Search Results (47)

Nephrogenic diabetes insipidus (NDI) is a rare hereditary disorder characterized by renal resistance to arginine vasopressin (AVP), resulting in the kidneys’ inability to concentrate urine. Approximately 90% of NDI cases follow an X-linked inheritance pattern and are associated with pathogenic variants in the AVPR2 gene, which encodes the vasopressin receptor type 2. The remaining 10% are attributed to mutations in the AQP2 gene, which encodes aquaporin-2, and may follow either autosomal dominant or recessive inheritance patterns. We present the case of a male infant, younger than nine months of age, who was clinically diagnosed with NDI at six months. The patient presented recurrent episodes of polydipsia, polyuria, dehydration, hypernatremia, and persistently low urine osmolality. Despite adjustments in pharmacologic treatment and strict monitoring of urinary output, the clinical response remained suboptimal. Given the lack of improvement and the radiological finding of an absent posterior pituitary (neurohypophysis), the possibility of coexistent central diabetes insipidus (CDI) was raised, prompting a therapeutic trial with desmopressin. Nevertheless, in the absence of clinical improvement, desmopressin was discontinued. The patient’s management was continued with hydrochlorothiazide, ibuprofen, and a high-calorie diet restricted in sodium and protein, resulting in progressive clinical stabilization. Whole-exome sequencing identified a novel homozygous missense variant in the AQP2 gene (c.398T > A; p.Val133Glu), classified as likely pathogenic according to the American College of Medical Genetics and Genomics (ACMG) criteria: PM2 (absent from population databases), PP2 (missense variant in a gene with a low rate of benign missense variation), and PP3 (multiple lines of computational evidence supporting a deleterious effect)]. NDI is typically diagnosed during early infancy due to the early onset of symptoms and the potential for severe complications if left untreated. In this case, although initial clinical suspicion included concomitant CDI, the timely initiation of supportive management and the subsequent incorporation of molecular diagnostics facilitated a definitive diagnosis. The identification of a previously unreported homozygous variant in AQP2 contributed to diagnostic confirmation and therapeutic decision-making. The diagnosis and comprehensive management of NDI within the context of polyuria-polydipsia syndrome necessitates a multidisciplinary approach, integrating clinical evaluation with advanced molecular diagnostics. The novel AQP2 c.398T > A (p.Val133Glu) variant described herein was associated with early and severe clinical manifestations, underscoring the importance of genetic testing in atypical or treatment-refractory presentations of diabetes insipidus. Full article

Background/Objectives: This study aimed to assess real-world toxicity and efficacy data of patients with early and advanced breast cancer (BC) who received treatment with abemaciclib. Methods: This was a prospective/retrospective multi-institutional collection of clinicopathological, toxicity, and outcome data from patients with early or metastatic hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative BC who received treatment with abemaciclib in combination with endocrine therapy in departments of oncology in Greece. Treatment combinations of abemaciclib with any endocrine therapy were accepted. The primary end point was toxicity rate in all patients of the study. Results: From June/2021 to May/2024, 245 women received abemaciclib/endocrine combination therapy; the median age was 57 years. Of these, 169 (69%) received abemaciclib as adjuvant therapy for early-stage disease, while 76 (31%) were treated for advanced BC. At the time of the data cutoff, 133 (84.7%) patients remained in the 2-year treatment period. The most common adverse event (AE) was diarrhea (51%), primarily Grade ≤ 2. Dose modifications due to AEs were required in 19.2% of cases, while treatment discontinuation occurred in 5.1%. There was no difference in dose modification/discontinuation rates between older patients (>65 years) and the remaining patients. For early-stage BC patients, the 2-year DFS and OS rates were 90.8% and 100%, respectively. In patients with advanced cancer (70, 30.8%), 1-year PFS and OS rates were 78% and 96.3%, respectively. Conclusions: This study confirms the safety and effectiveness of abemaciclib in alignment with registrational trials offering valuable insights into toxicity management and clinical outcomes in routine practice without identifying new safety concerns. Clinical Trial Registration: ClinicalTrials.gov NCT04985058. Full article

Background: Intracerebral hemorrhage management presents clinicians with a significant therapeutic challenge. Maintaining antiplatelet therapy potentially increases the risk of recurrent bleeding, while discontinuation heightens susceptibility to ischemic stroke, particularly during the critical first month after hemorrhage. In contemporary practice, physicians demonstrate considerable hesitancy regarding early antiplatelet reinitiation, complicated by the absence of clear evidence-based treatment guidelines. Aim: This meta-analysis assesses the safety of early antiplatelet resumption following ICH. Methods: We conducted a systematic review by searching Web of Science, Scopus, PubMed, and Cochrane Library from inception to April 2025. Articles were independently screened and data extracted by two reviewers who also assessed study quality. The inclusion criteria are enrollment of adults (≥18 years) with imaging-confirmed intracerebral hemorrhage surviving >24 h, comparing early vs. delayed or withheld antiplatelet therapy. Randomized trials underwent separate evaluation using Cochrane’s Risk of Bias. Statistical analysis was performed using R software (version 4.4.2), with categorical outcomes pooled as risk ratios (RRs) with 95% confidence intervals. Statistical significance was established at p < 0.05. The evidence is limited by the availability of few RCTs, variable antiplatelet regiments, male predominance, and other confounding factors. The review was registered in SFO. Results: Our meta-analysis included 10 studies (8 observational, 2 RCTs) with 5554 patients. Early antiplatelet therapy significantly reduced recurrent intracerebral hemorrhage by 46% (RR 0.54, 95% CI 0.37–0.78, p = 0.001). All-cause mortality showed a non-significant difference (RR 0.81, 95% CI 0.65–1.01, p = 0.06). No significant differences were found for ischemic stroke (RR 0.99, 95% CI 0.60–1.63, p = 0.96), major hemorrhagic events (RR 0.75, 95% CI 0.49–1.13, p = 0.17), or ischemic vascular outcomes (RR 0.71, 95% CI 0.49–1.02, p = 0.60). Conclusions: Our meta-analysis reveals that early antiplatelet therapy following intracerebral hemorrhage significantly reduces recurrent hemorrhagic events (46% reduction) without increasing major ischemic or hemorrhagic complications. Full article

Objective: The SHARON (Short course RadiatiON therapy for palliative treatment) Bone trial is a phase III randomized non-inferiority multicentric study comparing symptom relief for complicated bone metastases (BMs) achieved through hypofractionated accelerated palliative radiotherapy (RT) to a standard RT regimen. Methods: Eligible participants were adults with ECOG PS ≤ 3 who were referred for palliative RT for painful BMs. Patients were assigned to receive either 30 Gy delivered in 10 daily fractions or 20 Gy in 4 fractions over two consecutive days. The primary outcome was pain relief one month post-treatment. Pain relief and adverse events were also evaluated at 2, 3, 6, and 12 months after RT. This trial was registered at clinicaltrials.gov (NCT03503682). Results: Between February 2018 and November 2021, 83 patients were enrolled (30 Gy: 41; 20 Gy: 42). In the standard RT group, five patients did not complete the prescribed RT, while none in the experimental arm discontinued treatment (p = 0.026). Due to early mortality, the primary endpoint was evaluable in 73 patients (35 and 38 in the standard and experimental arms, respectively). The rate of complete pain response at one month was 22.9% and 28.9% in the 30 Gy and 20 Gy arms, respectively (p: 0.571). The overall pain response rates, which included complete and partial responses, were 74.3% and 78.9% in the 30 Gy and 20 Gy arms, respectively (p = 0.638), when considering at least a 2-point reduction in the numerical rating scale. In both arms, 4.8% of patients experienced Grade >2 toxicity. Conclusions: Administering 20 Gy in four fractions twice a day is non-inferior to the standard 30 Gy delivered in 10 fractions for pain relief in the context of complicated BMs. Furthermore, this regimen demonstrated comparable safety in terms of acute toxicity, with a lower incidence of definitive interruptions of radiotherapy. Full article

Background/Objectives: Systemic sclerosis (SSc) is a progressive autoimmune disease characterized by widespread fibrosis, including skin thickening. Mycophenolate mofetil (MMF) is commonly used in SSc-associated interstitial lung disease, but its efficacy in improving skin fibrosis has not been systematically evaluated. This study aimed to assess the therapeutic effect of MMF on cutaneous sclerosis in SSc, as measured by the modified Rodnan skin score (mRSS). Methods: A systematic review and meta-analysis were conducted following PRISMA 2020 guidelines. PubMed, Embase, and Web of Science were searched from January 2000 to March 2025. Studies reporting mRSS outcomes in SSc patients treated with MMF were included, provided that the effect of MMF could be separately evaluated when used alongside other therapies. Risk of bias was assessed using the Cochrane RoB 2.0 tool for randomized controlled trials and the ROBINS-I tool for non-randomized studies. A random-effects model was used to estimate the pooled mean change in mRSS. Heterogeneity and publication bias were evaluated. Results: Eight studies involving 569 patients were included. The pooled mean reduction in mRSS following MMF treatment was −5.82 (95% CI: −7.46 to −4.19), exceeding the minimal clinically important difference. Heterogeneity across studies was substantial (I² = 82.6%). A post hoc exploratory subgroup analysis suggested greater improvement in early disease (<2 years), though this finding requires confirmation in prospective studies. MMF was generally well tolerated, with low discontinuation rates due to adverse events. Conclusions: MMF is associated with a statistically and clinically significant improvement in skin fibrosis in patients with SSc. These findings support its use as a frontline therapy for progressive cutaneous involvement, although further prospective studies are needed to identify optimal candidates for treatment. Full article

Background and objectives: Hypertension remains a leading global cause of cardiovascular morbidity and mortality, with suboptimal blood pressure (BP) control despite available treatments. Monotherapy often fails to achieve target BP, necessitating combination therapies. Quadruple low-dose combination therapy (quadpill) has emerged as a potential strategy to enhance efficacy while minimizing side effects. This systematic review evaluates the effectiveness and safety of quadpill therapy compared to standard monotherapy and dual therapy. Methods: A systematic search was conducted in PubMed, Web of Science, and Scopus from inception till January 2025 for randomized controlled trials (RCTs) investigating quadruple therapy in hypertensive patients. Studies comparing quadpill therapy with monotherapy, dual therapy, or placebo were included. Data on BP reduction, achievement of target BP, and adverse events were extracted and analyzed. The Cochrane Risk of Bias tool (RoB-2) was used to assess study quality. Results: Five RCTs were included in the current systematic review. Quadpill therapy resulted in greater reductions in systolic BP (SBP and diastolic BP (DBP) compared to monotherapy and dual therapy across all time points. The proportion of patients achieving target BP (<140/90 mmHg) was significantly higher in the quadpill group. The safety profile was favorable, with adverse event rates comparable to those in monotherapy and dual therapy groups. Notable adverse effects included mild dizziness, edema, and biochemical alterations (elevated fasting glucose and uric acid levels), but these did not lead to significant treatment discontinuation. Conclusions: Quadruple low-dose combination therapy is a promising approach for improving BP control while maintaining a favorable safety profile. Early initiation of quadpill therapy could mitigate treatment inertia and improve long-term cardiovascular outcomes. Full article

Introduction and Aim: Stage III Non-Small Cell Lung Cancer (NSCLC) has a poor prognosis, with median survival ranging from 9 to 34 months. The PACIFIC trial demonstrated that durvalumab after platinum-based chemoradiotherapy (CRT) improves overall survival (OS) and progression-free survival (PFS). This review evaluates real-world evidence (RWE) on durvalumab’s efficacy and safety, focusing on patient characteristics, prognostic factors, treatment protocols, and outcomes beyond progression. Materials and Methods: A literature search of PubMed, Embase, and Google Scholar identified 49 observational studies published from January 2017 to August 2024 on unresectable stage III NSCLC. Clinical trials, early-stage disease, and alternative treatments were excluded. Results: Compared to the PACIFIC trial, real-world patients were older, had poorer ECOG performance (≥2), and more comorbidities like COPD. Despite this, durvalumab provided consistent survival benefits. Positive prognostic factors included non-squamous histology, high PD-L1 expression, and timely durvalumab initiation (≤42 days post-CRT). Most radiotherapy regimens mirrored PACIFIC (54–66 Gy). Concomitant CRT was used in 90% of cases, with sequential CRT for frail patients. Chemotherapy regimens varied. Immune-mediated pneumonitis was a major adverse event, with incidence rates between 15% and 100%. Severe cases led to treatment discontinuation, impacting survival. Treatment beyond progression remains uncertain, with limited benefits from immunotherapy rechallenge. Conclusions: RWE supports durvalumab’s efficacy, emphasizing the need for personalized treatment strategies and further research to improve long-term outcomes. Full article

Antipsychotic medications are a vast class of drugs used for the treatment of psychotic disorders such as schizophrenia. Although numerous compounds have been developed since their introduction in the 1950s, several patients do not adequately respond to current treatments, or they develop adverse reactions that cause treatment discontinuation. Moreover, in the past few decades, discoveries in the pathophysiology of psychotic disorders have opened the way for experimenting with novel compounds that have alternative mechanisms of action, with some of them showing promising results in early trials. The scope of this review was to summarize the novel antipsychotics developed, their current experimental status, and their mechanisms of action. In particular, we analyzed the main classes of investigational antipsychotics, such as monoamine, glutamate, acetylcholine, cannabinoid receptor modulators, enzyme inhibitors, ion channel modulators, and mixed receptor modulators. In addition, the safety profiles and adverse effects of these drugs were carefully evaluated, considering the relevance of these aspects for patients’ drug adherence and quality of life, especially in the long-term treatment. Lastly, we tried to understand which compounds have greater potential to be approved by the principal drug regulatory agencies in the next years and if they could be used for diseases other than psychotic disorders. Full article

Background/Objectives: HER2-positive breast cancer (HER2⁺BC) is an aggressive subtype, with neoadjuvant treatment (NAT) aiming to achieve a pathological complete response (pCR) to improve long-term outcomes. Trastuzumab emtansine (T-DM1) has been established as the standard of care in the adjuvant setting for HER2⁺BC patients who do not obtain pCR. The ATD study aimed to evaluate the real-world tolerability of T-DM1 in this setting. The secondary objective was to assess the effectiveness. Methods: This was a multicenter, retrospective study across 24 Italian oncology centers, including 410 patients with HER2⁺BC treated with adjuvant T-DM1 following a lack of pCR after NAT. Patient characteristics, NAT regimens, and surgical outcomes were recorded. Tolerability was assessed by documenting adverse events (AEs) according to the CTCAE (v5.0). Preliminary effectiveness was evaluated in terms of relapse-free survival (RFS) and overall survival (OS). Results: Overall, 228 patients (55.6%) experienced at least one AE related to T-DM1, with 4.9% experiencing grade 3 or higher AEs. The most common AEs were hepatotoxicity (18.5%) and thrombocytopenia (17.6%). T-DM1 was discontinued in 10.0% of patients due to toxicity. After a median follow-up of 25 months, 31 relapse events (7.6%) and 22 deaths (5.4%) were reported. The preliminary incidence of RFS and OS events was similar between patients who completed the T-DM1 course and those who discontinued it early. Conclusions: T-DM1 demonstrated a manageable safety profile, and the adverse events were consistent with those reported in randomized trials. The data are not yet sufficient to allow for a formal analysis of RFS and OS, and long-term follow-up is required. Full article

Background/Objective: Dabrafenib and trametinib (D + T) have been approved for the treatment of stage III melanoma with BRAF V600E V600K mutations in an adjuvant setting, based on the results from the COMBI-AD trial. To provide early access to this combination therapy prior to its commercial availability in Italy, a Managed Access Program (MAP) was run in Italy from June 2018 to December 2019. Methods: The MADAM (Maximing ADjuvAnt MAP) study is an Italian retrospective–prospective observational study that included patients who received at least one dose of D + T through the MAP. The primary endpoints were relapse-free survival (RFS) and overall survival (OS). Results: This interim analysis presents findings after the first 24 months of follow-up. A total of 310 patients were included in the study; 240 completed the 12-month treatment with D + T, while 70 discontinued the combination. RFS rates were 93.2% at 12 months and 80.2% at 24 months. The median RFS was not reached for the overall population or any subgroups. Similarly, the median OS was not reached, with OS rates of 96.4% at 12 months and 92.5% at 24 months. Conclusions: D + T achieved an RFS benefit, with effects sustained beyond the treatment period, indicating positive outcomes in this patient population. Full article

Objectives: This study described real-world patient characteristics and outcomes among selpercatinib-treated patients in the United States, using the Flatiron Health electronic health record-derived deidentified database (FHD) for advanced/metastatic non-small cell lung cancer (a/mNSCLC) and Optum’s de-identified Clinformatics^® Data Mart Database (CDM). Methods: Patients initiating selpercatinib treatment between 08MAY2020 and 30JUN2023 were included. We evaluated real-world time to selpercatinib treatment discontinuation or death (rwTTDd) and time to next treatment or death (rwTTNTd) using Kaplan–Meier analyses. Medication possession ratio (MPR) was estimated as a measure of medication adherence in CDM patients. Results: In a/mNSCLC patients from the FHD (N = 68), the median rwTTDd and rwTTNTd were 22.4 [95%CI: 13.3–NR] and 21.0 [95%CI: 11.6–NR] months, respectively. In CDM, these durations were 12.1 [95%CI: 9.6–NR] and 16.2 [95%CI: 9.6–NR] months for lung cancer (n = 43), while these were not reached for thyroid cancer (n = 24) patients. The median MPR was 0.98 [IQR: 0.84–1.00] among all patients in the CDM (N = 75), with 77.3% of patients adhering (MPR ≥ 0.80) to selpercatinib. Conclusions: Real-world outcomes in this older and frailer patient cohort align with phase 3 trial results, further supporting selpercatinib as the standard of care for patients with RET-altered cancers. Early testing for the detection of RET alterations remains essential. Full article

Assessing the suitability of older adults with acute myeloid leukemia (AML) for intensive chemotherapy or stem cell transplantation remains a long-standing challenge. Geriatric assessment, which involves the evaluation of multiple dimensions of health, may influence a patient’s ability to tolerate intensive or mild-intensity approaches, including treatment-related mortality. Prospective studies are required to validate different fitness criteria, in addition to making it possible to compare the effectiveness of geriatric assessment-based fitness against other criteria, in order to identify which aspects of geriatric assessment are linked to treatment tolerance. It is hoped that validation studies will include different groups of patients receiving either intensive or lower-intensity chemotherapy. At a minimum, geriatric assessment should involve the measurement of the comorbidity burden, cognition, physical function, and emotional health—factors previously associated with mortality in AML. These assessments should be conducted before starting chemotherapy in order to minimize the treatment’s impact on the results. While treatment tolerance has traditionally been evaluated through toxicity rates in solid tumor patients, AML treatment often results in high toxicity rates regardless of the intensity. Therefore, early mortality should be the primary endpoint for assessing treatment tolerance, given its significant and clear implications. Other important endpoints might include declines in functional status and quality of life and treatment adjustments or discontinuation due to toxicity. Validating these fitness criteria is essential for guiding treatment choices, improving supportive care, determining trial eligibility, interpreting study outcomes, and informing drug labeling. Full article

Background: Despite early diagnosis, approximately 20% of patients with ER-positive and HER2-negative breast cancer (BC) will experience disease recurrence. Improved survival has been reported with adjuvant treatment combining cyclin-dependent kinase 4/6 inhibitors with endocrine therapy, in high-risk patients with ER-positive and HER2-negative BC, regardless of age. Older patients have higher rates of ER-positive/HER2-negative BC than younger patients. Methods: In this real-world data analysis, MonarchE and NataLEE high-risk patients accounted for 9.5% and 33% of patients undergoing upfront surgery, respectively. Significantly higher eligibility rates were observed in patients who underwent a mastectomy, >70 years and ≤40 years for adjuvant abemaciclib and ribociclib, and in patients >80 years for ribociclib. Results: Eligibility rates in patients ≤40 years and >80 years who underwent mastectomy were 27.8% and 24.7% for abemaciclib, respectively, and 56.6% and 65.2% for ribociclib, respectively. A higher discontinuation rate for abemaciclib was reported in patients aged ≥65 years and it can be assumed that discontinuation rates may increase in even older patients. Conclusions: If the results of the NataLEE trial translate into clinical practice, the number of patients potentially eligible for adjuvant CDK4/6 inhibitors may increase, especially in the elderly population. Full article

Objective: To provide a brief summary of the high incidence, symptomatology, different types, and diagnosis of adenomyosis and to explore various aspects of the disease, with the primary aim of raising awareness among gynecologists for appropriate and early detection. Background: Adenomyosis, a benign gynecological condition characterized by the infiltration of endometrial tissue into the myometrium, poses significant challenges to women’s reproductive health. Methods: A narrative review was conducted by searching PubMed, Scopus, and Cochrane databases and offering a non-systematic summary and critical analysis of current knowledge on the impact of adenomyosis on women’s health. Articles published in the English language up to May 2023, including original scientific papers, clinical trials, meta-analyses, and reviews focusing on various aspects of adenomyosis, were included in the synthesis of this review. Conclusions: Approximately 20% of women are affected by adenomyosis, which manifests with various subtypes, distinct epidemiological profiles, symptomatology, and treatment responses. Despite its clinical significance, adenomyosis remains understudied, resulting in a significant disparity in research and the literature compared to other gynecological conditions. The severity of adenomyosis is compounded when coexisting with endometriosis, particularly deep-infiltrating endometriosis (DIE), leading to exacerbated fertility issues and severe symptomatology. The wide range of symptoms, including adverse pregnancy outcomes such as pre-eclampsia, highlights its wider impact and emphasizes the need for increased awareness of the condition. Adenomyosis is frequently associated with treatment failure in endometriosis, contributing to dienogest resistance, elevated discontinuation rates, and persistent pain post-endometriosis surgery. Additionally, the lack of specific treatments tailored to adenomyosis poses a considerable challenge in clinical management. Full article

Background: Late infantile neuronal ceroid lipofuscinosis type 2 (CLN2) is a rare neurodegenerative disease that generally appears in children between 2 and 4 years old, leading to seizures and a progressive loss of language and motor functions. As the disease progresses, affected individuals typically experience blindness and ultimately pass away in late childhood. Treatment with intracerebroventricular cerliponase alfa has been shown to slow the deterioration of motor and language functions compared to the natural progression of the disease. We aim to highlight the early symptoms of CLN2 which help with early diagnosis and timely treatment initiation in children with specific medical indications, as well as identify medical contraindications for enzyme replacement therapy. Methods: We describe five Croatian patients and one Bosnia and Herzegovinian patient with CLN2 disease, analyzing the clinical characteristics, neuroimaging findings, electroencephalogram results, genetic analysis, treatment indications and contraindications, and disease progression. Results: All six patients presented with seizures: focal seizures (n = 1), myoclonic–atonic seizures (n = 1), febrile seizures (n = 2), and tonic–clonic seizures (n = 2), along with language delay (n = 6). Despite this, one patient refused treatment, two were initially included in the clinical trial and then continued treatment, one did not indicate starting treatment, and three continued treatment. One patient, after 4.5 years of treatment, no longer had medical indications for the therapy, which was discontinued. The other two patients who received treatment had a significant slowing of disease progression. Conclusions: The early onset of seizures between ages 2 and 4, alongside delayed language development, is a defining characteristic of CLN2 disease. Enzyme replacement therapy using cerliponase alfa represents the initial treatment for neuronal ceroid lipofuscinosis type 2, targeting the underlying cause of the disease. It effectively delays the progression of language and motor decline in patients diagnosed with this condition. Full article