Innsbruck Medical University

Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) have revolutionized the treatment of hormone-receptor positive (HR+), HER2 negative (HER2−) metastatic breast cancer, and are now also established agents in the treatment of high-risk and intermediate-risk HR+ early breast cancer. Several strategies regarding CDK4/6i combinations or continuation beyond progression have been successfully evaluated in the metastatic setting, and are considered a standard of care. Mechanism of action of and resistance mechanisms against CDK4/6i in addition to endocrine resistance represent an important research topic, important for the treatment of HR+ breast cancer. Clinically, CDK4/6i are efficient substances that are usually well tolerated. However, side effects differing between the substances have been reported, and might lead to treatment discontinuation, including in the early disease setting. In the adjuvant setting, the addition of palbociclib to standard endocrine treatment has not improved outcomes, whereas large randomized phase III trials have demonstrated significant disease-free survival benefit for the addition of ribociclib (NATALEE trial) and abemaciclib (monarchE trial). Patient selection, treatment duration, endocrine backbone therapy, and other study details differ between these pivotal trials. This review focuses on both the scientific background as well as all available clinical data of CDK4/6i, with particular emphasis on their use in early breast cancer.

Azoospermia, defined as the absence of sperm in the ejaculate, is a well-documented consequence of exogenous testosterone (ET) and anabolic–androgenic steroid (AAS) use. These agents suppress the hypothalamic–pituitary–gonadal (HPG) axis, leading to reduced intratesticular testosterone levels and impaired spermatogenesis. This review examines the pathophysiological mechanisms underlying azoospermia and outlines therapeutic strategies for recovery. Azoospermia is categorized into pretesticular, testicular, and post-testicular types, with a focus on personalized treatment approaches based on the degree of HPG axis suppression and baseline testicular function. Key strategies include discontinuing ET and monitoring for spontaneous recovery, particularly in patients with shorter durations of ET use. For cases of persistent azoospermia, gonadotropins (human chorionic gonadotropin [hCG] and follicle-stimulating hormone [FSH]) and selective estrogen receptor modulators (SERMs), such as clomiphene citrate, are recommended, either alone or in combination. The global increase in exogenous testosterone use, including testosterone replacement therapy and AAS, underscores the need for improved management of associated azoospermia, which can be temporary or permanent depending on individual factors and the type of testosterone used. Additionally, the manuscript discusses preventive strategies, such as transitioning to short-acting testosterone formulations or incorporating low-dose hCG to preserve fertility during ET therapy. While guidelines for managing testosterone-related azoospermia remain limited, emerging research indicates the potential efficacy of hormonal stimulation therapies. However, there is a notable lack of well-structured, controlled, and long-term studies addressing the management of azoospermia related to exogenous testosterone use, highlighting the need for such studies to inform evidence-based recommendations.

Symptomatic chronic subdural hematoma (cSDH) is amongst the most frequent neurological diseases with an upward trend due to an aging society and development in the field of anticoagulation therapies. Lately, subgaleal drainages and middle meningeal artery (MMA) embolization have been introduced to the standard armamentarium as treatment options for cSDH patients. Vascular anomalies, such as internal carotid artery (ICA) occlusion with spontaneous extra-intracranial anastomoses, usually lead to forfeiting embolization treatment from patients. This report presents a case of a 67-year-old male with a repeated recurrence of cSDH in conjunction with a history of middle cerebral artery territory stroke and consecutive platelet inhibition therapy. The patient was initially treated with a burr hole plus subgaleal and subdural drainage upon revision surgery. Due to repeated recurrence, MMA embolization was considered, even though an extra-intracranial anastomosis was present on angiography. The patient was deemed to be fully recovered three months after intervention and no further intervention was needed. We can conclude that MMA embolization is a feasible option also in patients with recurrent cSDH after territorial infarction secondary to ICA occlusion with present extra-intracranial anastomoses.

Diseases of the salivary glands are as common as they are diverse and can have different causes. Clinicians can differentiate salivary gland changes based on chronic systemic diseases, congenital and vascular malformations, and benign and malignant tumors. Acute infectious pathologies can also arise as a result of obstructive pathologies. A large number of diseases with similar clinical presentations have to be differentiated. Due to the improved resolution of ultrasound technology over the last 20 years, it is now used as the first imaging modality to examine salivary gland pathologies. It allows a quick, dynamic, and non-invasive examination of the salivary glands and the soft tissue of the neck. In order to accurately diagnose and treat patients, a very good knowledge of these diseases and their appearance on sonography is required.

Introduction Neurogenic bladder dysfunction is a prevalent condition characterized by impaired bladder control resulting from neurological conditions, for example, spinal cord injury or traumatic brain injury (TBI). Detrusor overactivity is a typical symptom of central nervous system damage. A lesion affecting the pontine neural network typically results in loss of tonic inhibition exerted by the pontine micturition center and causes involuntary detrusor contractions. Intrathecal baclofen (ITB), primarily indicated for spasticity management, holds potential in addressing the underlying mechanisms of neurogenic bladder dysfunction. Methods Urodynamic data were extracted from clinical charts of patients with severe supraspinal spasticity who received ITB treatment. Urodynamic studies were performed before pump implantation (PRE), after surgery (POST), and when achieving an effective steady state ITB dosage (ss‐ITB), as reflected by a reduction in Modified Ashworth Scale (MAS) score. To determine potential risk factors for a poor response to ITB with respect to bladder function, patients were post hoc categorized into good and poor responders based on post void residual volume at ss‐ITB. Results Apart from significantly reducing MAS scores, ITB caused significant increases in reflex volume, bladder capacity, and residual volume, and significant decreases in maximal detrusor and vesical pressures. Significant differences between good and poor responders (with respect to bladder function) were noted for reflex volume, bladder capacity, and residual volume at ss‐ITB, whereas no urodynamic parameter served to differentiate the two groups at PRE. Discussion This study confirms a beneficial effect of ITB on bladder function in patients with severe supraspinal spasticity. However, concurring with the literature, a small subgroup of patients experienced serious deterioration in terms of increased reflex volume and residual volume, posing the risk of subsequent renal damage. Unfortunately, no urodynamic parameter predicted such a poor response to ITB before treatment initiation.

The dynamic interactions between tumor endothelial cells (TECs) and the immune microenvironment play a critical role in the progression of non-small cell lung cancer (NSCLC). In general, endothelial cells exhibit diverse immunomodulatory properties, influencing immune cell recruitment, antigen presentation, and regulation of immune checkpoint expression. Understanding the multifaceted roles of TECs as well as assigning specific functional hallmarks to various TEC phenotypes offer new avenues for targeted development of therapeutic interventions, particularly in the context of advanced immunotherapy and anti-angiogenic treatments. This review provides insights into the complex interplay between TECs and the immune system in NSCLC including discussion of potential optimized therapeutic opportunities.

The role of anthracyclines in the treatment of early breast cancer (EBC) is increasingly being challenged, especially in de-escalation strategies. However, owing to their immunogenic effects, anthracyclines are promising combination partners with immunotherapies. In the randomized phase 2 trial ABCSG-52 (EudraCT no. 2019-002364-27), we investigated epirubicin plus immunotherapy in women with human epidermal growth factor receptor 2 (HER2)-positive EBC. A total of 58 patients were randomized 1:1 to two cycles of a chemotherapy-free induction phase (part 1) of dual HER2 blockade with trastuzumab and pertuzumab (TP) plus the anti-programmed death ligand 1 antibody atezolizumab (TP-A) or TP alone. Thereafter, all patients received four cycles of TP-A in combination with epirubicin (part 2). The primary endpoint, pathological complete response (pCR), was met in 35 patients (60.3%; 95% confidence interval (CI) 47.5% to 71.9%), 19 patients (65.5%) in the TP-A group and 16 patients (55.2%) in the TP group. The residual cancer burden 0/I rate and objective response rate (secondary endpoints) in all patients with evaluable data were 80.0% (n = 44/55; 95% CI 67.6% to 88.4%) and 89.3% (n = 50/56; 95% CI 78.5% to 95.0%), respectively. Grade ≥3 adverse events were reported in 17 patients (29.3%). Based on our findings, we conclude that a neoadjuvant chemotherapy de-escalation immunotherapy regimen with trastuzumab, pertuzumab, atezolizumab and epirubicin is effective and safe in patients with HER2-positive EBC.

Introduction The current study aims to give an overview of transition-to-home services provided by perinatal centres in Austria and Switzerland and to evaluate parental satisfaction with the care provided. Methods This cross-sectional multicentred study was conducted by performing two surveys between May 2022 and November 2023: one among all level III perinatal centres in Austria (n=7) and Switzerland (n=9) (institutional survey) and one among parents of very preterm infants treated at one selected perinatal centre in each of the two countries (parental survey). Both questionnaires consisted of matching questions focusing on current transition-to-home services. Results All perinatal centres participated in the institutional survey and 61 out of 84 parents completed the parental questionnaire (response rate 72.6%). The discharge process to home was identified as a multidisciplinary effort involving various healthcare professionals with discrepancies in responses within and between institutional and parental questionnaires. Certain disparities were observed in the timing of discharge conversations between healthcare providers and parents. Most physicians mentioned initiating discharge discussions while the child was still in the intensive care unit, but only 14.8% of parents recalled these early conversations. One-fourth of perinatal centres actively contact patients after discharge. So far, video consultations or mobile applications have not been offered. While 95.1% of parents expressed satisfaction with the care received, there were concerns about contradictory medical information, particularly regarding breastfeeding. Conclusion The transition-to-home process for very preterm infants presents several opportunities for improvement, especially concerning communication between healthcare providers and parents, lactation counselling services and the timely outreach to parents shortly after discharge. The findings of the current study may further improve this transition process and might aid in the development of a standardised programme that is tailored to parental needs.

Dysregulation at the intestinal epithelial barrier is a driver of inflammatory bowel disease (IBD). However, the molecular mechanisms of barrier failure are not well understood. Here, we demonstrate dysregulated mitochondrial fusion in intestinal epithelial cells (IECs) of patients with IBD and show that impaired fusion is sufficient to drive chronic intestinal inflammation. We found reduced expression of mitochondrial fusion–related genes, such as the dynamin-related guanosine triphosphatase (GTPase) optic atrophy 1 ( OPA1 ), and fragmented mitochondrial networks in crypt IECs of patients with IBD. Mice with Opa1 deficiency in the gut epithelium ( Opa1 i∆IEC ) spontaneously developed chronic intestinal inflammation with mucosal ulcerations and immune cell infiltration. Intestinal inflammation in Opa1 i∆IEC mice was driven by microbial translocation and associated with epithelial progenitor cell death and gut barrier dysfunction. Opa1 -deficient epithelial cells and human organoids exposed to a pharmacological OPA1 inhibitor showed disruption of the mitochondrial network with mitochondrial fragmentation and changes in mitochondrial size, ultrastructure, and function, resembling changes observed in patient samples. Pharmacological inhibition of the GTPase dynamin-1–like protein in organoids derived from Opa1 i∆IEC mice partially reverted this phenotype. Together, our data demonstrate a role for epithelial OPA1 in regulating intestinal immune homeostasis and epithelial barrier function. Our data provide a mechanistic explanation for the observed mitochondrial dysfunction in IBD and identify mitochondrial fusion as a potential therapeutic target in this disease.

Objectives The presented study aimed to evaluate the effect of mandibular protrusion with a temporarily applied mandibular advancement device (MAD) on the posterior airway space and to determine a reliable metric constant based on a three-dimensional computed tomography (CT) evaluation. Materials and methods The study population consisted of patients with oral squamous cell carcinoma who were treated at least six months prior to the follow-up CT in supine position. Each patient received an individually adjusted MAD that was temporarily applied with three different protrusion distances (P0 = 0 mm, P4 = 4 mm, and P8 = 8 mm) during follow-up CT. The open-source software Slicer was used to calculate three parameters: minimum cross-sectional area (minCSA), mean cross-sectional area (meanCSA), and volume. Results The results showed a significant increase for all three parameters. The minCSA increased as follows: P0 = 236.4 mm² ± 192.2; P4 = 309.2 mm² ± 235.4; and P8 = 430.6 mm² ± 265.3. The meanCSA increased significantly (p < 0.001) in all protrusion steps and all parts of the pharynx. The volume changed as follows: P0 = 24.0 cm³ ± 5.0; P4 = 29.6 cm³ ± 18.1; and P8 = 33.6 cm³ ± 19.0. The minCSA increased by 24.9 mm² ± 13.0 per millimeter mandibular protrusion. Conclusion and clinical relevance The results are interesting for both conservative and surgical therapy and could find future application in dental, orthodontic, and combined oral surgical therapy. With the results of this study, surgeons and dentists may better predict the change of PAS parameter in order to better prepare for orthognathic surgery. They also could ensure the right protrusion distance for mandibular advancement devices in the case of obstructive sleep apnea.

Objectives To assess the impact of a positive history of venous thromboembolism (VTE) on perioperative outcomes, including length of in‐hospital stay, readmission rates, 90‐day postoperative complications, and healthcare costs in bladder cancer (BCa) patients undergoing transurethral resection of bladder tumour (TURBT) in the United States. Patients and Methods Patients aged ≥18 years with a BCa diagnosis undergoing TURBT were identified in the Merative® Marketscan® Research de‐identified databases between 2007 and 2021. Multivariable logistic regression adjusted by relevant perioperative confounders was used to investigate the association between diagnosis of VTE before TURBT and 90‐day complication rates, new postoperative VTE events, re‐hospitalization, and total hospital expenditures (2021 US dollars). Sensitivity analyses on VTE severity (pulmonary embolism [PE], deep venous thrombosis [DVT] or superficial thrombophlebitis/phlebitis [SVT]), as well as TURBT extent (minor vs. major) were additionally examined. Results In total, 139 800 patients were identified, with 5.3% having preoperative VTE, including DVT (n = 3112, 42.20%), PE (n = 2046, 27.74%) and SVT (n = 2217, 30.06%). A history of preoperative VTE predicted higher rates of any complication (adjusted odds ratio [aOR] 1.28, 95% CI 1.14–1.43) and also higher rates of infectious and haemorrhagic complications. Additionally, preoperative VTE increased the risk of novel VTE events following TURBT (aOR 17.30, 95% CI 16.05–18.65), hospital length of stay (aOR 2.23, 95% CI 1.90–2.62), readmissions (aOR 1.47, 95% CI 1.39–1.56), and hospital associated costs (aOR 1.17, 95% CI 1.12–1.23). DVT and non‐minor TURBT procedures did not increase the risk of any, infectious, or haemorrhagic complications, but other associations were maintained regardless of the severity of VTE (PE, DVT, SVT) or TURBT extent (minor/major). Conclusions A history of VTE before undergoing transurethral procedures for BCa is associated with significantly worse perioperative outcomes and higher healthcare costs. These findings may help us to counsel on the risks of the intervention and hopefully improve our ability to mitigate such risks.

Purpose: To assess the association between neoadjuvant therapy and overall survival (OS) in patients with left-sided resectable pancreatic cancer (RPC) compared to upfront surgery. Background: Left-sided pancreatic cancer is associated with worse OS compared to right-sided pancreatic cancer. Although neoadjuvant therapy is currently seen as not effective in patients with RPC, current randomized trials included mostly patients with right-sided RPC. Methods: International multicenter retrospective study including consecutive patients after left-sided pancreatic resection for pathology-proven RPC, either after neoadjuvant therapy or upfront surgery in 76 centers from 18 countries on 4 continents (2013-2019). Primary endpoint is OS from diagnosis. Time-dependent Cox regression analysis was performed to investigate the association of neoadjuvant therapy with OS, adjusting for confounders at time of diagnosis. Adjusted OS probabilities were calculated. Results: Overall, 2,282 patients after left-sided pancreatic resection for RPC were included of whom 290 patients (13%) received neoadjuvant therapy. The most common neoadjuvant regimens were (m)FOLFIRINOX (38%) and gemcitabine-nab-paclitaxel (22%). After upfront surgery, 72% of patients received adjuvant chemotherapy, mostly a single-agent regimen (74%). Neoadjuvant therapy was associated with prolonged OS compared to upfront surgery (adjusted HR=0.69 [95%CI 0.58-0.83]) with an adjusted median OS of 53 vs. 37 months (P=0.0003) and adjusted 5-year OS rates of 47% vs. 35% (P=0.0001) compared to upfront surgery. Interaction analysis demonstrated a stronger effect of neoadjuvant therapy in patients with a larger tumor (Pinteraction=0.003) and higher serum CA19-9 (Pinteraction=0.005). In contrast, the effect of neoadjuvant therapy was not enhanced for splenic artery (Pinteraction=0.43), splenic vein (Pinteraction=0.30), retroperitoneal (Pinteraction=0.84), and multivisceral (Pinteraction=0.96) involvement. Conclusions: Neoadjuvant therapy in patients with left-sided RPC was associated with improved OS compared to upfront surgery. The impact of neoadjuvant therapy increased with larger tumor size and higher serum CA19-9 at diagnosis. Randomized controlled trials on neoadjuvant therapy specifically in patients with left-sided RPC are needed.

Background Anterolateral ligament reconstruction (ALLR) or lateral extra-articular tenodesis (LET) has been used more frequently in conjunction with anterior cruciate ligament reconstruction (ACLR) in recent years. However, there are still concerns that these procedures may lead to complications such as overconstraint of the lateral compartment, stiffness, infections, tunnel convergence, and other intra- and postoperative complications because of increased surgical time and the need for additional procedures. Hypothesis/Purpose The lateral extra-articular procedure will reduce the failure rate of reconstructed ACLs without increasing the number of complications. The purpose was to compare the complication and graft reinjury rates of 2 main anterolateral complex procedure categories described in the literature—LET and ALLR with isolated ACLR. Study Design Systematic review and meta-analysis of randomized controlled trials (RTCs); Level of evidence, 2. Methods The methodology followed the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines. The PubMed, Embase, and Cochrane Library databases were searched on March 15, 2024, to identify RTCs comparing isolated ACLR with ACLR + LET or ALLR. The methodological index for nonrandomized studies was employed for the quality evaluation. Complications and graft reinjury rates were recorded and meta-analyzed from all included studies. Results The initial search yielded 1411 articles. Seventeen studies that included the complication rates (5 in the ALLR group and 12 in the LET group) were included in the review. No significant differences were found in the incidence of complications between the ACLR and ACLR + ALLR groups (Mantel-Haenszel [M-H], 1.20 [95% CI, 0.05-29.30]; P = .91) or between the ACLR and ACLR + LET groups (M-H, 0.39 [95% CI, 0.05-2.98]; P = .36). Significant differences were observed in the failure rate between the ACLR + ALLR group (M-H, 6.78 [95% CI, 1.98-23.22]; P = .002) and the ACLR + LET group (M-H, 3.14 [95% CI, 1.96- 5.04]; P < .00001). Conclusion Adding a lateral extra-articular procedure, regardless of the surgical technique, can reduce the failure rate without increasing the number of complications at the mid-term follow-up. Study Registration PROSPERO (CRD42023458354).

Background Friedreich ataxia is a rare neurodegenerative disorder caused by frataxin deficiency. Both underweight and overweight occur in mitochondrial disorders, each with adverse health outcomes. We investigated the longitudinal evolution of anthropometric abnormalities in Friedreich ataxia and the hypothesis that both weight loss and weight gain are associated with faster disease progression. Methods Participants were drawn from the European Friedreich's Ataxia Consortium for Translational Studies (EFACTS). Age‐ and sex‐specific BMI and height scores were calculated using the KIGGS‐BMI percentiles for children. Height correction was applied for scoliosis. Longitudinal data were analysed using linear mixed effects models and incremental standard deviation scores and growth mixture models identified subclasses with varying BMI trajectories. Results Five hundred and forty‐three adults and fifty‐nine children were assessed for up to 5 years. In children, severe underweight (26%), underweight (7%), severe short stature (16%) and short stature (23%) were common. The corrected BMI percentile was stable in children, although 48% had negative incremental BMI scores over 1 year and 63% over 3 years versus 10%/year in a normal reference cohort. Overweight was common in adults (19%), with a slight increase in BMI over time. Longer GAA repeat size was linked to lower BMI in adults. Weight trajectory was not associated with ataxia progression in adults. Conclusion Significant anthropometric abnormalities were identified, with underweight and short stature prevalent in children and overweight in adults. These findings highlight the need for regular nutritional monitoring and interventions to manage underweight in children and promote healthy weight in adults.

Objective To evaluate the oncological efficacy and safety of sequential intravesical gemcitabine/docetaxel (Gem/Doce) therapy in a European cohort of patients with high‐risk and very‐high‐risk non‐muscle‐invasive bladder cancer (NMIBC) after previous Bacillus Calmette–Guérin (BCG) treatment. Materials and Methods Data were retrospectively collected from 95 patients with NMIBC, treated with Gem/Doce at 12 European centres between 2021 and 2024. Patients previously treated with BCG who had completed a full induction course and received at least one follow‐up evaluation were included. One‐year disease‐free survival (DFS), high‐grade DFS and progression‐free survival (PFS) were estimated using Kaplan–Meier curves. Adverse events (AEs) were recorded through medical interviews. Results Of 75 patients, 63 (84%) were classified as having high‐risk and 12 (16%) as having very‐high‐risk NMIBC. Over a median (interquartile range) follow‐up of 9 (5–14) months, 20 patients (27%) relapsed and five (6.7%) underwent radical cystectomy. The 1‐year DFS was 73% (95% confidence interval [CI] 62–86%), 1‐year high‐grade DFS was 79% (95% CI 68–91%) and 1‐year PFS was 95% (95% CI 90–100%). AEs occurred in 34 patients (45%), with six (8.7%) experiencing severe AEs. Limitations of the study include the short follow‐up and variability in both treatment dwelling times and dosage across centres. Conclusion The intravesical Gem/Doce regimen demonstrated promising short‐term oncological outcomes and was well tolerated in this cohort of patients with high‐ and very‐high‐risk NMIBC previously treated with BCG. Prospective studies and randomised trials are awaited to define the ideal candidates for Gem/Doce therapy and to standardise treatment protocols.

Background Catechol‐O‐methyl transferase (COMT) inhibitors are routinely used to manage motor fluctuations in Parkinson's disease (PD). We assessed the effect of opicapone on motor symptom severity in levodopa‐treated patients without motor complications. Methods This was a randomized, double‐blind, 24‐week, placebo‐controlled study of opicapone 50 mg as adjunct to levodopa (NCT04978597). Levodopa‐treated patients without motor complications were randomized to 24 weeks of double‐blind treatment with adjunct opicapone 50 mg or matching placebo. The primary efficacy endpoint was the mean change from baseline to week 24 in Movement Disorder Society‐Unified Parkinson's Disease Rating Scale Part III (MDS‐UPDRS‐III) total score. Results A total of 355 patients were randomized (opicapone 50 mg n = 177, placebo n = 178) and 322 (91%) completed the double‐blind period. The adjusted mean [95% CI] change from baseline to week 24 in MDS‐UPDRS‐III subscore was −6.5 [−7.9, −5.2] in the opicapone group versus −4.3 [−5.7, 3.0] in the placebo group resulting in a significant difference of −2.2 [−3.9, −0.5] favoring opicapone (p = 0.010). There was no difference in the incidence of patients who developed motor complications (5.5% with opicapone vs. 9.8% with placebo) and the incidence of adverse events considered related to study medication was similar between groups (opicapone 10.2% vs. placebo 13.5%). Conclusions Treatment with once‐daily adjunct opicapone was well tolerated, improved motor severity, and did not induce the development of motor complications. These results support the clinical usefulness of opicapone in the management of PD patients without motor complications.