Exploring the Pharmacological Potential of Chlorogenic acid as an Anti-Cancer Agent and a Call for Advance Research.

Chlorogenic acid (CHA) is a phenolic substance found in various edible plants, such as tea and green coffee extracts. This chemical has demonstrated significant efficacy in reducing the probability of many diseases in preclinical and clinical environments. Chlorogenic acid (CHA) possesses several pharmacological attributes, such as anticancer, hepatoprotective, antimicrobial, immune-suppressant, antioxidant, and antidiabetic activities. Its applications extend to multiple industries, such as food, chemicals, medicine, and healthcare. Studies have shown that CHA can exert its anticancer effects through numerous mechanisms. It can hinder the process of cell division, trigger cell apoptosis, and suppress an increase in cancerous cell growth. The literature research conducted for this study revealed a variety of molecular and cellular processes influencing distinct signaling pathways. These mechanisms include angiogenesis, invasion and migration, oxidative stress, inflammation, cell cycle arrest, and proliferation.However, significant issues surround the use of CHA, primarily due to its limited bioavailability in animal models. This review focuses on the chemistry, natural sources, pharmacokinetics, and underlying mechanisms of action of CHA and its clinical utility in treating life-threatening diseases, such as cancer. The manuscript provides insight into novel formulation approaches.

Exploring Marine Alkaloids: A Natural Approach to Cancer Treatment.

Cancer is one of the most complicated and prevalent diseases in the world, and its incidence is growing worldwide. Natural products containing pharmacological activity are widely used in the pharmaceutical industry, especially in anticancer drugs, due to their diverse structures and distinctive functional groups that inspire new drug results by means of synthetic chemistry. Terrestrial medicinal plants have traditionally been the primary source for developing natural products (NPs). However, over the past thirty years, marine organisms such as invertebrates, plants, algae, and bacteria have revealed many new pharmaceutical compounds known as marine NPs. This field constantly evolves as a discipline in molecular targeted drug discovery, incorporating advanced screening tools that have revolutionised and become integral to modern antitumor research. This review discusses recent studies on new natural anticancer alkaloids obtained from marine organisms. The paper illustrates the structure and origin of marine alkaloids and demonstrates the cytotoxic action of new alkaloids from several structural families and their synthetic analogs. The most recent findings about the potential or development of some of them as novel medications, together with the status of our understanding of their current mechanisms of action, are also compiled.

Innovations in Skin Cancer Nanotechnology: A Comprehensive Review.

Skin cancer is the most common type of cancer among white people, according to the World Health Organisation. The incidence of melanoma and non-melanoma skin cancers has increased to epidemic levels, making them the most widespread type of skin cancer. Melanoma is a very aggressive form of cancer, characterized by limited treatment choices due to multidrug resistance and an extremely low probability of patient survival. This article explores the various impediments and limitations associated with conventionally available treatments. Chemotherapy, radiation, immunotherapy, and targeted therapy are among the conventional treatments for melanoma; however, each of these approaches has several adverse reactions. Recently, there has been a focus on biological and pharmacological research on developing alternative, site-specific therapy approaches. Nanotechnology offers several benefits in this regard, with the potential to enhance the longevity of melanoma patients while minimizing adverse effects. Nanoparticles serve as effective drug carrier systems due to their capacity to improve the solubility of medications with low water solubility, modify pharmacokinetics, prolong drug half-life by reducing immunogenicity, boost bioavailability, and decrease drug metabolism. This article highlights recent advancements in utilizing several nanotechnological techniques, including solid lipid nanoparticles, nanostructured lipid carriers, liposomes, transferosomes, ethosomes, and nanoemulsion polymeric mixed micelles.

Lignans: Advances in Biosynthesis, Bioavailability, and Pharmacological Activity.

Lignans, a group of naturally occurring compounds abundant in various plant-based foods, are becoming increasingly popular due to their potential health benefits. The literature suggests that these bioactive substances can reduce the risk of certain types of cancer, such as postmenopausal colon and breast cancer. Moreover, the significance of lignans for improving cardiovascular health has been recognized, as studies have revealed a potential correlation between the intake of lignans and a decreased risk of cardiovascular disease. These complex molecules possess diverse bioactive capabilities, rendering them potential alternatives for preventing chronic diseases. Further research is needed to examine the mechanisms responsible for their beneficial outcomes. Recent research has emphasized the pharmacological properties of lignans as effective substances for human health. Incorporating foods rich in lignans into the diet may be a practical approach to enhancing protection against life-threatening ailments, such as cardiovascular diseases and malignancies.

Exploring the Therapeutic Potential of Flavonoids in the Management of Cancer.

Flavonoids are a class of polyphenolic compounds that can be classified into six distinct categories, namely isoflavonoids, flavanones, flavanols, flavonols, flavones, and anthocyanidins. These compounds are naturally occurring and can be found in a diverse range of plant species. Flavonoids, a class of bioactive compounds, are mostly obtained through the consumption of vegetables, fruits and plant-derived beverages such as wine, cocoa-based products and green tea. Flavonoids have been demonstrated to exhibit a diverse range of anticancer properties. These include the modulation of activities of enzymes involved in scavenging reactive oxygen species, involvement in cell cycle arrest, induction of apoptosis and autophagy, as well as suppression of cancer cell proliferation and invasiveness. Flavonoids exhibit a dual role in maintaining reactive oxygen species balance. They function as antioxidants in regular physiological conditions, while also demonstrating significant pro-oxidant properties in cancer cells. This prooxidant activity induces apoptotic pathways and downregulates pro-inflammatory signalling pathways. The paper explores the biochemical characteristics, bioavailability, anticancer efficacy, and modes of action of flavonoids.

Nano-Based Theranostics Approach in the Management of Cancer: Review.

Cancer is a prevalent and potentially fatal disease worldwide. The proliferation of abnormal cells and uncontrolled cellular growth characterizes cancer. Cancerous tumors exhibit distinct microenvironments characterized by a deficient lymphatic drainage system and aberrant blood supply. Various medications and diagnostic systems exist for cancer treatment, but they all have inherent limitations and undesirable consequences. Consequently, the achievement of effective cancer detection and treatment remains challenging. Theranostics nanoparticles are becoming increasingly popular in nano drug delivery systems. These nanoparticles can diagnose and treat tumors, making them a promising approach in the field. They are designed to be small in size, allowing them to be effective in delivering drugs to targeted areas. Furthermore, these nanoparticles can fundamentally transform the identification and management of several ailments, including cardiovascular disorders and infectious diseases. Such nanoparticles possess dual capabilities, functioning as therapeutic agents and diagnostic tools. They can transport medicinal substances, such as medications, nucleic acids, or therapeutic proteins, and include substances that can be used for imaging, such as contrast agents or fluorescent dyes, to enable non-invasive diagnostics and monitoring of the effectiveness of the treatment. These techniques can be employed for diagnostic purposes to identify, locate, and determine the extent of disorders using imaging modalities such as magnetic resonance imaging, computed tomography, positron emission tomography, and fluorescence imaging. These nanoparticles can deliver therapeutic compounds to specific locations accurately during therapy. This leads to improved effectiveness of the treatment, decreased adverse effects, and better patient outcomes. They offer a potential nanomedicine approach by providing diagnostic and therapeutic capabilities for disease diagnosis and treatment. Theranostics nanoparticles have distinct characteristics and adaptability, which can transform the healthcare sector by facilitating personalized and precise medical treatments.

Meralgia Paresthetica as a Result of Surgery With an Emphasis on Harvesting Iliac Bone Grafts: A Review.

Meralgia paresthetica is a neurological disorder characterized by a symptom complex of numbness, burning, tingling, aching, or stabbing in the anterolateral portion of the upper thigh. Typically, this disorder is seen in patients with diabetes mellitus, obesity, and pregnancy. Also, it may result from a wide array of surgical interventions involving the region of the anterior superior iliac spine. Underlying pathophysiology concentrates on entrapment neuropathy of the lateral femoral cutaneous nerve (LFCN). Due to its location and wide anatomic variation, the LFCN is susceptible to compression, scarring, and injury during surgery. It is important to understand the regional anatomy. In addition, the plastic surgeon must have a working knowledge of the most common variations that can precipitate entrapment and increase susceptibility to injury during surgery. Surgeons lacking a substantial background on the numerous risk factors, origins, and anatomic variations of the LFCN may place patients at an even higher risk of damage to the nerve. An extensive knowledge of the anatomy and careful technique may be utilized by surgeons to prevent iatrogenic neuropathy of the LFCN.

FDA Approval Summary: Alpelisib for PIK3CA-Related Overgrowth Spectrum.

On April 5, 2022, FDA granted accelerated approval to alpelisib for the treatment of adult and pediatric patients 2 years of age and older with severe manifestations of PIK3CA-related overgrowth spectrum (PROS) who require systemic therapy. Efficacy was evaluated using real-world data (RWD) from EPIK-P1 (NCT04285723), a single-arm clinical study in patients 2 years of age and older with severe or life-threatening PROS who received alpelisib as part of an expanded access program (EAP) for compassionate use. The primary endpoint was confirmed radiologic response rate at week 24 as determined by blinded independent central review (BICR), using volumetric-based criteria given the atypical growth pattern and irregular shape of PROS lesions. Radiologic response was defined as a ≥20% reduction from baseline in the sum of measurable target lesion volume in up to three lesions. Of the 37 patients in the efficacy population, 27% [95% confidence interval (CI), 14-44] had a radiologic response at week 24. Duration of response (DOR) was an additional efficacy outcome measure, and among responders, 60% had a response lasting ≥12 months. Furthermore, supportive clinical documentation suggested early signals of clinical benefit (i.e., improvement in PROS-related signs and symptoms). The most common (≥10%) adverse reactions were diarrhea, stomatitis, and hyperglycemia.

Chemical Probes Review: Choosing the Right Path Towards Pharmacological Targets in Drug Discovery, Challenges and Future Perspectives.

Chemical probes are essential for academic research and target validation for disease identification. They facilitate drug discovery, target function investigation, and translation studies. A chemical probe provides starting material that can accelerate therapeutic values and safety measures for identifying any biological target in drug discovery. Essential read outs depend on their versatility in biochemical testing, proving the hypothesis, selectivity, specificity, affinity towards the target site, and valuable in new therapeutic approaches. Disease management will depend upon chemical probes as a primitive tool to ascertain the physicochemical stability for in vivo and in vitro studies useful for clinical trials and industrial application in the future. For cancer research, bacterial infection, and neurodegenerative disorders, chemical probes are integrated circuits which are on pipeline for the drug discovery process Furthermore, pharmacological modulators incorporate activators, crosslinkers, degraders, and inhibitors. Reports accessed depend on their structural, mechanical, biochemical, and pharmacological characterization in drug discovery research. The perspective for designing any chemical probes concludes with the utilization of drug discovery and identification of the potential target. It focuses mainly on evidence-based studies and produces promising results in successfully delivering novel therapeutics to treat cancers and other disorders at the target site. Moreover, natural product pharmacophores like rapamycin, cephalosporin, and ß-lactamase are utilized for drug discovery. Chemical probes revolutionize computational-based study design depending on identifying novel targets within the database framework. Chemical probes are the clinical answers for drug development and goforward tools in solving other riddles for scientists and researchers working in this industries.

Overview of Natural Supplements for the Management of Diabetes and Obesity.

Bioactive compounds found in various natural sources, such as fruits, vegetables, and herbs, have been studied for their potential benefits in managing obesity and diabetes. These compounds include polyphenols, flavonoids, other antioxidants, fiber, and certain fatty acids. Studies have found that these compounds may improve insulin sensitivity, regulate blood sugar levels, and promote weight loss. However, the effects of these compounds can vary depending on the type and amount consumed, as well as individual factors, such as genetics and lifestyle. Nutraceutical substances have multifaceted therapeutic advantages, and they have been reported to have disease-prevention and health-promoting properties. Several clinically used nutraceuticals have been shown to target the pathogenesis of diabetes mellitus, obesity, and metabolic syndrome and their complications and modulate various clinical outcomes favorably. This review aims to highlight and comment on some of the most prominent natural components used as antidiabetics and in managing obesity.

Multifunctional Drug Delivery System: Nanosponges.

In recent years, nanotechnology has been the focus of study for the cure of different diseases, among which nanosponge delivery system is one of a kind. Nano sponges are tiny, highly porous, three-dimensional nanostructures with a size range of 250nm-1µm in an amorphous or crystalline structure. Nanosponges usually act as an excipient or carrier of a drug in the different delivery systems. The type of polymers and cross-linkers, along with their concentration ratio, causes variation in nanosponges's dimension and encapsulation efficiency. Nanosponges have gained prominence in recent times due to their distinct ability to encapsulate both hydrophilic and lipophilic drugs within their internal cavity, thereby improving the solubility of drugs that have low water solubility. Virus-like size helps the nanosponges to circulate within the body without getting eliminated by the immune system until they stick to the targeted part of the body, which makes it the perfect candidate for a targeted drug delivery system and controlled delivery system as well because of its slow drug release property for a more extended period. Cyclodextrin-based nanosponges are the best choice for anticancer drug delivery as their small virus-like diameter helps them in passive targeting by enhancing the enhanced permeability and retention effect, allowing the anticancer drug to stay inside the tumour cell to show more significant therapeutic action on cancer, while for active targeting to the cancerous cell, nanosponges are attached with a ligand on it for receptor binding purpose. It can be used for drug delivery in many major diseases like brain-related diseases, diabetes, cancer, fungal, hypertension, etc., in different dosage forms, like oral, topical, hydrogel, parenteral, etc.

Review on Nutritional Potential of Underutilized Millets as a Miracle Grain.

The current situation, which includes changes in eating habits, an increasing population, and the unrestricted use of natural resources, has resulted in a lack of resources that could be used to provide nourishing food to everyone. Natural plant resources are quickly being depleted, so it is necessary to consider new alternatives. In addition to the staple grains of rice and wheat, many other crops are being consumed that need to be utilized to their full potential and have the potential to replace the staple crops. Millets are one of the most important underutilized crops that have the potential to be used as a nutricereal. Millets have a high nutritional value, do not produce acids, do not contain gluten, and can contribute to a healthy diet. Due to a lack of awareness regarding the nutritional value of millets, their consumption is still restricted to the population that adheres to conventional diets and is economically disadvantaged even though millets contain a significant amount of nutrients. Millets are becoming increasingly unpopular due to a lack of processing technologies, food subsidies, and the inconvenience of preparing food with millets. Millets are a Nutricereal rich in carbohydrates, dietary fibers, energy, essential fatty acids, proteins, vitamin B, and minerals such as calcium, iron, magnesium, potassium, and zinc. These nutrients help to protect against post-translational diseases such as diabetes, cancer, cardiovascular disease, and celiac disease, among others. Millets are beneficial for controlling blood pressure, blood sugar level, and thyroid function; however, despite these functional properties, millets consumption has declined. Utilizing millets and other staple food crops to develop alternative food sources has become a new area of focus for businesses in the food industry. In addition, millet consumption can help foster immunity and health, which is essential in strengthening our fight against malnutrition in children and adolescents. In this article, the authors examine the potential of millets in terms of their nutricereal qualities.

Review on Natural Agents as Aromatase Inhibitors: Management of Breast Cancer.

Breast cancer is a prevalent type of cancer that is typically hormone-dependent, caused by estrogen. Aromatase inhibitors are frequently utilised in the treatment of hormonereceptor- positive breast cancer because they prevent the enzyme aromatase from converting androgens to estrogens. Natural medicines with aromatase inhibitory characteristics have attracted interest as potential alternatives or complementary therapy to manufactured medications. This review discusses the function of natural agents as aromatase inhibitors in treating breast cancer. A variety of natural compounds have been investigated for their capacity to inhibit aromatase activity and lower estrogen levels. These agents include resveratrol from red wine and grapes, curcumin from turmeric extract and green teahigh in catechins, and other flavonoids such as genistein, luteolin and quercetin. It has been demonstrated that by decreasing estrogen synthesis, they can slow the growth of breast cancer cells that are dependent on estrogen. However, the clinical evidence supporting their efficacy and safety in breast cancer treatment is inadequate. More research is required to investigate the therapeutic potential of natural medicines, such as aromatase inhibitors, in treating breast cancer. The clinical trials are required to assess their efficacy, appropriate doses, and potential interactions with other therapies. In conclusion, natural aromatase inhibitory drugs are promising adjuncts in the treatment of hormone receptor-positive breast cancer. Their clinical value and safety profile, however, require additional investigation.

Natural Polyphenols in Cancer Management: Promising Role, Mechanisms, and Chemistry.

BACKGROUND: Although cancers emerge rapidly and cancer cells divide aggressively, which affects our vital organ systems. Recently, cancer treatments are targeted immune systems mediating intrinsic cellular mechanisms. Natural efficacious polyphenols have been exhibited to help prevent most cancers and reverse the progression of cancers. METHODS: Many resources have been used to know the promising role of polyphenols in preventing and treating cancers. The electronic databases include Science Direct, Google, Google Scholar, PubMed, and Scopus. The search was limited to the English language only. RESULTS: Polyphenols have been reported as anti-metastatic agents that explore the promising role of these compounds in cancer prevention. Such agents act through many signaling pathways, including PI3K/Akt and TNF-induced signaling pathways. The chemical modifications of polyphenols and the structure-activity relationships (SARs) between polyphenols and anti-cancer activities have also been discussed. CONCLUSION: Many research papers were reported to explain the anti-cancer potential of Polyphenols, The SARs between polyphenols and anti-cancer activities, which correlate structures of polyphenols with significant chemotherapeutic action. The mechanism of anti-cancer potential is to be added for searching for new anti-cancer natural products.

Emerging Applications of Nanotechnology in Drug Delivery and Medical Imaging: Review.

The use of the one-of-a-kind qualities possessed by substances at the nanoscale is the core concept of nanotechnology. Nanotechnology has become increasingly popular in various business sectors because it enables better construction and more advanced product design. Nanomedicine is the name given to the application of nanotechnology in the medical and healthcare fields. It has been used to fight against some of the most prevalent diseases, such as cancer and cardiovascular diseases. This current manuscript provides an overview of the recent advancements in nanotechnology in drug delivery and imaging.

An Overview of Dietary Flavonoids as a Nutraceutical Nanoformulation Approach to Life-threatening Diseases.

Obesity, heart disease, diabetes, and cancer are just a few chronic diseases for which proper nutrition has been demonstrated to be a crucial factor in prevention. Flavonoids, found in many fruits and vegetables, are a type of dietary polyphenol with potent antioxidant activity and anti-carcinogenic characteristics. Flavonoids and foods rich in flavonoids have been shown in recent years to have profound effects on cognitive function, aging, and neurodegenerative diseases like Alzheimer's. Foods high in flavonoids, such as green tea, chocolate, blueberries, and other fruits and vegetables, have ameliorated symptoms of cognitive impairment, Alzheimer's disease, and dementia in several animal models. As a result of their ability to prevent neuronal death generated by neurotoxic chemicals such as free radicals and ß-amyloid proteins. Furthermore, flavonoids are also effective in slowing the evolution of clinical signs of neurodegenerative illnesses. In addition, flavonoids can improve lipid profiles by preventing the oxidation of low-density lipoproteins, and these antioxidant capabilities are responsible for their therapeutic impacts. Finally, the potential of flavonoids to induce vasodilation and control apoptotic processes in the endothelium is another way in which they benefit the cardiovascular system. This review aims to offer up-to-date information on categorizing these compounds, their primary methods of action in the human body, and their positive impacts on the management of neurodegenerative diseases, cardiovascular disorders, and other life-threatening diseases.

Decreased Human Immunodeficiency Virus Diagnosis Rates Among Black and Hispanic or Latino Men Who Have Sex With Men in US Jurisdictions Supported by the THRIVE Demonstration Project, 2014-2019.

BACKGROUND: Black and Hispanic/Latino men who have sex with men (MSM) are disproportionately affected by human immunodeficiency virus (HIV). In the Targeted Highly Effective Interventions to Reverse the HIV Epidemic (THRIVE) demonstration project, 7 community collaboratives were developed to provide comprehensive HIV prevention services for these populations. METHODS: We analyzed National HIV Surveillance System data to determine the number of HIV diagnoses for each year from 2014 to 2019 among Black, Hispanic/Latino, and White MSM in 7 THRIVE-eligible Metropolitan Statistical Areas (MSAs) that were awarded funding and 12 THRIVE-eligible MSAs that were not awarded funding. We used generalized linear Poisson regression models to estimate adjusted estimated annual percentage changes (EAPCs) with 95% confidence intervals for HIV diagnosis rates controlling for HIV prevalence, viral suppression, HIV testing rates, preexposure prophylaxis (PrEP) prescription rates, poverty, education, and insurance status. RESULTS: We found larger estimated decreases in HIV diagnosis rates in THRIVE jurisdictions compared with non-THRIVE jurisdictions. The adjusted EAPC among Black MSM was -8.2 (-11.7 to -4.6) in THRIVE MSAs compared with -4.2 (-7.8 to -0.4) in non-THRIVE MSAs. The adjusted EAPC among Hispanic/Latino MSM was -8.6 (-12.2 to -4.8) in THRIVE MSAs compared with -2.6 (-5.1 to -0.1)in non-THRIVE MSAs. The adjusted EAPC among White MSM was -7.6 (-12.0 to -3.1) in THRIVE MSAs compared with 5.9 (1.8-10.1) in non-THRIVE MSAs. CONCLUSIONS: The THRIVE community collaborative model was associated with a decrease in HIV diagnoses among Black and Hispanic/Latino MSM. To achieve the goals of the US Ending the HIV Epidemic initiative, effective interventions aimed to increase PrEP use need to be focused on Black and Hispanic/Latino MSM.

Manual small-incision cataract surgery under topical anesthesia for post-uveitis complicated cataract.

Purpose: Cataract development is a common sequelae associated with uveitis. Despite phacoemulsification being the popular method of cataract surgery today, manual small-incision cataract surgery (MSICS) may still be a safe and effective alternative because of several inherent benefits. There is not much literature and studies on the efficacy and safety of MSICS under topical anesthesia in complicated cataract in patients with uveitis. We aimed to study the safety and visual outcome of MSICS under topical anesthesia for post uveitis complicated cataract. Methods: This was a retrospective observational study. The electronic medical records of adult patients who underwent MSICS under topical anesthesia for post uveitis cataract were reviewed. The records were reviewed and analyzed for preoperative clinical characteristics and visual acuity, intraoperative complications and postoperative visual acuity, and complications. Results: A total of 71 eyes of 59 patients were taken for final analysis. The average age of patients was 59.9 years. There was improvement in the best corrected visual acuity by 0.7 logMAR (P value <0.0001). Average follow-up period was 9.8 months. The mean gain in visual acuity in eyes that received preoperative steroids was 0.6 logMAR compared to the eyes that did not receive steroids (0.71 logMAR). The difference was not statistically significant (P = 0.407). Complications seen during long-term follow-up were recurrence (15.5%), cystoid macular edema (7%), Epiretinal membrane (8.5%), and posterior capsular opacification (5.5%). Conclusion: With proper technique and precautions, MSICS can be safely and comfortably performed under topical anesthesia even in complicated cataracts with excellent visual and safety outcomes.

Second Paediatric Strategy Forum for anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies: ACCELERATE in collaboration with the European Medicines Agency with the participation of the Food and Drug Administration.

The first (2017) and sixth (2021) multistakeholder Paediatric Strategy Forums focused on anaplastic lymphoma kinase (ALK) inhibition in paediatric malignancies. ALK is an important oncogene and target in several paediatric tumours (anaplastic large cell lymphoma [ALCL], inflammatory myofibroblastic tumour [IMT], neuroblastoma and hemispheric gliomas in infants and young children) with unmet therapeutic needs. ALK tyrosine kinase inhibitors have been demonstrated to be active both in ALK fusion-kinase positive ALCL and IMT. ALK alterations differ, with fusions occurring in ALCL, IMT and gliomas, and activating mutations and amplification in neuroblastoma. While there are many ALK inhibitors in development, the number of children diagnosed with ALK driven malignancies is very small. The objectives of this ALK Forum were to (i) Describe current knowledge of ALK biology in childhood cancers; (ii) Provide an overview of the development of ALK inhibitors for children; (iii) Identify the unmet needs taking into account planned or current ongoing trials; (iv) Conclude how second/third-generation inhibitors could be evaluated and prioritised; (v) Identify lessons learnt from the experience with ALK inhibitors to accelerate the paediatric development of other anti-cancer targeted agents in the new regulatory environments. There has been progress over the last four years, with more trials of ALK inhibitors opened in paediatrics and more regulatory submissions. In January 2021, the US Food and Drug Administration approved crizotinib for the treatment of paediatric and young adult patients with relapsed or refractory ALCL and there are paediatric investigation plans (PIPs) for brigatinib and for crizotinib in ALCL and IMT. In ALCL, the current goal is to investigate the inclusion of ALK inhibitors in front-line therapy with the aim of decreasing toxicity with higher/similar efficacy compared to present first-line therapies. For IMT, the focus is to develop a joint prospective trial with one product in children, adolescents and adults, taking advantage of the common biology across the age spectrum. As approximately 50% of IMTs are ALK-positive, molecular analysis is required to identify patients to be treated with an ALK inhibitor. For neuroblastoma, crizotinib has not shown robust anti-tumour activity. A focused and sequential development of ALK inhibitors with very good central nervous system (CNS) penetration in CNS tumours with ALK fusions should be undertaken. The Forum reinforced the strong need for global academic collaboration, very early involvement of regulators with studies seeking possible registration and early academia-multicompany engagement. Innovations in study design and conduct and the use of 'real-world data' supporting development in these rare sub-groups of patients for whom randomised clinical trials are not feasible are important initiatives. A focused and sequenced development strategy, where one product is evaluated first with other products being assessed sequentially, is applicable for ALK inhibitors and other medicinal products in children.