Inborn errors of immunity: A field without frontiers.

The study of primary immunodeficiencies or inborn errors of immunity continues to drive our knowledge of the function of the human immune system. From the outset, the study of inborn errors has focused on unraveling genetic etiologies and molecular mechanisms. Aided by the continuous growth in genetic diagnostics, the field has moved from the study of an infection dominated phenotype to embrace and unravel diverse manifestations of autoinflammation, autoimmunity, malignancy, and severe allergy in all medical disciplines. It has now moved from the study of ultrarare presentations to producing meaningful impact in conditions as diverse as inflammatory bowel disease, neurological conditions, and hematology. Beyond offering immunogenetic diagnosis, the study of underlying inborn errors of immunity in these conditions points to targeted treatment which can be lifesaving.

Molecular mechanisms and emerging therapies in wild-type transthyretin amyloid cardiomyopathy.

Wild-type transthyretin amyloid cardiomyopathy (ATTRwt-CM) is an underrecognized cause of heart failure due to misfolded wild-type transthyretin (TTRwt) myocardial deposition. The development of wild-type TTR amyloid fibrils is a complex pathological process linked to the deterioration of homeostatic mechanisms owing to aging, plausibly implicating multiple molecular mechanisms. The components of amyloid transthyretin often include serum amyloid P, proteoglycans, and clusterin, which may play essential roles in the localization and elimination of amyloid fibrils. Oxidative stress, impaired mitochondrial function, and perturbation of intracellular calcium dynamics induced by TTR contribute to cardiac impairment. Recently, tafamidis has been the only drug approved by the U.S. Food and Drug Administration (FDA) for the treatment of ATTRwt-CM. In addition, small interfering RNAs and antisense oligonucleotides for ATTR-CM are promising therapeutic approaches and are currently in phase III clinical trials. Newly emerging therapies, such as antibodies targeting amyloid, inhibitors of seed formation, and CRISPR‒Cas9 technology, are currently in the early stages of research. The development of novel therapies is based on progress in comprehending the molecular events behind amyloid cardiomyopathy. There is still a need to further advance innovative treatments, providing patients with access to alternative and effective therapies, especially for patients diagnosed at a late stage.

Current and emerging drug treatment strategies to tackle sickle cell anemia.

INTRODUCTION: Since its discovery in the early 1900s, sickle cell disease (SCD) has contributed significantly to the scientific understanding of hemoglobin and hemoglobinopathies. Despite this, now almost a century later, optimal medical management and even curative options remain limited. Encouragingly, in the last decade, there has been a push toward advancing the care for individuals with SCD and a diversifying interest in options to manage this disorder. AREAS COVERED: Here, we review the current state of disease modifying therapies for SCD including fetal hemoglobin inducers, monoclonal antibodies, anti-inflammatory modulators, and enzyme activators. We also discuss current curative strategies with specific interest in transformative gene therapies. EXPERT OPINION: SCD is a chronic, progressive disease that despite a century of clinical description, only now is seeing a growth and advance in therapeutic options to improve the lifespan and quality of life for individuals with SCD. We anticipate newly designed and even repurposed therapies that may work as a single agent or combination agents to tackle the progression of SCD. The vast majority of individuals living with SCD are unlikely to receive gene therapy, therefore improved disease management is critical even for those that may ultimately chose to pursue a potentially curative strategy.

Current Treatment Options in Relapsed and Refractory Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma: a Review.

OPINION STATEMENT: Treatment of relapsed and refractory (R/R) chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL) has changed dramatically over the past decade due to the development of oral targeted agents in several therapeutic classes, including BTK inhibitors (such as ibrutinib, acalabrutinib, zanubrutinib, and the non-covalent BTK inhibitor pirtobrutinib), the first in class BCL2 inhibitor venetoclax, PI3K inhibitors (idelalisib and duvelisib), and monoclonal antibodies in monotherapy and in combination. My approach to treatment of the R/R patient draws heavily on prior therapies, such that a patient with no exposure to prior novel therapies would be offered either a BTK or BCL2-based regimen, whereas patients with prior BTK inhibitor exposure would likely receive a BCL2 inhibitor and vice versa. For patients who are intolerant to a BTK inhibitor but are otherwise responding, an alternate BTK inhibitor may be considered. For those patients who have received a fixed-duration BCL2 inhibitor-based regimen and have maintained a response for greater than 12-24 months, re-treatment with a BCL2 inhibitor-based regimen at progression may be considered based on limited data, recognizing that robust prospective clinical trials are lacking in this space. For those patients who are "double refractory" and have progressed on both a BTK inhibitor and a BCL2 inhibitor-based regimen, clinical trials are strongly preferred. In absence of a clinical trial, these patients can be challenged with PI3K inhibitors, though responses are usually not durable, and toxicity is high. Combination cytotoxic chemotherapy with novel agents, allogeneic hematopoietic stem cell transplant, and cellular therapy may be considered for very high-risk populations, such as patients with Richter's transformation, though novel approaches are urgently needed and clinical trial enrollment is highly encouraged.

Comparing the traditional and emerging therapies for enhancing wound healing in diabetic patients: A pivotal examination.

Chronic non-healing ulcers are common among diabetic patients, posing significant therapeutic challenges. This study compared traditional therapies (TT) and emerging therapies (ET) for enhancing diabetic patients' wound healing. A total of 150 diabetic patients with chronic ulcers, ages 30-65, were randomly assigned to one of two groups: TT (n = 75) or ET (n = 75). ET included growth factors, bioengineered skin substitutes, and hyperbaric oxygen therapy, while TT for wound healing predominantly included debridement, saline-moistened dressings, and off-loading techniques. The primary outcome was the percentage of lesions that healed within 12 weeks, which was assessed at intervals. Secondary outcomes included time to wound recovery, pain using Visual Analogue Scale (VAS), and life quality via Wound-QoL questionnaire. By the 12th week, the ET group had a repair rate of 81.33% compared to 57.33% in TT group (p < 0.05). ET exhibited superior pain reduction (VAS score: 4.7 ± 1.6 for ET vs. 6.2 ± 1.4 for TT, p < 0.05) and improved life quality (Wound-QoL score: 61.8 ± 9.1 for ET vs. 44.3 ± 10.3 for TT, p < 0.05). However, there were slightly more cases of cutaneous irritation and hematomas among ET patients. ET have demonstrated significant efficacy in accelerating wound healing in diabetic patients, surpassing traditional methods, with additional advantages in pain management and life quality. Due to the observed minor complications, however, caution is required.

New Insights Into Pancreatic Cancer: Notes from a Virtual Meeting.

Pancreatic ductal adenocarcinoma remains a major challenge in cancer medicine. Given the increase in incidence and mortality, interdisciplinary research is necessary to translate basic knowledge into therapeutic strategies improving the outcome of patients. On the 4th and 5th of February 2021, three German pancreatic cancer research centers, the Clinical Research Unit 5002 from Göttingen, the Collaborative Research Center 1321 from Munich, and Clinical Research Unit 325 from Marburg organized the 1st Virtual Göttingen-Munich-Marburg Pancreatic Cancer Meeting in order to foster scientific exchange. This report summarizes current research and proceedings presented during that meeting.

Emerging hormonal agents for the treatment of prostate cancer.

INTRODUCTION: Prostate cancer is the most common solid organ malignancy in men in the United States. Until recently, treatment options for men with metastatic disease were limited and patients faced poor outcomes with minimal alternatives. The landscape of prostate cancer treatment has transformed and taken shape over the last 20 years with novel hormonal and non-hormonal therapeutics that have demonstrated significant improvement in survival. However, patients with advanced disease still face imminent progression on hormone blockade therapy. AREAS COVERED: There is a significant market opportunity to devise novel, more potent agents for patients with hormone-resistant disease. Here we review the existing treatment options in men with advanced prostate cancer, the market opportunity within this field, goals of current research, and the novel agents under investigation, including androgen receptor degraders, testosterone synthesis pathway inhibitors, DNA-binding domain and N-terminal domain antagonists, and the combination of hormonal and non-hormonal agents. EXPERT OPINION: Combination therapy regimens and novel agents targeting alternative binding domains of the androgen receptor are of great interest, as they may overcome resistance mechanisms and hold promise as the future of advanced prostate cancer treatment.

Emerging drugs for the treatment of hereditary angioedema due to C1-inhibitor deficiency.

INTRODUCTION: Hereditary angioedema due to C1-inhibitor (C1-INH-HAE) is a rare disease characterized by unpredictable swelling attacks that may be life-threatening when affecting the upper airways. Understanding the pathophysiology of HAE and the mechanism of bradykinin-mediated angioedema allowed the development of new therapies for the treatment of HAE: clinical trials are ongoing to expand the number of drugs available for on-demand treatment and prophylaxis. AREAS COVERED: Authors discuss the products that have been used to treat this disease for many years and present the most recently marketed products and those which are under development. EXPERT OPINION: Significant therapeutic progress has been made in HAE. In particular, drugs targeting specific molecules involved in the angioedema formation were developed and studies with new drugs are ongoing. In the coming years, more effective therapies with easier administration route options for on-demand treatment and long-term prophylaxis will be available to treat this disease and the variety of patients. Gene therapy strategies may offer a definitive treatment. High costs of current and new drugs may be a limiting factor for their availability, especially in developing countries.

Molecular Mechanisms, Biomarkers and Emerging Therapies for Chemotherapy Resistant TNBC.

Triple-negative breast cancer (TNBC) is associated with high recurrence rates, high incidence of distant metastases, and poor overall survival (OS). Taxane and anthracycline-containing chemotherapy (CT) is currently the main systemic treatment option for TNBC, while platinum-based chemotherapy showed promising results in the neoadjuvant and metastatic settings. An early arising of intrinsic or acquired CT resistance is common and represents the main hurdle for successful TNBC treatment. Numerous mechanisms were uncovered that can lead to the development of chemoresistance. These include cancer stem cells (CSCs) induction after neoadjuvant chemotherapy (NACT), ATP-binding cassette (ABC) transporters, hypoxia and avoidance of apoptosis, single factors such as tyrosine kinase receptors (EGFR, IGFR1), a disintegrin and metalloproteinase 10 (ADAM10), and a few pathological molecular pathways. Some biomarkers capable of predicting resistance to specific chemotherapeutic agents were identified and are expected to be validated in future studies for a more accurate selection of drugs to be employed and for a more tailored approach, both in neoadjuvant and advanced settings. Recently, based on specific biomarkers, some therapies were tailored to TNBC subsets and became available in clinical practice: olaparib and talazoparib for BRCA1/2 germline mutation carriers larotrectinib and entrectinib for neurotrophic tropomyosin receptor kinase (NTRK) gene fusion carriers, and anti-trophoblast cell surface antigen 2 (Trop2) antibody drug conjugate therapy for heavily pretreated metastatic TNBC (mTNBC). Further therapies targeting some pathologic molecular pathways, apoptosis, miRNAS, epidermal growth factor receptor (EGFR), insulin growth factor 1 receptor (IGF-1R), and androgen receptor (AR) are under investigation. Among them, phosphatidylinositol 3 kinase (PI3K)/protein kinase B (Akt)/mammalian target of rapamycin (mTOR) and EGFR inhibitors as well as antiandrogens showed promising results and are under evaluation in Phase II/III clinical trials. Emerging therapies allow to select specific antiblastics that alone or by integrating the conventional therapeutic approach may overcome/hinder chemoresistance.

Oral Therapy for the Treatment of Transthyretin-Related Amyloid Cardiomyopathy.

The care of systemic amyloidosis has improved dramatically due to improved awareness, accurate diagnostic tools, the development of powerful prognostic and companion biomarkers, and a continuous flow of innovative drugs, which translated into the blooming of phase 2/3 interventional studies for light chain (AL) and transthyretin (ATTR) amyloidosis. The unprecedented availability of effective drugs ignited great interest across various medical specialties, particularly among cardiologists who are now recognizing cardiac amyloidosis at an extraordinary pace. In all amyloidosis referral centers, we are observing a substantial increase in the prevalence of wild-type transthyretin (ATTRwt) cardiomyopathy, which is now becoming the most common form of cardiac amyloidosis. This review focuses on the oral drugs that have been recently introduced for the treatment of ATTR cardiac amyloidosis, for their ease of use in the clinic. They include both old repurposed drugs or fit-for-purpose designed compounds which bind and stabilize the TTR tetramer, thus reducing the formation of new amyloid fibrils, such as tafamidis, diflunisal, and acoramidis, as well as fibril disruptors which have the potential to promote the clearance of amyloid deposits, such as doxycycline. The development of novel therapies is based on the advances in the understanding of the molecular events underlying amyloid cardiomyopathy.

New and Emerging Targeted Therapies for Advanced Breast Cancer.

In the United States, breast cancer is among the most frequently diagnosed cancers in women. Breast cancer is classified into four major subtypes: human epidermal growth factor receptor 2 (HER2), Luminal-A, Luminal-B, and Basal-like or triple-negative, based on histopathological criteria including the expression of hormone receptors (estrogen receptor and/or progesterone receptor) and/or HER2. Primary breast cancer treatments can include surgery, radiation therapy, systemic chemotherapy, endocrine therapy, and/or targeted therapy. Endocrine therapy has been shown to be effective in hormone receptor-positive breast cancers and is a common choice for adjuvant therapy. However, due to the aggressive nature of triple-negative breast cancer, targeted therapy is becoming a noteworthy area of research in the search for non-endocrine-targets in breast cancer. In addition to HER2-targeted therapy, other emerging therapies include immunotherapy and targeted therapy against critical checkpoints and/or pathways in cell growth. This review summarizes novel targeted breast cancer treatments and explores the possible implications of combination therapy.

Rectovaginal Fistula in Crohn's Disease: When and How to Operate?

Rectovaginal fistula (RVF) occurring during the course of Crohn's disease (CD) constitutes a therapeutic challenge and is characterized by a high rate of recurrence. To optimize the outcome of CD-related RVF repair, the best conditions for correct healing should be obtained. Remission of CD should be achieved with no active proctitis, the perianal CD activity should be minimized, and local septic complications should be controlled. The objective of surgical repair is to close the fistula tract with minimal recurrence and functional disturbance. Several therapeutic strategies exist and the approach should be tailored to the anatomy of the RVF and the quality of the local supporting tissues. Herein, we review the medical and surgical management of CD-related RVF.

Postpartum Depression: Pathophysiology, Treatment, and Emerging Therapeutics.

Postpartum depression (PPD) is common, disabling, and treatable. The strongest risk factor is a history of mood or anxiety disorder, especially having active symptoms during pregnancy. As PPD is one of the most common complications of childbirth, it is vital to identify best treatments for optimal maternal, infant, and family outcomes. New understanding of PPD pathophysiology and emerging therapeutics offer the potential for new ways to add to current medications, somatic treatments, and evidence-based psychotherapy. The benefits and potential harms of treatment, including during breastfeeding, are presented.

Emerging Therapies for Prehospital Control of Hemorrhage.

BACKGROUND: The aim of this review was to describe emerging therapies that could serve as a prehospital intervention to slow or stop noncompressible torso hemorrhage in the civilian and military settings. Hemorrhage accounts for 90% of potentially survivable military deaths and 30%-40% of trauma deaths. There is a great need to develop novel therapies to slow or stop noncompressible torso hemorrhage at the scene of the injury. METHODS: A comprehensive literature search was performed using PubMed (1966 to present) for therapies not approved by the Food and Drug Administration for noncompressible torso hemorrhage in the prehospital setting. Therapies were divided into compressive versus intravascular injectable therapies. Ease of administration, skill required to use the therapy, safety profile, stability, shelf-life, mortality benefit, and efficacy were reviewed. RESULTS: Multiple potential therapies for noncompressible torso hemorrhage are currently under active investigation. These include (1) tamponade therapies, such as gas insufflation and polyurethane foam injection; (2) freeze-dried blood products and alternatives such as lyophilized platelets; (3) nanoscale injectable therapies such as polyethylene glycol nanospheres, polyethylenimine nanoparticles, SynthoPlate, and tissue factor-targeted nanofibers; and (4) other injectable therapies such as polySTAT and adenosine, lidocaine, and magnesium. Although each of these therapies shows great promise at slowing or stopping hemorrhage in animal models of noncompressible hemorrhage, further research is needed to ensure safety and efficacy in humans. CONCLUSIONS: Multiple novel therapies are currently under active investigation to slow or stop noncompressible torso hemorrhage in the prehospital setting and show promising results.

Treatment of malignant peripheral nerve sheath tumors in pediatric NF1 disease.

BACKGROUND: Malignant peripheral nerve sheath tumors (MPNSTs) are rare yet highly aggressive soft tissue sarcomas. Children with neurofibromatosis type 1 (NF1) have a 10% lifetime risk for development of MPNST. Prognosis remains poor and survival seems worse for NF1 patients. METHODS: This narrative review highlights current practices and pitfalls in the management of MPNST in pediatric NF1 patients. RESULTS: Preoperative diagnostics can be challenging, but PET scans have shown to be useful tools. More recently, functional MRI holds promise as well. Surgery remains the mainstay treatment for these patients, but careful planning is needed to minimize postoperative morbidity. Functional reconstructions can play a role in improving functional status. Radiotherapy can be administered to enhance local control in selected cases, but care should be taken to minimize radiation effects as well as reduce the risk of secondary malignancies. The exact role of chemotherapy has yet to be determined. Reports on the efficacy of chemotherapy vary as some report lower effects in NF1 populations. Promisingly, survival seems to ameliorate in the last few decades and response rates of chemotherapy may increase in NF1 populations when administering it as part of standard of care. However, in metastasized disease, response rates remain poor. New systemic therapies are therefore desperately warranted and multiple trials are currently investigating the role of drugs. Targeted drugs are nevertheless not yet included in first line treatment. CONCLUSION: Both research and clinical efforts benefit from multidisciplinary approaches with international collaborations in this rare malignancy.

Optimizing Dyslipidemia Management for the Prevention of Cardiovascular Disease: a Focus on Risk Assessment and Therapeutic Options.

Primary prevention of incident atherosclerotic cardiovascular disease (ASCVD) as well as decreasing the risk of future events in those with established atherosclerosis is critical from a public health perspective. Management of dyslipidemias constitutes a key target in decreasing the risk of developing ASCVD events. While there have been great strides in the treatment of dyslipidemia over the last three decades, there are important recent developments and ongoing research that will expand the available therapeutic options and enable further cardiovascular risk reduction. PURPOSE OF REVIEW: The purpose of this paper is to review new developments relating to the primary prevention and management of ASCVD with a specific focus on optimizing the treatment of dyslipidemias. RECENT FINDINGS: In the realm of ASCVD risk prediction, mounting evidence over the last decade has demonstrated that coronary artery calcium testing is superior to any serum biomarker in the prediction of future ASCVD events and in discriminating future cardiovascular risk. As such, it has been incorporated into the most recent ACC/AHA primary prevention guideline to help guide management decisions in select patients. In terms of the management of dyslipidemias, PCSK9 inhibitors lower LDL-C by 50-70% and provide an additional 15% reduction in key cardiovascular events in high-risk patients with known ASCVD, as demonstrated in the ODYSSEY and FOURIER trials. Cholesteryl ester transfer protein (CETP) inhibitors, which significantly increase HDL-C levels, demonstrated mixed results in large clinical trials and have helped reframe HDL-C as a risk marker rather than a modifiable risk factor. In regard to the management of triglycerides, the REDUCE-IT trial demonstrated a nearly 5% absolute reduction in key cardiovascular events with a highly purified fish-oil derivative named icosapent ethyl in high-risk patients already on statin therapy. Finally, in regard to lipoprotein(a)-which is a strong risk factor for ASCVD-there are exciting developments in the therapeutic pipeline which reduce circulating lipoprotein(a) levels by nearly 90%. The management of dyslipidemias continues to be an exciting field with several ongoing cardiovascular outcomes trials, improvement in risk prediction models, and new therapeutic agents in the pipeline that will further mitigate residual cardiovascular risk in both primary and secondary prevention patients.

Expert opinion on emerging urate-lowering therapies.

INTRODUCTION: There has been a resurgence in gout therapeutics in the last decade, not only for the management of gout flares, but also for the treatment of hyperuricemia. This editorial summarizes new, emerging therapies for people with gout. Areas covered: We review several new therapies for gout, including those that are focused on lowering serum urate (levotofisopam, ulodesine, verinurad, merbarone, KUX-1151, UR-1102, FYU-981, SEL-212), or treating gout flares (canakinumab, bucillamine) or both (arhalofenate, diacerein). Expert opinion: Among therapies with both urate lowering and anti-inflammatory action, arhalofenate seems promising, but more data are needed. Examining therapies aimed at treating gout flares [anti-inflammatory action], bucillamine has some potential, but more data and Phase III studies are needed, to better understand its efficacy and safety. Among the urate-lowering therapies (ULTs), verinurad seems to be the most promising, while levotofisopam and ulodesine require more data. A uricase-replacement therapy with improved immune reaction (SLE-212) is in a Phase II trial. A number of ULTs including KUX-1151, UR-1102 and FYU-981 are in early development and more will be known once initial data and studies are published.

Current strategies in the non-clinical safety assessment of biologics: New targets, new molecules, new challenges.

Nonclinical safety testing of biopharmaceuticals can present significant challenges to human risk assessment with these innovative and often complex drugs. Emerging topics in this field were discussed recently at the 2016 Annual US BioSafe General Membership meeting. The presentations and subsequent discussions from the main sessions are summarized. The topics covered included: (i) specialty biologics (oncolytic virus, gene therapy, and gene editing-based technologies), (ii) the value of non-human primates (NHPs) for safety assessment, (iii) challenges in the safety assessment of immuno-oncology drugs (T cell-dependent bispecifics, checkpoint inhibitors, and costimulatory agonists), (iv) emerging therapeutic approaches and modalities focused on microbiome, oligonucleotide, messenger ribonucleic acid (mRNA) therapeutics, (v) first in human (FIH) dose selection and the minimum anticipated biological effect level (MABEL), (vi) an update on current regulatory guidelines, International Council for Harmonization (ICH) S1, S3a, S5, S9 and S11 and (vii) breakout sessions that focused on bioanalytical and PK/PD challenges with bispecific antibodies, cytokine release in nonclinical studies, determining adversity and NOAEL for biologics, the value of second species for toxicology assessment and what to do if there is no relevant toxicology species.

Emerging Systemic Therapies for Colorectal Cancer.

Despite advances over the past 20 years in colorectal cancer (CRC) screening, diagnosis, and treatment, survival outcomes remain suboptimal. Five-year survival for patients with locally advanced CRC is 69%; 5-year survival drops to 12% for patients with metastatic disease. Novel, effective systemic therapies are needed to improve long-term outcomes. In this review, we describe currently available systemic therapies for the treatment of locally advanced and metastatic CRC and discuss emerging therapies, including encouraging advances in identifying novel targeted agents and exciting responses to immunotherapeutic agents.

Bench to bedside: NK cells and control of metastasis.

Natural killer (NK) cells play a critical role in host immune responses against tumor growth and metastasis. The numerous mechanisms used by NK cells to regulate and control cancer metastasis include interactions with tumor cells via specific receptors and ligands as well as direct cytotoxicity and cytokine-induced effector mechanisms. NK cells also play a role in tumor immunosurveillance and inhibition of metastases formation by recognition and killing of tumor cells. In this review, we provide an overview of the molecular mechanisms of NK cell responses against tumor metastases and discuss multiple strategies by which tumors evade NK cell-mediated surveillance. With an increasing understanding of the molecular mechanisms driving NK cell activity, there is a growing potential for the development of new cancer immunotherapies. Here we provide a historical background on NK cell-based therapies and discuss the implications of recent and ongoing clinical trials using novel NK cell-based immunotherapy.