Successful Trials Research Articles

Intraperitoneal chemotherapy is now back for ovarian cancer.

The Intraperitoneal Carboplatin for Ovarian Cancer (iPocc) trial demonstrated that intraperitoneal (IP) administration of carboplatin is more effective than intravenous (IV) administration for advanced ovarian cancer, especially in cases with large residual tumors, challenging previous assumptions that IP chemotherapy is only beneficial for small residual tumors. Additionally, the iPocc trial showed that IP chemotherapy has a comparable safety profile to IV chemotherapy, with the exception of port-related toxicities. This review summarizes the principles, development, and significance of IP chemotherapy and discusses its future potential in light of recent studies. Notably, the iPocc trial, conducted under Japan's new clinical trial regulations, achieving regulatory approval based on investigator-initiated results. The iPocc regimen offers a viable treatment option for patients with advanced ovarian cancer (stages II-IV). However, bevacizumab is recommended for later-line treatments rather than combining it with IP chemotherapy until further trials support such combinations. Future studies are needed to identify biomarkers that predict response to the iPocc regimen. The trial's success underscores the dedication of patients and families who contributed to this groundbreaking research.

Images: Pharmacological treatment of pediatric insomnia: a successful trial of doxepin.

Images: Pharmacological treatment of pediatric insomnia: a successful trial of doxepin.

Xenotransplantation: future frontiers and challenges.

Recent advancements in genetic engineering have propelled the field of xenotransplantation from preclinical models to early compassionate use cases. As first-in-human clinical trials (FIHCTs) approach, we examine recent developments, ethical and regulatory challenges, immunological considerations, and the clinical infrastructure necessary for successful xenotransplantation trials. Expanded access transplants of pig hearts, kidneys, and livers have identified key challenges. Heart xenotransplants revealed risks of antibody-mediated rejection and zoonotic infections, while kidney xenotransplants suggest that patient selection, rather than immune rejection, may have caused failures. While there has been a report of auxiliary liver transplantation conducted abroad, profound thrombocytopenia poses an obstacle. As FIHCTs draw near, critical clinical challenges include determining the optimal donor genetic constructs and immunosuppressive regimens. Enrollment criteria and patient selection pose additional complexity, alongside ethical concerns such as lifelong zoonosis monitoring. Only a limited number of centers have the expertise needed to conduct these complex trials. Xenotransplantation holds great promise as a solution to organ shortages, but success in FIHCTs will require careful design, multidisciplinary collaboration, and strong infrastructure. Addressing immunologic, ethical, and patient selection challenges will be critical. With proper preparation, xenotransplantation could transform organ transplantation.

Barriers and new opportunities in developing effective therapies for diabetic neuropathy: International expert consensus recommendations.

Diabetic neuropathy (DN) affects up to half of individuals with type 1 and type 2 diabetes. Despite evidence that improving metabolic and cardiovascular health can slow its progression, DN remains a significant clinical challenge due to the lack of disease-modifying therapies and effective pain management strategies. This consensus aimed to identify gaps and recommend strategies to address these challenges. A workshop, initiated by Steno Diabetes Centre Copenhagen and the Danish Diabetes and Endocrinology Academy, conducted a gap analysis based on insights from clinical studies, observational cohorts, and clinical practice. Online invitations targeted experienced clinicians, researchers, and drug developers committed to improving DN treatment through innovative clinical trials. Thirty-five participants from six countries reached consensus via a Delphi process on key steps to advance DN therapy. Four critical barriers and needs were addressed: (1) Translating bench research to clinical practice, (2) Enhancing clinical trial design, (3) Improving outcome measures, and (4) Identifying effective treatments for painful DN. Successful interventional trials require robust outcome measures to capture clinically meaningful changes in DN phenotypes, providing the basis for developing effective, disease-modifying treatments.

Ultrasound-based abdominal muscles and diaphragm assessment in predicting extubation failure in patients requiring neurointensive care: a single-center observational study

Extubation failure rates are notably high in patients in neurointensive care. Ineffective cough is the variable independently associated with extubation failure, but its quantification remains challenging. Patients with primary central nervous system injury requiring invasive mechanical ventilation were included. After a successful spontaneous breathing trial (SBT), abdominal muscles and diaphragm ultrasound were performed under tidal breathing and coughing. 98 patients were initially recruited for the study, and 40 patients were ultimately included in the final analysis. Extubation failure occurred in 8 (20%) patients. Rectus abdominis (RA) and internal oblique (IO) muscles showed difference regarding cough thickening fraction (TF) between the extubation success and failure group (P < 0.05). The logistic regression that analysis suggested cough TFRA, cough TFIO and cough TIO were the factors associated with extubation outcome (P < 0.05). In the receiver operating characteristic analysis, cough TFIO exhibited the strongest predictive value (AUC = 0.957, 95% CI:0.8979–1). A threshold of cough TFIO ≥ 34.15% predicted extubation success with a sensitivity of 93.8% and specificity of 75%. Abdominal muscles ultrasound was a promising tool to predict extubation for patients requiring neurointensive care.Trial registration: The study was registered on Chinese Clinical Trial Registry: ChiCTR2400088210, Registered 13 August 2024 - Retrospectively registered, https://www.chictr.org.cn/bin/project/edit?pid=234150.

Risky actions: Why and how to estimate variability in motor performance.

We describe the difficulties of measuring variability in performance, a critical but largely ignored problem in studies of risk perception. The problem seems intractable if a large number of successful and unsuccessful trials are infeasible. We offer a solution based on estimates of task-specific variability pooled across the sample. Using a dataset of adult performance in throwing and walking tasks, we show that mischaracterizing the slope leads to unacceptably large errors in estimates of performance levels that undermine analyses of risk perception. We introduce a "pooled-slope" solution that approximates estimates of individual variability in performance and outperforms arbitrary assumptions about performance variability within and across tasks. We discuss the advantages of objectively measuring performance based on the rate of successful attempts-modeled via psychometric functions-for improving comparisons of risk across participants, tasks, and studies.

Current developments in T-cell receptor therapy for Acute Myeloid Leukaemia.

T-cell receptor (TCR) therapies are a promising modality for the treatment of cancers, with significant efforts being directed towards acute myeloid leukaemia (AML), a particularly challenging disease. Chimeric antigen receptor (CAR) T-cells targeting single surface antigens have shown remarkable efficacy for B-cell lymphoblastic leukaemia, lymphomas and multiple myeloma. However, AML presents formidable obstacles to the effectiveness of CAR T-cells due to the widespread expression of heterogenous leukaemia immunophenotypes and surface antigen targets additionally present on normal myeloid cells. TCR therapies are an evolving field of cell therapies that allow targeting intracellular antigenic peptides presented via HLA molecules. The development of TCR therapy for AML is progressing rapidly through preclinical research and successful clinical trials. This review specifically explores the antigens targeted in AML, the diverse methodologies and strategies employed in TCR identification and preclinical TCR T-cell development. The review also discusses innovative molecular designs to improve functional efficacy, mitigate safety concerns and overcome HLA restriction. Specific outcomes of early clinical trials targeting important antigens WT1, PRAME and HA-1 are also highlighted. Ultimately, this review underscores why TCR therapy is poised to become an indispensable component of AML immunotherapy.

Comprehensive surgery of complex scalp arteriovenous fistula: a successful trial.

Traumatic scalp arteriovenous fistula is a rare vascular abnormality. Open surgical removal and embolization have been employed to address this condition. In this report, we present a case involving a 41-year-old man who exhibited a progressively enlarging pulsatile mass in his right occipital scalp. Computerized tomography angiography (CTA) and digital subtraction angiography (DSA) identified a complex scalp arteriovenous fistula (S-AVF). The combination of clinical symptoms and neuroimaging findings facilitated the diagnosis. Following a thorough discussion, we implemented a comprehensive strategy that included both endovascular embolization and surgical resection. The patient demonstrated an excellent prognosis with no reported discomfort. A comprehensive surgical approach should be considered in the management of patients with complex scalp arteriovenous fistula.

Medication reviews in hospitalised patients for reduced hospital readmission and mortality. Systematic review, meta-analysis and meta-regression of RCTs.

Efforts to reduce preventable medication-related harm through medication reviews have increased, but interventions often yield null-results regarding clinical outcomes. We conducted a systematic literature search in four data bases and summarised the available evidence from randomised controlled trials (RCTs) comparing medication reviews and usual care in hospitalised patients regarding hospital readmissions and all-cause mortality by random-effects meta-analyses. Effect size differences by methodological study differences were of special interest. The meta-analysis of all 24 trials on hospital readmissions, including 12,539 participants, showed a statistically significant 8% decrease in hospital readmissions (risk ratio (RR) [95% confidence interval]: (0.92 [0.88-0.97], p=0.002). The number of patient contacts was the most prominent effect modifier in meta-regression (p=0.003) and the effect of medication reviews was approximately twice as strong (15%) in 11 trials with 2 or more patient contacts (0.85 [0.78-0.92], p<0.001). No statistically significant reduction in all-cause mortality was observed in a meta-analysis of all 22 trials with data for this outcome (0.95 [0.86-1.04], p=0.24), including 12,350 participants. The method of mortality assessment was identified as an effect modifier by meta-regression (p=0.01). A meta-analysis of 10 trials with complete mortality ascertainment via registries or primary care data showed a significantly 19% reduced mortality (0.81 [0.70-0.94], p<0.01)). In conclusion, medication reviews reduce the risk of hospital readmission and might also reduce all-cause mortality. Comprehensive mortality assessment was essential for successful trials. Clinical guidelines should recommend medication reviews with multiple patient contacts, involving pharmacists, either for repeated medication reviews or to improve adherence.

Preclinical evaluation of DC-CIK cells as potentially effective immunotherapy model for the treatment of glioblastoma

Despite the favorable effects of immunotherapies in multiple types of cancers, its complete success in CNS malignancies remains challenging. Recently, a successful clinical trial of cytokine-induced killer (CIK) cell immunotherapy in patients with glioblastoma (GBM) has opened a new avenue for adoptive cellular immunotherapies in CNS malignancies. Prompt from these findings, herein, we investigated whether dendritic cells (DC) in combination with cytokine-induced killer cells (DC-CIK) could also provide an alternative and more effective way to improve the efficacy of GBM treatment. The analysis showed that DC-CIK cells exerted a significant cytotoxic effect on the glioblastoma cell lines, especially with the phenotype of stem-like cells (GSCs). In addition, the increased specific lysis of these cells subsequent to DC-CIK co-culture was confirmed with confocal fluorescence microscope. The direct interactions between tumor and effector cells were found to be highly effective in GBM organoids (GBOs). Moreover, a significant increase in apoptosis and elevated levels of IFN-γ (and not TNF-α) secretion were observed as a targeting mechanism of DC-CIK cells against GBM cell models. Overall, we provide important preliminary evidence that DC-CIK cells may have potential in the treatment of CNS malignancies, particularly glioblastoma.

Current advance in comprehensive management of hilar cholangiocarcinoma and navigation in surgery: non-systematic reviews.

Hilar Cholangiocarcinoma (h-CCA) originates from the epithelial cells, which characters as longitudinal growth along the bile ducts and invasion of peripheral vascular nerves. Due to the tumours insidious progression and usually become advanced stage disease at presentation, patients' mortality could parallel incidence rates. For patients who are not amenable to resection, systemic therapy and palliative treatment become the way to go. Dawn of the immunotherapy era offers new opportunity for patients with advanced tumours. Numbers of successful clinical trials have been conducted these years, giving us the chance to optimise multiple treatment modalities. Although liver transplantation is worth to be considered, there is no high-level evidence to support it better outcomes over surgical resection. Given the poor prognosis of h-CCA, radical resection (R0) undoubtfully become the only irreplaceable treatment to prolonged survival. Thus, tumours free boundary assessment along the bile duct hit the crucial point. Over the years, numerous imaging techniques leveraging CT, MRI, intraoperation ultrasound and endoscopy with the aim of guiding operation to eliminating cancers. Novel fiberscopes utilizing the second near-infrared region light (NIR-II) offer the potential to assist surgeon visualize tumours precisely. In this review, we summarize the clinical palliative care for advanced h-CCA patients and new opportunities for medications, discussing liver transplantation and other available treatment that not widely disseminated. In addition, we mainly focus on the novel technique of real-time intraoperation imaging navigation to achieve R0 resection and potential molecule prognosis development in the intractable disease.

Management of Catheter-Related Urethral Injuries in Male Children.

Management of urethral trauma lacks clarity in the paediatric population.There is no clear guidance for management and follow-up of these patientswhich can lead to missing the long-term sequelae of the primary injury. Catheter-associated urethral injuriesare less likely to cause a complete transaction of the urethra. This is due to the mechanism, typically caused by creating a false passage or inflating the balloon in the urethra.In partial urethral injuries, the European Association of Urology (EAU) guidelines suggest follow-up after one-two weeks of bladder drainage or a urethrogram. The purpose of this study was to reviewliterature related to the management and follow-up of catheter-induced urethral injuries,subsequently comparing this toa case seriesin a single paediatric tertiary centre. The aim was to propose a unique algorithm to safely and effectively guide clinicians for thispresentation. In our case series, 11 of 12 required initial bladder drainage.The data demonstrated an inconsistent approach to investigations throughout their admissions. Most cases had a successful trial without catheter (TWOC) or ability to resume continuous intermittent catheterisation. One patient needed a vesicostomy.We had a single bulbar urethral stricture, which wouldn't permit an 8fr catheter. This was managed using cystoscopy and serial urethral dilations. Our cohort islikely an underrepresentation of the actual number of catheter-related injuries in our institute. Some injuries are managed by the parent team without referring to paediatric urologists if spontaneous micturition occurs or if they manage to catheterise after an initial traumatic attempt. Conclusion: Catheter-related urethral injuries arecommonbut underreported. They are less likely to have long-term sequelae than other mechanisms of trauma. The majority of casesdo well following a period of initial bladder drainage. Current practise varies even in one institute as there are no clear management and follow-up guidance in current literature. Our proposed algorithmis a useful tooland decreases the incidence of missing long-term sequelae. Management algorithm: Post urethral injury, a child who is passing urine with conservative management is likely to have good long-term function. They would require re-assessment after discharge. In clinic they would require urinary flow assessment and post-void residuals. If not toilet trained, parental impression of whether their child's stream is interrupted or if they strain during urination would be assessed. Back-pressure changes would be considered on ultrasound scan (USS). If the assessment indicates concern, then a micturating cystourethrogram (MCUG) assessment for children younger than one or a cystoscopic assessment for children older than one would be recommended. Post urethral injury, if a child is unable to pass urine conservatively, then an urgent urological assessment would be appropriate. An attempt at catheterisation would be made. If unsuccessful, the patient would be assessed for theatre. If unfit for it, an ultrasound-guided suprapubic (SP) catheter would be advised. If the patient is fit, then a cystoscopic and wire-guided catheter would be preferred. Later, if they passed a TWOC, they would be managed as per the algorithm described above. If they failed the TWOC, MCUG would be proceeded to. Catheter management and regular follow-up, or for a definitive intervention would be planned for.

The Evolving Applications of Bispecific Antibodies: Reaping the Harvest of Early Sowing and Planting New Seeds.

After decades of gradual progress from conceptualization to early clinical trials (1960-2000), the therapeutic potential of bispecific antibodies (bisp Abs) is now being fully realized. Insights gained from both successful and unsuccessful trials are helping to identify which mechanisms of action, antibody formats, and targets prove most effective, and which may benefit from further refinement. While T-cell engagers remain the most commonly used class of bisp Abs, current efforts aim to increase their effectiveness by co-engaging costimulatory molecules, reducing escape mechanisms, and countering immunosuppression. Strategies to minimize cytokine release syndrome (CRS) are also actively under development. In addition, novel antibody formats that are selectively activated within tumors are an exciting area of research, as is the precise targeting of specific T-cell subsets. Beyond T cells, the recruitment of macrophages and dendritic cells is attracting increasing interest, with researchers exploring various macrophage receptors to promote phagocytosis or to carry out specialized functions, such as the immunologically silent clearance of amyloid-beta plaques in the brain. While bisp Abs targeting B cells are relatively limited, they are primarily aimed at inhibiting B-cell activity in autoimmune diseases. Another evolving application involves the forced interaction between proteins. Beyond the successful development of Hemlibra for hemophilia, bispecific antibodies that mimic cytokine activity are being explored. Additionally, the recruitment of cell surface ubiquitin ligases and other enzymes represents a novel and promising therapeutic strategy. In regard to antibody formats, some applications such as the combination of T-cell engagers with costimulatory molecules are driving the development of trispecific antibodies, at least in preclinical settings. However, the increasing structural complexity of multispecific antibodies often leads to more challenging development paths, and the number of multispecific antibodies in clinical trials remains low. The clinical success of certain applications and well-established production methods position this therapeutic class to expand its benefits into other therapeutic areas.

Mapping the Clinical Development Trajectory of Cell and GeneTherapy Products.

While cell and gene therapies (CGTs) have emerged as promising modalities to treat conditions with limited therapeutic options, their unconventional development is fraught with uncertainty, rendering them high-risk assets for many pharmaceutical companies. Here, we assess the clinical development trajectories of CGT products by estimating probabilities of successful clinical trial phase transitions and the likelihood of achieving regulatory approval. We included all CGT products entering clinical development from 1993 to 2023 and intended for marketing in the United States, Europe, Japan, Canada, and Switzerland. Associations between product success and characteristics were investigated. In sub-analyses, we examined the clinical trajectories of two promising product types, chimeric antigen receptor T (CAR T) cell therapies and adeno-associated viral (AAV) vector-based gene therapies. We identified 995 CGT products corresponding to 1,961 development programs. A total of 44 CGTs secured at least one regulatory approval, corresponding to an overall likelihood of approval of 5.3% (95% CI 4.0-6.9). Development programs with an orphan designation had a higher likelihood of approval than those without (9.4%, 95% CI 6.6-13.3 vs. 3.2%, 95% CI 2.0-4.9), while programs for oncology indications had a lower likelihood of approval compared to those for non-oncology indications (3.2%, 95% CI 1.6-5.1 vs. 8.0%, 95% CI 5.7-11.1). CAR T cells and AAV gene therapies had a similar overall likelihood of approval of 13.6% (95% CI 7.3, 23.9) and 13.6% (95% CI 6.4, 26.7), respectively. In conclusion, CGT products have a low overall likelihood of approval with variability based on orphan status, therapeutic area, and product type.

Drafting a blueprint for designing successful clinical trials in clonal haematopoiesis.

'As our understanding of the biology of clonal hematopoiesis expands, a pressing need in the field becomes the design and implementation of clinical trials to help mitigate the risk for progression to overt myeloid neoplasm. Effective clinical trial design will be informed by use of personalized genetic risk to determine eligibility, strategic endpoint selection, and identification of suitable interventions with a goldilocks balance of toxicity and reduced risk of progression. We will only reach this milestone through collaboration'. Commentary on: Haque etal. A blueprint for pursuing therapeutic interventions and early phase clinical trials in clonal haematopoiesis. Br J Haematol 2024 (Onlineahead of print). doi: 10.1111/bjh.19925.

Applications of bio-printing to promote spinal cord regeneration.

The spinal cord is one of the most important part of the human nervous system and great importance is placed on developing the best treatment for its damage. 3D bio-printing technology, and the fabrication of special scaffolds using it, is a potential solution for regenerating damage in spinal cord injuries (SCIs). Bio-printing can be divided into indirect and direct bio-printing, while among the bio-printing methods, inkjet bio-printing, fused deposition modeling (FDM), extrusion bio-printing, or light-assisted bio-printing can be distinguished. The last group can be in turn divided into several separate techniques such as digital light processing (DLP), stereolithography (SLA) and laser-assisted bio-printing (LAB). While bio-printing technology for the treatment of SCI is in the early stages of research, several successful trials have already been performed, where the use of such scaffolds has resulted in at least partial restoration of autonomic nervous system function in patients with chronic and acute SCI.

Drug Treatments for Neurodevelopmental Disorders: Targeting Signaling Pathways and Homeostasis.

Preclinical and clinical evidence support the notion that neurodevelopmental disorders (NDDs) are synaptic disorders, characterized by excitatory-inhibitory imbalance. Despite this, NDD drug development programs targeting glutamate or gamma-aminobutyric acid (GABA) receptors have been largely unsuccessful. Nonetheless, recent drug trials in Rett syndrome (RTT), fragile X syndrome (FXS), and other NDDs targeting other mechanisms have met their endpoints. The purpose of this review is to identify the basis of these successful studies. Despite increasing evidence of disruption in synaptic homeostasis, most genetic variants associated with NDDs implicate proteins involved in cell regulation and not in neurotransmission. Metabolic processes, in particular mitochondrial function, appear to play a role in NDD pathophysiology. NDDs are also characterized by distinctive cell signaling abnormalities, which link cellular and synaptic homeostasis. Recent successful trials in NDDs, including those of trofinetide, the first drug specifically approved for one of these disorders (i.e., RTT), implicate the targeting of downstream processes (i.e., signaling pathways) rather than neurotransmitter receptors. Recent positive drug studies in NDDs and their underlying mechanisms, in conjunction with new knowledge on the pathophysiology of these disorders, support the concept that targeting signaling and cellular and synaptic homeostasis may be a preferred approach for ameliorating synaptic abnormalities in many NDDs.

Peripheral Mechanisms Underlying Bacillus Calmette-Guerin-Induced Lower Urinary Tract Symptoms (LUTS).

Non-muscle invasive bladder cancer (NMIBC) accounts for approximately 70-75% of all bladder cancer cases. The standard treatment for high-risk NMIBC involves transurethral tumour resection followed by intravesical Bacillus Calmette-Guerin (BCG) immunotherapy. While BCG immunotherapy is both safe and effective, it frequently leads to the development of lower urinary tract symptoms (LUTS) such as urinary urgency, frequency, dysuria, and pelvic discomfort. These symptoms can significantly diminish patients' quality of life and may result in the discontinuation of BCG treatment, adversely affecting oncological outcomes. Despite the considerable clinical impact of BCG-induced LUTS, the underlying mechanisms remain unclear, hindering the implementation or development of effective treatments. This review provides novel insights into the potential mechanisms underlying BCG-induced LUTS, focusing on the integrated roles of afferent and efferent nerves in both normal and pathological bladder sensation and function. Specifically, this review examines how the body's response to BCG-through the development of inflammation, increased urothelial permeability, and altered urothelial signalling-might contribute to LUTS development. Drawing from known mechanisms in other common urological disorders and data from successful clinical trials involving NMIBC patients, this review summarises evidence supporting the likely changes in both sensory nerve signalling and bladder muscle function in the development of BCG-induced LUTS. However, further research is required to understand the intricate mechanisms underlying the development of BCG-induced LUTS and identify why some patients are more likely to experience BCG intolerance. Addressing these knowledge gaps could have profound implications for patients' quality of life, treatment adherence, and overall outcomes in NMIBC care.

A successful clinical trial ecosystem offers equal opportunities for all citizens.

An inclusive clinical trial ecosystem is essential to obtain scientific results that can be generalized to a broad patient population. When possible, all efforts should be made to remove geographic, demographic, cultural and ethnic barriers for enrolment in clinical trials. However, to do this effectively, we need more knowledge about factors influencing clinical trial participation and practical frameworks to enhance diversity in clinical trials. Commentary on: Jones etal. Inequalities in geographic barriers and patient representation in lymphoma clinical trials across England. Br J Haematol 2024 (Online ahead of print). doi: 10.1111/bjh.19907.

Successful collaborative trials of simple gear modifications to reduce entanglement of whales and other megafauna in Scotland’s static pot (creel) fisheries

Abstract Entanglement in ropes associated with static fishing gear (pots/traps/creels) is a welfare and conservation concern for minke whales (Balaenoptera acutorostrata), humpback whales (Megaptera novaeangliae), basking sharks (Cetorhinus maximus), and other megafauna in Scottish waters. The Scottish Entanglement Alliance estimated that six humpback whales and 30 minke whales become entangled annually. Where entanglement type was known, 83% of minke whales, 50% of humpback whales, and 76% of basking sharks were caught in floating groundlines between pots. We collaborated with fishers on Scotland’s west coast to trial sinking groundline (which lies on the seabed) to assess its practicality. A total of 15 Nephrops (langoustine) and crab fishers re-roped 61 sets of creel gear and fished the gear for ∼15 months, reporting on each haul. Over 1500 hauls were reported; the fishers encountered few problems, in some cases preferring the modified gear. We also deployed depth sensors/accelerometers and filmed a range of sinking and floating rope configurations with a Remotely Operated Vehicle (ROV) to collect data on performance underwater. This project is encouraging, both because of its results—that there may be a simple option to greatly reduce entanglement risk—and because of the successful, bottom-up, partnership approach with Scottish creel fishers.