Stargardt and Fundus Flavimaculatus; Current and Developing Treatments

2021 ◽  
pp. 190-200
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Macular Dystrophy ◽  
Stargardt Disease ◽  
Need For Treatment ◽  
Complement Inhibitors ◽  
Abca4 Gene ◽  
Hereditary Retinal Degeneration ◽  
Pigment Epithelial Cells ◽  
Fundus Flavimaculatus

Stargardt macular dystrophy is a hereditary retinal degeneration that lacks effective treatment options. The pathophysiology of the disease is still not fully understood. While there are currently no available treatments for Stargardt disease, there are many categories of therapeutics under investigation to fulfill this unmet need for treatment. These include investigational visual cycle modulators, complement inhibitors, ABCA4 gene therapy, and subretinal transplantation of stem cell-derived retina pigment epithelial cells. Further trials are warranted to assess efficacy and safety in humans. In this review, the treatments investigated for the Stargardt disease are explained.

scholarly journals A combination of potently neutralizing monoclonal antibodies isolated from an Indian convalescent donor protects against the SARS-CoV-2 delta variant

2021 ◽  
Author(s):  
Nitin Hingankar ◽  
Suprit Deshpande ◽  
Payel Das ◽  
Zaigham Abbas Rizvi ◽  
Alison Burns ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Local Level ◽  
Treatment Options ◽  
Unmet Need ◽  
Mice Model ◽  
Middle Income ◽  
Virus Attachment ◽  
Vaccine Responses ◽  
Need For Treatment ◽  
Global Pandemic

Although efficacious vaccines have significantly reduced the morbidity and mortality due to COVID-19, there remains an unmet medical need for treatment options, which monoclonal antibodies (mAbs) can potentially fill. This unmet need is exacerbated by the emergence and spread of SARS-CoV-2 variants of concern (VOCs) that have shown some resistance to vaccine responses. Here we report the isolation of two highly potently neutralizing mAbs (THSC20.HVTR04 and THSC20.HVTR26) from an Indian convalescent donor, that neutralize SARS-CoV-2 VOCs at picomolar concentrations including the delta variant (B.1.617.2). These two mAbs target non-overlapping epitopes on the receptor-binding domain (RBD) of the spike protein thereby preventing the virus attachment to its host receptor, human angiotensin converting enzyme-2 (hACE2). Furthermore, the mAb cocktail demonstrated protection against the Delta variant at low antibody doses when passively administered in the K18 hACE2 transgenic mice model, highlighting their potential as cocktail for prophylactic and therapeutic applications. Developing the capacity to rapidly discover and develop mAbs effective against highly transmissible pathogens like coronaviruses at a local level, especially in a low- and middle-income country (LMIC) such as India, will enable prompt responses to future pandemics as an important component of global pandemic preparedness.

Multicentric reticulohistiocytosis: the Mayo Clinic experience (1980–2017)

Rheumatology ◽  
2019 ◽  
Vol 59 (8) ◽  
pp. 1898-1905 ◽  
Author(s):  
Catalina Sanchez-Alvarez ◽  
Avneek Singh Sandhu ◽  
Cynthia S Crowson ◽  
David A Wetter ◽  
Gavin A McKenzie ◽  
...  
Keyword(s):  
Mayo Clinic ◽  
Treatment Options ◽  
Unmet Need ◽  
Skin Lesions ◽  
Multicentric Reticulohistiocytosis ◽  
Need For Treatment ◽  
Clinic Experience ◽  
Joint Effusions ◽  
Rheumatic Conditions ◽  
Record Review

Abstract Objectives Multicentric reticulohistiocytosis (MRH), a rare histiocytic disease that can mimic other rheumatic conditions, may be associated with cancer and other autoimmune disorders. To better understand the disorder and its other associations, we aimed to evaluate clinical correlates and outcomes of all patients with MRH seen at Mayo Clinic, Rochester between 1980 and 2017. Methods A retrospective medical record review was conducted to identify all patients with MRH between 1 January 1980 and 30 April 2017. Results We identified 24 patients with biopsy-proven MRH (58% female, 75% Caucasian, median age at diagnosis 52 years, median follow-up of 2.3 years). All patients had cutaneous and articular involvement; 23 (96%) patients had papulonodular skin lesions (87% periungual and dorsal hand) and seven (30%) mucosal nodules; and 22 (92%) patients had arthralgias, 21 (88%) joint effusions and 13 (54%) synovitis. Most frequently used therapies included corticosteroids, cyclophosphamide, methotrexate and bisphosphonates. Biologics were used in four patients. Nine patients had symptomatic resolution at 1 year and 12 partial improvement. Radiological findings included erosive changes in three (60%) patients and arthritis mutilans in two patients (40%). Twenty-nine per cent of patients had a concomitant autoimmune disease and 25% malignancy including melanoma, endometrial, peritoneal and lung carcinoma. The 5-year survival rate was 85% (95% CI: 74, 100%). Conclusion To our knowledge, this is the largest single-centre series of patients with MRH highlighting the rarity of the condition and an unmet need for treatment options that can allow sustained disease remission. It also highlights the need for a high vigilance for malignancy and autoimmune diseases.

scholarly journals PRPH2-Related Retinal Diseases: Broadening the Clinical Spectrum and Describing a New Mutation

Genes ◽  
2020 ◽  
Vol 11 (7) ◽  
pp. 773
Author(s):  
Rosa M. Coco-Martin ◽  
Hortensia T. Sanchez-Tocino ◽  
Carmen Desco ◽  
Ricardo Usategui-Martín ◽  
Juan J. Tellería
Keyword(s):  
Gene Mutations ◽  
Large Family ◽  
Macular Dystrophy ◽  
Retinal Diseases ◽  
New Mutation ◽  
Pattern Dystrophy ◽  
Pathogenic Mutations ◽  
Abca4 Gene ◽  
Central Areolar Choroidal Dystrophy ◽  
Fundus Flavimaculatus

Over 175 pathogenic mutations in the Peripherin-2 (PRPH2) gene are linked to various retinal diseases. We report the phenotype and genotype of eight families (24 patients) with retinal diseases associated with seven distinct PRPH2 gene mutations. We identified a new mutation, c.824_828+3delinsCATTTGGGCTCCTCATTTGG, in a patient with adult-onset vitelliform macular dystrophy (AVMD). One family with the p.Arg46Ter mutation presented with the already described AVMD phenotype, but another family presented with the same mutation and two heterozygous pathogenic mutations (p.Leu2027Phe and p.Gly1977Ser) in the ATP Binding Cassette Subfamily A Member 4 (ABCA4) gene that cause extensive chorioretinal atrophy (ECA), which could be a blended phenotype. The p.Lys154del PRPH2 gene mutation associated with the p.Arg2030Glu mutation in the ABCA4 gene was found in a patient with multifocal pattern dystrophy simulating fundus flavimaculatus (PDsFF), for whom we considered ABCA4 as a possible modifying gene. The mutation p.Gly167Ser was already known to cause pattern dystrophy, but we also found ECA, PDsFF, and autosomal-dominant retinitis pigmentosa (ADRP) as possible phenotypes. Finally, we identified the mutation p.Arg195Leu in a large family with common ancestry, which previously was described to cause central areolar choroidal dystrophy (CACD), but we also found ADRP and observed that it caused ECA more frequently than CACD in this family.

scholarly journals Immunotherapy Predictive Molecular Markers in Advanced Gastroesophageal Cancer: MSI and Beyond

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1715
Author(s):  
Robin Park ◽  
Laercio Lopes ◽  
Anwaar Saeed
Keyword(s):  
Treatment Options ◽  
Unmet Need ◽  
Predictive Biomarkers ◽  
Phase Iii ◽  
Gastroesophageal Cancer ◽  
Programmed Death ◽  
Phase Iii Trials ◽  
Tumor Mutational Burden ◽  
Large Phase ◽  
Programmed Death 1

Advanced gastroesophageal cancer (GEC) has a poor prognosis and limited treatment options. Immunotherapy including the anti-programmed death-1 (PD-1) antibodies pembrolizumab and nivolumab have been approved for use in various treatment settings in GEC. Additionally, frontline chemoimmunotherapy regimens have recently demonstrated promising efficacy in large phase III trials and have the potential to be added to the therapeutic armamentarium in the near future. There are currently several immunotherapy biomarkers that are validated for use in the clinical setting for GEC including programmed death ligand-1 (PD-L1) expression as well as the tumor agnostic biomarkers such as mismatch repair or microsatellite instability (MMR/MSI) and tumor mutational burden (TMB). However, apart from MMR/MSI, these biomarkers are imperfect because none are highly sensitive nor specific. Therefore, there is an unmet need for immunotherapy biomarker development. To this end, several biomarkers are currently being evaluated in ongoing trials with some showing promising predictive potential. Here, we summarize the landscape of immunotherapy predictive biomarkers that are currently being evaluated in GEC.

scholarly journals MP-AzeFlu in Moderate-to-Severe Allergic Rhinitis: A Literature Review

2021 ◽  
pp. 1-10
Author(s):  
Ludger Klimek ◽  
William E. Berger ◽  
Jean Bousquet ◽  
Paul K. Keith ◽  
Peter Smith ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Allergic Rhinitis ◽  
Fluticasone Propionate ◽  
Treatment Options ◽  
Symptomatic Disease ◽  
Intranasal Corticosteroids ◽  
Need For Treatment ◽  
Ocular Symptoms ◽  
Symptom Complex

Allergic rhinitis (AR) is prevalent, and many patients present with moderate-to-severe symptomatic disease. The majority of patients are not satisfied with their AR treatment, despite the use of concurrent medications. These gaps underscore the need for treatment with more effective options for moderate-to-severe AR. The authors’ objective was to review systematically the efficacy and safety of MP-AzeFlu for the treatment of AR. The primary outcomes studied were nasal, ocular, and total symptoms. Other outcomes included time to onset and of AR control, quality of life, and safety. Searches of PubMed and Cochrane databases were conducted on May 14, 2020, with no date restrictions, to identify publications reporting data on MP-AzeFlu. Clinical studies of any phase were included. Studies were excluded if they were not in English, were review articles, did not discuss the safety and efficacy of MP-AzeFlu for AR symptoms. Treatment of AR with MP-AzeFlu results in effective, sustained relief of nasal and ocular symptoms, and faster onset and time to control compared with intranasal azelastine or fluticasone propionate. Long-term use of MP-AzeFlu was safe, with benefits in children, adults, and adults aged ≥65 years. Other treatment options, including fluticasone propionate and azelastine alone or the combination of intranasal corticosteroids and oral antihistamine, do not provide the same level of efficacy as MP-AzeFlu in terms of rapid and sustained relief of the entire AR symptom complex. Furthermore, MP-AzeFlu significantly improves patient quality of life. MP-AzeFlu is a currently available combination that may satisfy all these patient needs and expectations.

Management of maxillary midline diastema with emphasis on etiology

2008 ◽  
Vol 32 (4) ◽  
pp. 265-272 ◽  
Author(s):  
Nikolaos Gkantidis ◽  
Olga-Elpis Kolokitha ◽  
Nikolaos Topouzelis
Keyword(s):  
Treatment Options ◽  
Mixed Dentition ◽  
Therapeutic Approaches ◽  
Need For Treatment ◽  
Treatment Plans ◽  
Treatment Objective ◽  
Laboratory Examinations ◽  
Genetic And Environmental Factors ◽  
Scientific Documentation ◽  
Normal Feature

The importance of the presence of a maxillary midline diastema resides in its position and the concern it causes to patients. This specific diastema has been attributed to genetic and environmental factors, even though it is often a normal feature of growth, especially in primary and mixed dentition. The need for treatment is mainly attributed to esthetic and psychological reasons, rather than functional ones. Although it is often the case, treatment plans should not be selected empirically but rather should be based on adequate scientific documentation. Possible therapeutic approaches include orthodontics, restorative dentistry, surgery and various combinations of the above. The ideal treatment should seek to manage not only the diastema in question but also the cause behind it. Irrespective of the treatment alternative selected, permanent retention of stable results should be considered as a treatment objective. The aim of this paper is to underscore the main etiological factors for the presence of a maxillary midline diastema and to illustrate the clinical and laboratory examinations required to recognize these factors. Furthermore, alternative treatment options are discussed depending on the etiology of the problem.

scholarly journals Practical guidance for the management of iron deficiency in patients with inflammatory bowel disease

2018 ◽  
Vol 11 ◽  
pp. 175628481876907 ◽  
Author(s):  
Dorothea Niepel ◽  
Thomas Klag ◽  
Nisar P. Malek ◽  
Jan Wehkamp
Keyword(s):  
Iron Deficiency ◽  
Treatment Options ◽  
Intravenous Iron ◽  
Underlying Disease ◽  
Deficiency Anemia ◽  
Diagnostic Tools ◽  
Systemic Complications ◽  
Need For Treatment ◽  
Inflammatory Bowel ◽  
Practical Guidance

Iron deficiency or iron deficiency anemia (IDA) are some of the most common systemic complications of inflammatory bowel diseases (IBD). Symptoms such as fatigue, reduced ability to concentrate and reduced exercise tolerance can mimic common symptoms of IBD and can therefore easily be overseen. Furthermore, clinicians tend to see mild to moderate anemia as an inevitable accompaniment of IBD that is sufficiently explained by the underlying disease and does not require further workup. But in contrast to these clinical routines, current guidelines recommend that any degree of anemia in patients with IBD should be further evaluated and treated. Multiple studies have shown that anemia is a main factor for decreased quality of life (QoL) in patients with IBD. Correction of anemia, however, can significantly improve the QoL of patients with IBD. It is therefore recommended that every patient with IBD is regularly screened for iron deficiency and anemia. If detected, appropriate workup and treatment should be initiated. Over the last years, a number of new diagnostic tools and treatment options have been developed. Multiple studies have demonstrated the safety of newer formulations of intravenous iron in patients with IBD and have compared oral and intravenous iron in various situations. Treatment recommendations have changed and new evidence-based guidelines were developed. However, to date these guidelines are still not widely implemented in clinical practice. The aim of this review is to draw attention to the need for treatment for every level of anemia in patients with IBD and to provide some practical guidance for screening, diagnostics, treatment and follow up of IDA in patients with IBD following current international guidelines.

Phase II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS253-TPS253
Author(s):  
Farshid Dayyani ◽  
Chloe Thomas ◽  
Gwendolyn Ung ◽  
Thomas H Taylor
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Objective Response ◽  
Unmet Need ◽  
Primary Objective ◽  
Phase 2 ◽  
Open Label ◽  
Secondary Resistance ◽  
Phase 2 Trial ◽  
Number Of Patients

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

Definitions and measurement of negative symptoms in schizophrenia

2020 ◽  
pp. 1-18
Author(s):  
István Bitter
Keyword(s):  
Substance Abuse ◽  
Mental Disorders ◽  
Negative Symptoms ◽  
Rating Scales ◽  
Social Deprivation ◽  
Unmet Need ◽  
Disease Process ◽  
Extrapyramidal Symptoms ◽  
Positive Symptoms ◽  
Need For Treatment

Negative symptoms of schizophrenia represent deficits in different domains, e.g. loss or diminution in emotions, thinking and movement. Persistent primary negative symptoms are considered to be part of the schizophrenia disease process and represent an unmet need for treatment, while secondary negative symptoms are associated with positive symptoms of schizophrenia, other mental disorders (e.g. depression, substance abuse), extrapyramidal symptoms, social deprivation, etc. Validated rating scales are helpful in the evaluation and measurement of negative symptoms. Current consensus supports the focus on the following five domains (five ‘As’): blunted affect, alogia, anhedonia, asociality, and avolition.

scholarly journals Intratumoural immunotherapies for unresectable and metastatic melanoma: current status and future perspectives

2020 ◽  
Vol 123 (6) ◽  
pp. 885-897
Author(s):  
Mark R. Middleton ◽  
Christoph Hoeller ◽  
Olivier Michielin ◽  
Caroline Robert ◽  
Caroline Caramella ◽  
...  
Keyword(s):  
Immune Response ◽  
Metastatic Melanoma ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Unmet Need ◽  
Systemic Exposure ◽  
Oncolytic Viruses ◽  
Current Status ◽  
Local Concentration ◽  
Major Step

Abstract The emergence of human intratumoural immunotherapy (HIT-IT) is a major step forward in the management of unresectable melanoma. The direct injection of treatments into melanoma lesions can cause cell lysis and induce a local immune response, and might be associated with a systemic immune response. Directly injecting immunotherapies into tumours achieves a high local concentration of immunostimulatory agent while minimising systemic exposure and, as such, HIT-IT agents are associated with lower toxicity than systemic immune checkpoint inhibitors (CPIs), enabling their potential use in combination with other therapies. Consequently, multiple HIT-IT agents, including oncolytic viruses, pattern-recognition receptor agonists, injected CPIs, cytokines and immune glycolipids, are under investigation. This review considers the current clinical development status of HIT-IT agents as monotherapy and in combination with systemic CPIs, and the practical aspects of administering and assessing the response to these agents. The future of HIT-IT probably lies in its use in combination with systemic CPIs; data from Phase 2 trials indicate a synergy between HIT-IT and CPIs. Data also suggest that the addition of HIT-IT to a CPI might generate responses in CPI-refractory tumours, thereby overcoming resistance and addressing a current unmet need in unresectable and metastatic melanoma for treatment options following progression after CPI treatment.

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