entecavir were enrolled in this study. HBx mutants were identified by sequence analysis and their roles in the HBV replication cycle were characterized. RESULTS: We show that deletion/truncation/insertion mutations were only detected in the Lamivudine resistance group, while synonymous mutations were found in both groups. Follow-up analyses revealed that five patients in the Lamivudine group developed hepatocellular carcinoma, while patients in the Entecavir group did not. These mutants were characterized by a significant decrease in transactivation of the pre-S1 promoter, and varying effects on transactivation of the X promoter. Co-transfection of HBx-mutant plasmid and HBV replication-competent clone into HepG2 cells resulted in increased nuclear-to-cytoplamic HBV core antigen, HBV-DNA ratios, and nuclear covalently closed circular DNA (cccDNA). Antiviral drug sensitivity assays revealed that these mutants exhibited a compensatory effect to counteract antiviral drug suppression, resulting in elevated secretory HBV-DNA levels. CONCLUSIONS: Our study demonstrates that HBx mutants can emerge during Lamivudine or Entecavir therapy. These mutants exhibit altered transactivation of the HBV pre-S1 and X promoters, leading to increased cccDNA levels to compensate for replication suppression.

Suboptimal response to GnRH-agonist trigger during oocyte cryopreservation: a case series.

BACKGROUND: Random-start, controlled ovarian stimulation (COS) has advanced the field of fertility preservation, allowing patients to expedite fertility treatment and avoid further delays to their cancer therapy. This novel approach allows patients to initiate ovarian stimulation at any point, regardless of where they are in their menstrual cycle. Luteal-phase start (LPS) protocols describe treatment cycles where COS is initiated during the luteal-phase of the menstrual cycle. LPS protocols have not been studied or optimized to the same degree as conventional, early-follicular COS. Particularly, there is a paucity of evidence evaluating treatment outcomes using different trigger medications in LPS protocols. The present study aims to evaluate the efficacy of using a GnRH agonist (GnRH-a) trigger in patients undergoing oocyte cryopreservation in LPS protocols. METHODS: This descriptive case series describes two patients, recently diagnosed with cancer, who underwent oocyte cryopreservation using an LPS protocol and a GnRH-a trigger at a university-affiliated, academic center. RESULTS: The patients described in our case series both failed to adequately respond to a GnRH-a trigger, based on their serum levels of luteinizing hormone (LH) and progesterone 12 h after their GnRH-a trigger. They both required a single rescue dose of human chorionic gonadotropin (hCG). CONCLUSIONS: These findings highlight the potential risk of a suboptimal response to a GnRH-a trigger in patients undergoing LPS, controlled ovarian stimulation for oocyte cryopreservation. This risk might be attributed to the downregulation of GnRH receptors by elevated serum progesterone levels during the luteal phase. Currently, there is insufficient evidence to recommend for or against the use of a GnRH-a trigger during LPS controlled ovarian stimulation. This case series offers a number of management strategies to mitigate this risk and emphasizes the need for further research in this area.