Slipping Away: Slippage in hazard ratios over datacuts and its impact on immuno-oncology combination economic evaluations.

OBJECTIVES: This study examines the impact of slippage in hazard ratios (tending towards the null over subsequent datacuts) for overall survival for combination treatment with a PD-(L)-1 inhibitor and a tyrosine kinase inhibitor (TKI) in advanced renal cell carcinoma (RCC). METHODS: Four trials' Kaplan Meier curves were digitized over several datacuts and fitted with standard parametric curves. Accuracy and consistency of early data projections were calculated versus observed restricted mean survival time (RMST) and fitted lifetime survival from the longest follow-up datacut. The change in economically justifiable price (eJP) was calculated fitting the same curve to both arms, using an assumed average utility of 0.7 and willingness-to-pay threshold of £30,000 per QALY. The eJP represents the lifetime justifiable price increment for the new treatment, including differences in drug, administration and disease-related costs. RESULTS: Slippage in hazard ratios was observed in trials with longer follow-up, potentially influenced by subsequent PD-(L)-1 use after TKI monotherapy, early stoppage of PD-(L)-1 and development of resistance. Lognormal and log-logistic curves were more likely to over-predict the observed result; Gompertz and gamma under-predicted. Statistical measures for goodness of fit did not reliably predict the RMST. Large differences in incremental mean life years were observed between even the penultimate and final datacuts for the majority of the fitted curves, meaningfully impacting the eJP. CONCLUSIONS: This work demonstrates the challenge in predicting treatment benefits with novel therapies using immature data. Incorporating information on the impact of subsequent treatment is likely to play a key role in improving predictions.

Passiflora incarnata L., herba, in benzodiazepine tapering: long-term safety and efficacy in a real-world setting.

Introduction: Chronic and inappropriate benzodiazepine (BDZ) prescription and intake represent an important health and social concern worldwide. The aim of our study was to investigate the safety and efficacy of P. incarnata L., herba in reducing BDZ misuse in a real-world population of depressed and anxious patients in a long-term treatment with BDZs. Methods: Over an 18-month period (from July 2021 to December 2022), we previously conducted a retrospective and naturalistic study on euthymic outpatients with a diagnosis of anxiety or depression and chronically taking BDZs. In this study we contacted patients 12 months after their enrollment in the previous study to assess their disease status and their BDZs and P. incarnata intake. Results: Our findings support the effectiveness of a dry extract of P. incarnata L., herba, as an add-on treatment during BDZ tapering in patients with anxiety or depression. We confirmed this effect to be sustained over time, and P. incarnata showed to be easily discontinued with no rebound, withdrawal or psychological dependence effect. The absence of side effects and adverse events confirmed the safety of P. incarnata in a real-world population. Personality disorders confirmed to be a relevant risk factor for maintaining addictive behavior, even when symptoms associated to withdrawal seem to be not particularly relevant. Discussion: We confirmed the possible effectiveness of P. incarnata as an add-on treatment in BDZ reduction. Further studies may be helpful to better investigate the promising properties of P. incarnata in the management of relevant clinical issues, such as anxiety disorders and addiction, that are classically known to benefit from GABAergic treatments.

LONG-TERM REPEATED BOTULINUM TOXIN A TREATMENT OVER 12 YEARS GRADUALLY CHANGES GAIT CHARACTERISTICS: SINGLE-CASE STUDY.

Objective: To demonstrate the long-term efficacy of repeated botulinum toxin A injections into the same muscles for ameliorating lower limb spasticity and gait function. Design: Single-case study. Patient: A 36-year-old woman with right cerebral haemorrhage received her first botulinum toxin A injection 1,296 days after onset. The patient underwent 30 treatments over 12 years after the first injection to improve upper and lower limb spasticity and abnormal gait patterns. The mean duration between injections was 147 days. Methods: The Modified Ashworth Scale, passive range of motion, gait velocity, and degree of abnormal gait patterns during treadmill gait were evaluated pre-injection and at 2, 6, and 12 weeks after every injection. Results: The follow-up period showed no injection-related adverse events. Comfortable overground gait velocity gradually improved over 30 injections. The Modified Ashworth Scale and passive range of motion improved after each injection. Pre-injection values of the degree of pes varus, circumduction, hip hiking, and knee extensor thrust improved gradually. However, the degree of contralateral vaulting, excessive lateral shift of the trunk, and insufficient knee flexion did not improve after 30 injections. Conclusion: Repeated botulinum toxin A injections effectively improve abnormal gait patterns, even when a single injection cannot change these values.

Botulinum toxin A (BoNTA) is used to treat spasticity in the arms and legs of adult patients. We report a case of a woman who was treated with BoNTA 30 times over 12 years to improve limb spasticity and abnormal gait patterns. The range of motion improved after each injection, and some other features of her gait improved gradually. We did not observe any injection-related adverse events during the follow-up period. We conclude that repeated BoNTA injections can effectively improve some abnormal gait patterns and comfortable overground gait velocity, even when a single injection cannot change these values. Cumulative effects were also shown. The combination of BoNTA and rehabilitation may lead to better results.

Long-term Efficacy and Safety of Sodium Oxybate in Treating Alcohol Use Disorder: A Systematic Review and Meta-Analysis.

BACKGROUND: Worldwide, three million deaths each year are reported due to the harmful use of alcohol. To date, only a few drugs have been approved for the treatment of Alcohol Use Disorder (AUD). This systematic review and meta-analysis aim to assess the long-term efficacy and safety of sodium oxybate (SMO) treatment in patients with AUD. METHODS: We followed the PRISMA statement guidelines and searched PubMed and ISI Web of Science to retrieve the studies of interest. In total, 13 studies on long-term (>12 weeks) SMO administra- tion in patients with AUD were included in this systematic review, and 7 were included in the meta- analysis. RESULTS: Overall, the abstinence rate after 12 weeks of treatment was similar in the SMO and placebo groups, while it was significantly in favour of SMO compared to Naltrexone (NTX). The completion rate was similar in all three conditions. Mean corpuscular volume (MCV) levels favoured SMO over NTX, while Alcohol Craving Scale (ACS) scores did not favour SMO. The incidence of adverse reactions varied widely between studies. CONCLUSION: SMO in the chronic treatment of patients with AUD showed no superiority to placebo in our analysis of published RCTs, although many observational studies reported its beneficial effect in the long term. On the contrary, SMO was superior to NTX treatment on abstinence. The rate of study completion was similar in the three groups. Safety was not an issue in any of the studies included. Further studies are needed to better assess SMO efficacy and safety in the long term.

Embodied suffering: Uncovering the illness experiences of patients with severe psoriasis.

BACKGROUND: The visibility of skin lesions significantly burdens people with psoriasis, leading to social hostility and numerous emotional and psychological problems. These issues adversely affect self-esteem, can result in chronic mental health challenges and cause numerous life problems. This study aimed to explore patients' long-term experiences with severe psoriasis. METHODS: A qualitative study was conducted with 20 patients with psoriasis (PASI ≥12) recruited from general and specialist dermatology practices in a regional teaching hospital in Taiwan. Interviews lasted 60-90 min and data were analysed using content analysis. FINDINGS: A core theme emerged: 'Embodied suffering-life worse than death'. This overarching concept comprised three interrelated themes: (i) Experiencing physical suffering, (ii) Experiencing psychological suffering and (iii) Experiencing the stigma of suffering. CONCLUSION: This study highlights the holistic nature of suffering among individuals with severe psoriasis. It emphasises the need for healthcare professionals to consider the entirety of a patient's circumstances when addressing their suffering.

A 3-Year Experience with Tildrakizumab Treatment for Patients with Plaque Psoriasis in Clinical Practice.

INTRODUCTION: The efficacy and safety of tildrakizumab for the treatment of plaque psoriasis were demonstrated by randomized clinical studies, but the reappraisal of prolonged experiences in the clinical practice helps to optimize the use of this biologic drug. The aim of this study was to evaluate the long-term efficacy of tildrakizumab in patients with moderate-to-severe psoriasis in the real world. METHODS: This is a long-term retrospective observational study in a real-life setting. Overall, 136 adult patients with moderate-to-severe plaque psoriasis and treated with tildrakizumab were included. RESULTS: One hundred percent reduction of Psoriasis Area Severity Index (PASI100) was reached by 21.7% of patients at 4 weeks of therapy and by 51.2% at week 16, and the proportion of patients with this improvement was between 66.9% and 64.5% from 36 weeks to 3 years. The mean PASI of the cohort progressively improved from 12.6 at baseline to 1.8 at week 36 and was stable at 1 year, 2 years and 3 years. We could not confirm a previous observation that patients naïve to biologic had a better response, but we observed that those with a short history of psoriasis had a higher probability of 90% PASI reduction (PASI90) or PASI 100 within 36 weeks, suggesting that early treatment could be useful. CONCLUSION: This long-term observation in the real life of patients with moderate-to-severe plaque psoriasis receiving tildrakizumab 100 mg showed that PASI100 can be obtained in a high proportion of patients by week 36 and be maintained for up to 3 years.

Long-term exposure and response to azacitidine for post-hematopoietic stem cell transplantation relapse of early T-cell precursor acute lymphoblastic leukemia: a case report and review of the literature.

Adult T-cell acute lymphoblastic leukemia has a poor outcome after relapse. Because the subtype of early T-cell precursor displays characteristics close of those of acute myeloid leukemia, such as epigenetic dysregulation, hypomethylating agents might prove of interest. We describe the case of a patient relapsing 3 months only after allogeneic stem cell transplantation who achieved complete remission on azacitidine, and is still on therapy 9 years later. We discuss the biological background of this very long-term response, underlining the immunological effects of hypomethylating agents, and the perspectives opened by combination of hypomethylating agents with other drugs such as venetoclax.

Improvement of bone mineral density and new vertebral fractures during 8 years of TNF-α inhibition in patients with axial spondyloarthritis.

OBJECTIVE: In our prospective cohort with standardized bi-annual measurements of bone mineral density (BMD) and spinal radiographs, we evaluated the long-term course of BMD and the development of radiographic vertebral fractures (VFs) during 8 years of TNFi treatment in patients with radiographic axial spondyloarthritis (r-axSpA). METHODS: Consecutive axSpA patients from the GLAS cohort receiving TNFi for ≥8 years were included. Patients who received anti-osteoporotic treatment were excluded. Lumbar spine (LS) BMD was assessed at baseline, 1 year and bi-annually using DEXA. Radiographic VFs were evaluated using the Genant classification. RESULTS: 126 axSpA patients were included; 75 % male, mean age 42 ± 11 years, ASDAS 3.8 ± 0.8, median LS BMD Z-score -0.5 (IQR -1.4-0.7) and 20 % had radiographic VFs at baseline. Disease activity improved rapidly and sustained. LS BMD Z-score improved significantly up to 4 years compared to the previous time point and sustained thereafter. Median percentage of improvement compared to baseline was 8.9 % (2.8-15.8) and 7.2 % (2.2-14.7) after 4 and 8 years, respectively. Of 90 patients with baseline and 8-year radiographs, 14 (16 %) developed new VFs and 5 (6 %) showed an increase in severity of existing VFs. Of all 44 VFs present at 8 years, 30 % were grade 2 (n = 12) or grade 3 (n = 1). CONCLUSION: In r-axSpA patients treated with TNFi for 8 years, LS BMD Z-score increased significantly, especially during the first 4 year of treatment. Radiographic VFs continued to develop or progressed, irrespective of improvement in BMD. Therefore, clinical attention for trabecular bone loss is important in daily clinical practice.

Long-term survival outcome of childhood acute myeloid leukemia: a 43-year experience in Thailand, a resource-limited country.

Although there have been advances in treating pediatric patients with acute myeloid leukemia (AML) in developed countries, outcomes in low- to middle-income countries remain poor. The goal of this study was to investigate the outcomes in children with AML who were treated at a tertiary care center in Thailand. We divided the study into 4 research periods based on the chemotherapy protocols employed. The 5-year probabilities of event-free survival (pEFS) rates for periods 1-4 were 19.0%, 20.6%, 17.4%, and 37.3% (p value = 0.32), while the 5-year probabilities of overall survival (pOS) rates were 19.0%, 24.7%, 18.7%, and 42.5% (p value = 0.18), respectively. The multivariable model indicated an improvement in 5-year pOS between periods 1 and 4 (p value = 0.04). Age, white blood cell count, and study period were significant predictors of survival outcomes. The pOS of AML patients improved over time, increasing from 19.0% to 42.5%.

Hematological and Biochemical Effects Associated with Prolonged Administration of the NSAID Firocoxib in Adult Healthy Horses.

Non-steroidal anti-inflammatory drugs (NSAIDs) represent one of the most commonly used classes of drugs in both human and veterinary medicine. However, many clinical side effects have been observed, especially when treatment has been prolonged. While the anti-inflammatory efficacy and safety of repeated administration of firocoxib (Previcox®), which is a selective NSAID COX-2 inhibitor, has been evaluated for short-term use (one to fourteen days), its clinical relevance for longer-term use is not known. As a preliminary study, healthy, adult male and female horses (n = 7) were treated with firocoxib for 40 days concomitant with the collection of blood samples encompassing treatment to assess hematological and biochemical endpoints. Daily oral administration of firocoxib was performed with one 57 mg tablet/animal (0.11-0.14 mg/kg), which was crushed and mixed with feed. Blood samples were collected one day before treatment (D0 or basal sample), during (D10, D20, D30, and D40), and after treatment (D55 and D70). Results indicated some hematological and biochemical effects were significantly reduced (p < 0.05) towards the end of treatment on D40 relative to pre-treatment or baseline values on D0. Post-treatment, all values returned to pre-treatment values within 30 days without any apparent clinical adversities. In conclusion, while these preliminary results are favorable for prolonged use of firocoxib in horses, future studies are required to evaluate the efficacy of prolonged use accompanied with other clinically relevant endpoints in healthy as well as injured or diseased animals.

Impact of relugolix combination therapy on functioning and quality of life in women with endometriosis-associated pain.

OBJECTIVE: To evaluate the effect of relugolix combination therapy (relugolix CT; 40 mg relugolix, 1 mg estradiol, and 0.5 mg norethisterone acetate) for up to 2 years in the SPIRIT long-term extension study on functioning and health-related quality of life (QoL), using the Endometriosis Health Profile (EHP)-30 questionnaire, and assess how changes in QoL domains correlated with improvements in dysmenorrhea as well as nonmenstrual pelvic pain (NMPP). DESIGN: Long-term extension study of the SPIRIT phase 3 trials. SETTING: Clinics and University Hospitals. PATIENT(S): Premenopausal women with moderate-to-severe endometriosis pain who previously completed the randomized SPIRIT trials were eligible to enroll in an 80-week long-term extension where all women received relugolix CT. INTERVENTION(S): Relugolix CT (relugolix 40 mg, estradiol 1 mg, and norethindrone acetate 0.5 mg). MAIN OUTCOME MEASURE(S): Least squares (LS) mean changes in the EHP-30 domain and total scores from baseline (pivotal) were analyzed using a mixed-effects model. Results up to 104 weeks are reported by a pivotal trial treatment group with a focus on the relugolix CT group (i.e., relugolix CT or placebo for 24 weeks, or delayed relugolix CT [relugolix 40 mg monotherapy for 12 weeks, followed by relugolix CT for 12 weeks]). In addition, the relationships between changes in dysmenorrhea and NMPP as well as changes in EHP-30 scores were assessed. RESULT(S): In the 277 women treated with relugolix CT, LS mean EHP-30 pain domain scores improved by 57.8% (LS mean change: -32.8; 95% CI: -35.5, -30.1), 66.4% (LS mean change: -37.7; 95% CI: -40.3, -35.0), and 72.2% (LS mean change: -41.3; 95% CI: -43.9, -38.7) at weeks 24, 52, and 104, respectively. The proportions of women with clinically meaningful improvement in the EHP-30 pain domain were 75.9%, 83.6%, and 88.6% at weeks 24, 52, and 104, respectively. Non-pain EHP-30 domain and total scores likewise improved. A positive correlation between changes in dysmenorrhea/NMPP and all EHP-30 domain scores was observed. Results were similar for the delayed relugolix CT and placebo → relugolix CT groups. CONCLUSION(S): Sustained reduction of endometriosis-associated pain with relugolix CT observed up to 104 weeks was accompanied by improvements in functioning and health-related QoL. These findings complement the results of the pivotal SPIRIT trials, which showed that relugolix combination therapy significantly reduced dysmenorrhea, NMPP, and dyspareunia vs. placebo in premenopausal women with endometriosis-associated pain. CLINICAL TRIAL REGISTRATION NUMBER: Registration/clinicaltrials.gov identifier: SPIRIT Extension Study (NCT03654274).

Effect of long-term inorganic arsenic exposure on erythropoietin production in vitro.

Arsenic is widely present in the environment in trivalent and pentavalent forms; long-term arsenic exposure due to environmental pollution has become a problem. Previous reports have shown that 24-h exposure to arsenate (as pentavalent arsenic) potentiates erythropoietin (EPO) production via reactive oxygen species (ROS) in EPO-producing HepG2 cells. However, the effects of long-term arsenate exposure on EPO production remain unclear. In HepG2 cells subcultured for 3 weeks in the presence of arsenate, EPO mRNA levels were lower than those in untreated cells. Levels of ARSENITE METHYLTRANSFERASE mRNA, as well as those of Nuclear factor erythroid 2-related factor 2, glutathione, and superoxide dismutase proteins, were increased compared to untreated cells, but levels of malondialdehyde were not significantly altered. Thus, long-term exposure to arsenate enhances ROS scavenging, suggesting that the ROS-induced accumulation of EPO mRNA is attenuated by arsenate exposure. The induction of EPO accumulation by hypoxia also was attenuated by long-term arsenate exposure, suggesting an impairment in responsivity of EPO production. Furthermore, mRNA levels of SIRTUIN-1, which affects EPO transcription, were potentiated by long-term arsenate exposure. These results suggest that long-term arsenate exposure has multiple, distinct effects on EPO production in vitro.

Biodegradable Mesoporous Organosilica-Based Nanostabilizer Targeting Mast Cells for Long-Term Treatment of Allergic Diseases.

Allergic diseases are immune system dysfunctions mediated by mast cell (MC) activation stimulated by specific allergens. However, current small molecular MC stabilizers for allergic disease prevention often require multiple doses over a long period of time and are associated with serious side effects. Herein, we develop a diselenide-bridged mesoporous silica nanostabilizer, proving that it could specifically target sensitized MCs via the recognition of IgE aptamer and IgE. Meantime, the IgE aptamer can also mitigate allergic reactions by preventing re-exposure of allergens from the surface of sensitized MCs. Furthermore, the diselenide-bridged scaffold can be reduced by the intracellular excessive ROS, subsequently achieving redox homeostasis via ROS depletion. Finally, the precise release of small molecular MC stabilizers along with the biodegradation of nanocarrier can stabilize the membranes of MCs. In vivo assays in passive cutaneous anaphylactic (PCA) and allergic rhinitis (AR) mice indicated that our current strategy further endowed it with a high efficacy, long-term therapeutic time window, as well as negligible inflammatory side effects for allergic diseases, offering a promising therapeutic strategy for the clinical generalization of allergic diseases.

Localized anaplastic lymphoma kinase-positive histiocytosis in a cerebellar hemisphere with long-term treatment: illustrative case.

BACKGROUND: Anaplastic lymphoma kinase (ALK)-positive histiocytosis (ALK-H) is an emerging entity in the category of histiocytic neoplasms that was first reported as a multisystemic disease in three infants in 2008. The clinicopathological spectrum of ALK-H has been expanded to include localized disorders in specific organs, but the features of this subtype are not well known. The authors report a case of ALK-H localized in the central nervous system that was difficult to treat and review the relevant literature. OBSERVATIONS: The authors reviewed archival histiocytic tumors at their institute and found a pediatric case of ALK-H localized in a cerebellar hemisphere that had previously been reported as histiocytic sarcoma. Chemotherapy (approximately 1 year), additional surgery, and conventional chemotherapy (approximately 2.5 years) led to clinical remission, and maintenance chemotherapy was continued (approximately 1.5 years). Three years after completing treatment, a high-grade glioma was found in a cerebral hemisphere, and the patient died of the glioma 2 years later. LESSONS: Although the prognosis of ALK-H is generally good according to prior cases, the authors' case required long-term conventional chemotherapy, suggesting the tumor displayed aggressive characteristics. Early administration of ALK inhibitors may be necessary.

Unmet challenges in cystic fibrosis treatment with modulators.

INTRODUCTION: 'Highly effective' modulator therapies (HEMTs) have radically changed the Cystic Fibrosis (CF) therapeutic landscape. AREAS COVERED: A comprehensive search strategy was undertaken to assess impact of HEMT in life of pwCF, treatment challenges in specific populations such as very young children, and current knowledge gaps. EXPERT OPINION: HEMTs are prescribed for pwCF with definite genotypes. The heterogeneity of variants complicates treatment possibilities and around 10% of pwCF worldwide remains ineligible. Genotype-specific treatments are prompting theratyping and personalized medicine strategies. Improvement in lung function and quality of life increase survival rates, shifting CF from a pediatric to an adult disease. This implies new studies addressing long-term efficacy, side effects, emergence of adult co-morbidities and possible drug-drug interactions. More sensitive and predictive biomarkers for both efficacy and toxicity are warranted. As HEMTs cross the placenta and are found in breast milk, studies addressing the potential consequences of treatment during pregnancy and breastfeeding are urgently needed. Finally, although the treatment and expected outcomes of CF have improved dramatically in high- and middle-income countries, lack of access in low-income countries to these life-changing medicines highlights inequity of care worldwide.

Estimating treatment effect in randomized trial after control to treatment crossover using external controls.

In clinical trials, it is common to design a study that permits the administration of an experimental treatment to participants in the placebo or standard of care group post primary endpoint. This is often seen in the open-label extension phase of a phase III, pivotal study of the new medicine, where the focus is on assessing long-term safety and efficacy. With the availability of external controls, proper estimation and inference of long-term treatment effect during the open-label extension phase in the absence of placebo-controlled patients are now feasible. Within the framework of causal inference, we propose several difference-in-differences (DID) type methods and a synthetic control method (SCM) for the combination of randomized controlled trials and external controls. Our realistic simulation studies demonstrate the desirable performance of the proposed estimators in a variety of practical scenarios. In particular, DID methods outperform SCM and are the recommended methods of choice. An empirical application of the methods is demonstrated through a phase III clinical trial in rare disease.

Low-dose-rate brachytherapy and long-term treatment outcomes in patients younger than 60 years of age.

Purpose: Low-dose-rate (LDR) brachytherapy in young men remains controversial amongst urologists due to their concerns regarding long-term biochemical control and treatment-related toxicities. The purpose of this study was to evaluate the treatment outcomes of men under 60 years of age who underwent LDR brachytherapy with iodine-125 (125I) for clinically localized low- to intermediate-risk prostate cancer. Material and methods: All consecutive patients with clinically localized prostate cancer treated at our institution from 2003 to 2016 with 125I monotherapy were included in the study. Prescription dose was 145.0 Gy modified peripheral loading (MPD). All patients were assessed for biochemical progression-free survival using Phoenix definition (nadir +2 ng/ml), clinical progression-free survival, overall survival (OS), and any associated treatment toxicity. Results: A total of 161 patients were included, with a median follow-up of 6.8 years (range, 3-14.54 years). Median age at implant was 57 years (range, 53-59 years). Mean prostate specific antigen (PSA) level at diagnosis was 4.43 ng/ml (SD = 2.29). Majority of men had low-risk prostate cancer (70.2%). Biochemical progression-free survival at 8 years was 94% for the entire cohort. Median PSA at 4 years was 0.169 (IQR, 0.096-0.360), with 45% of patients having a PSA greater than 0.2. OS was 96.9%, with 5 deaths reported but only one was secondary to prostate cancer. Late grade > 2 genitourinary toxicities were reported in 18 patients (11.2%). Three patients (1.9%) developed secondary cancers, all considered unrelated to their LDR brachytherapy. Conclusions: With excellent long-term treatment outcomes and minimal associated toxicities, our results showed that LDR brachytherapy can be an effective treatment of choice in younger men.

Long-term treatment for endometriosis with dienogest: efficacy, side effects and tolerability.

BACKGROUND: Dienogest (DNG) improves endometriosis-associated pain (EAP) and patients' quality of life; however, the modern cornerstone of the management of endometriosis is the long-term adherence of the patient to medical treatment. OBJECTIVE: To evaluate DNG as a long-term treatment of endometriosis, focusing on patients' compliance and side effects, also correlating with different phenotypes of endometriosis. METHODS: This was a cohort study on a group of patients with endometriosis (n = 114) undergoing long-term treatment with DNG. During the follow up visits (12, 24, and 36 months) patients were interviewed: an assessment of EAP was performed by using a visual analogue scale (VAS) and side effects were evaluated by using a specific questionnaire of 15 items. RESULTS: At 12 months, 81% were continuing the DNG treatment, with a significant reduction of dysmenorrhea, dyspareunia, dyschezia, dysuria and chronic pelvic pain. Of the 19% that discontinued the treatment: 62% was due to spotting, reduced sexual drive, vaginal dryness, and mood disorders. The improvement of EAP was significant for all endometriosis phenotypes, especially in patients with the deep infiltrating type. At 36 months, 73% of patients were continuing the treatment, showing a significant reduction of EAP through the follow up, along with an increase of amenorrhea (from 77% at 12 months to 93% at 36 months). In a subgroup of 18 patients with gastrointestinal disorders, DNG was administered vaginally at the same dosage, showing similar results in terms of efficacy and tolerability. CONCLUSIONS: DNG was an effective long-term treatment for all endometriosis phenotypes, with few side effects that caused the discontinuation of the treatment mainly during the first year. Thus, the course of 1-year treatment is a predictive indicator for long-term treatment adherence.

Safe long-term therapy of Cushing's syndrome over 37 years with mitotane.

While suggested, surgery is not always possible as a first-line treatment of Cushing's Disease (CD). In such cases, patients require medical therapy in order to prevent complications resulting from hypercortisolism. Although there has been a wide expansion in pharmacological options in recent years, mitotane was the agent of choice for treating hypercortisolism decades ago. Due to the introduction of other therapies, long-term experience with mitotane remains limited. Here, we report the case of a woman with CD who was treated with mitotane for 37 years. During the treatment period, biochemical and clinical disease control was achieved and the patient had two uncomplicated pregnancies. Drug-related side effects remained moderate and could be controlled by several dose adjustments. Our case highlights the ability of mitotane to allow an effective control of hypercortisolism and to represent a safe treatment option in special situations where CD requires an alternative therapeutic approach. Furthermore, we provide a literature review of the long-term use of mitotane and reported cases of pregnancy in the context of mitotane therapy.

Non-Infectious Pneumonitis and Acute Respiratory Distress Syndrome in a Patient on Ustekinumab Treatment: Case Report and Literature Review.

Ustekinumab is a monoclonal antibody targeting the p40 subunit of IL-12 and IL-23, approved for treating psoriasis, psoriatic arthritis, and inflammatory bowel disease. Despite a remarkable success in treating chronic inflammatory conditions and a generally favorable safety profile, its role in inducing rare adverse events, such as interstitial pneumonia and acute respiratory distress syndrome (ARDS), remains largely uncharted. We report a case of a 66-year-old male patient treated with Ustekinumab for severe psoriasis who, after almost two years of treatment, developed dyspnea, asthenia, and fever progressing to non-infectious pneumonia and ARDS leading to ICU admission. Moreover, we conducted a literature review on Ustekinumab-associated pulmonary complications. Our case underscores the importance of appropriate and long-term clinical monitoring in patients on Ustekinumab treatment, particularly considering the potential lung complications. The possibility of non-infectious pneumonitis should be considered alongside infectious causes, facilitating prompt management in the case of negative infectious screening. Additionally, the severity of ARDS underscores the importance of timely recognition and proper management. Further investigations are recommended to investigate the immunological basis of Ustekinumab-induced ARDS for designing appropriate monitoring strategies.