Cancers (Basel). 2023 May 27;15(11):2940. doi: 10.3390/cancers15112940.

ABSTRACT

Malignant pleural mesothelioma (MPM) is a malignancy associated with asbestos exposure and is typically categorized as an orphan disease. Recent developments in immunotherapy with anti-PD-1 and anti-CTLA-4 antibodies, specifically with agents nivolumab and ipilimumab, have demonstrated an improvement in overall survival over the previous standard chemotherapy leading to their FDA-approval as first-line therapy for unresectable disease. For quite some time, it has been known that these proteins are not the only ones that function as immune checkpoints in human biology, and the hypothesis that MPM is an immunogenic disease has led to an expanding number of studies investigating alternative checkpoint inhibitors and novel immunotherapy for this malignancy. Early trials are also supporting the notion that therapies that target biological molecules on T cells, cancer cells, or that trigger the antitumor activity of other immune cells may represent the future of MPM treatment. Moreover, mesothelin-targeted therapies are thriving in the field, with forthcoming results from multiple trials signaling an improvement in overall survival when combined with other immunotherapy agents. The following manuscript will review the current state of immune therapy for MPM, explore the knowledge gaps in the field, and discuss ongoing novel immunotherapeutic research in early clinical trials.

PMID:37296902 | DOI:10.3390/cancers15112940

Cancers (Basel). 2023 May 23;15(11):2873. doi: 10.3390/cancers15112873.

ABSTRACT

Adrenocortical cancer is an aggressive endocrine malignancy with an incidence of 0.72 to 1.02 per million people/year, and a very poor prognosis with a five-year survival rate of 22%. As an orphan disease, clinical data are scarce, meaning that drug development and mechanistic research depend especially on preclinical models. While a single human ACC cell line was available for the last three decades, over the last five years, many new in vitro and in vivo preclinical models have been generated. Herein, we review both in vitro (cell lines, spheroids, and organoids) and in vivo (xenograft and genetically engineered mouse) models. Striking leaps have been made in terms of the preclinical models of ACC, and there are now several modern models available publicly and in repositories for research in this area.

PMID:37296836 | DOI:10.3390/cancers15112873

Front Immunol. 2023 May 24;14:1203876. doi: 10.3389/fimmu.2023.1203876. eCollection 2023.

ABSTRACT

OBJECTIVE: To investigate the clinical features, pathological characteristics, immunophenotype, differential diagnosis and prognosis of pulmonary hepatoid adenocarcinoma using a clinical case and literature report.

METHODS: We analyzed the clinical presentation, histological pattern and immunohistochemistry of a case of primary hepatoid adenocarcinoma of the lung in April 2022. We also reviewed literature on hepatoid adenocarcinoma of the lung from PubMed database.

RESULTS: The patient was a 65-year-old male with smoking history, who was admitted to hospital with an enlarged axillary lymph node. The mass was round, hard, and grayish-white and grayish-yellow in color. Microscopically, it presented hepatocellular carcinoma-like and adenocarcinoma differentiation features, with abundant blood sinuses visible in the interstitium. Immunohistochemistry showed that the tumor cells were positive for hepatocyte markers, including AFP, TTF-1, CK7 and villin, and negative for CK5/6, CD56, GATA3, CEA and vimentin.

CONCLUSION: Pulmonary hepatoid adenocarcinoma is a rare epithelial malignancy of primary origin in the lung with poor prognosis. Establishing the diagnosis relies mainly on the detection of hepatocellular structural morphology resembling hepatocellular carcinoma, and on clinicopathological and immunohistochemical testing to exclude diseases such as hepatocellular carcinoma. Combination treatment, mainly surgery, can prolong the survival of early-stage cases of the disease, whereas radiotherapy is mostly used for intermediate and advanced cases. Individualized treatment with molecular-targeted drugs and immunotherapy has shown different therapeutic effects for different patients. Further research is needed to better understand this rare clinical condition for the development and optimization of treatment strategies.

PMID:37292208 | PMC:PMC10244673 | DOI:10.3389/fimmu.2023.1203876

Nat Med. 2023 Jun;29(6):1468-1475. doi: 10.1038/s41591-023-02398-1. Epub 2023 Jun 8.

ABSTRACT

Rett syndrome is a rare, genetic neurodevelopmental disorder. Trofinetide is a synthetic analog of glycine-proline-glutamate, the N-terminal tripeptide of the insulin-like growth factor 1 protein, and has demonstrated clinical benefit in phase 2 studies in Rett syndrome. In this phase 3 study ( https://clinicaltrials.gov identifier NCT04181723 ), females with Rett syndrome received twice-daily oral trofinetide (n = 93) or placebo (n = 94) for 12 weeks. For the coprimary efficacy endpoints, least squares mean (LSM) change from baseline to week 12 in the Rett Syndrome Behaviour Questionnaire for trofinetide versus placebo was -4.9 versus -1.7 (P = 0.0175; Cohen's d effect size, 0.37), and LSM Clinical Global Impression-Improvement at week 12 was 3.5 versus 3.8 (P = 0.0030; effect size, 0.47). For the key secondary efficacy endpoint, LSM change from baseline to week 12 in the Communication and Symbolic Behavior Scales Developmental Profile Infant-Toddler Checklist Social Composite score was -0.1 versus -1.1 (P = 0.0064; effect size, 0.43). Common treatment-emergent adverse events included diarrhea (80.6% for trofinetide versus 19.1% for placebo), which was mostly mild to moderate in severity. Significant improvement for trofinetide compared with placebo was observed for the coprimary efficacy endpoints, suggesting that trofinetide provides benefit in treating the core symptoms of Rett syndrome.

PMID:37291210 | PMC:PMC10287558 | DOI:10.1038/s41591-023-02398-1

Orphanet J Rare Dis. 2023 Jun 8;18(1):141. doi: 10.1186/s13023-023-02765-8.

ABSTRACT

The World Health Organization supports early delivery of palliative care as it reduces unnecessary hospital admissions and the inappropriate use of health care services. A community pharmacist can play a key role in advocating timely access to palliative care. Medication reconciliation must alert them to start communicating with the patient and/or his relatives about refocusing treatment and care as part of palliative and terminal care. Pharmaceutical activities for these patients include dispensing of devices and medicinal products, compounding personalized medication and participating as a member of the Palliative Support Team. Most of the several thousands of rare diseases are caused by genetic defects and up to now have no cure and a late diagnosis.

PMID:37291601 | PMC:PMC10249311 | DOI:10.1186/s13023-023-02765-8

Orphanet J Rare Dis. 2023 Jun 8;18(1):143. doi: 10.1186/s13023-023-02762-x.

ABSTRACT

BACKGROUND: Rare diseases (RDs) may impose a considerable financial burden on patients and their families. Public acceptance is essential to ensure sustainable public systems supporting RDs, especially in countries with universal healthcare coverage, such as Japan. This study aimed to explore the public's understanding of RDs and identify crucial factors associated with the public acceptance of prioritizing financial support for RDs in Japan.

METHODS: An online questionnaire was sent to 131,220 Japanese residents aged 20-69 years. The items included in the questionnaire were general interest in medical science and medical care, general knowledge regarding RDs and health care systems, opinions on the cost of medical care, opinions on the research and development of RDs and common diseases, and individual characteristics.

RESULTS: The responses of 11,019 respondents were analyzed. Several respondents agreed to partially cover the medication cost of adult and pediatric RDs (59.5% and 66.8%, respectively) with public funding. The major reasons for agreeing were the huge financial burden imposed on patients and their families, limited available treatment options, effects of RDs on the life planning of patients, and difficulties caused by RDs in the patient's social life. Furthermore, the respondents ranked RDs (56.0%) higher than common diseases (44.0%) for government funding for research and development. The reasons for supporting government-funded research and development for RDs included the lack of treatment options for numerous RDs (34.9%) and difficulty of studying RDs owing to the small number of researchers (25.9%). The chief reasons for supporting government-funded research and development for common diseases were the large number of affected patients (59.7%) and the possibility of more treatment options becoming available through the promotion of research and development (22.1%).

CONCLUSIONS: The general public considers burdens associated with daily living or finance more than the epidemiological characteristics of RD while making funding decisions, demonstrating that rarity was less prioritized. A gap appears to exist between the general public and RD experts regarding the understanding of the epidemiological characteristics of RD and its thresholds. This gap should be bridged to ensure that prioritization of financial support for RDs is accepted by the society.

PMID:37291571 | PMC:PMC10249302 | DOI:10.1186/s13023-023-02762-x

Cutis. 2023 Apr;111(4):E4-E8. doi: 10.12788/cutis.0752.

ABSTRACT

Dercum disease is a rare condition characterized by multiple painful fatty tumors distributed throughout the body. There currently are no US Food and Drug Administration-approved treatments for Dercum disease, and the treatments tried have shown little to no efficacy, leaving many patients with a profoundly negative impact on quality of life. We present a case series of 3 patients who were diagnosed with Dercum disease and were treated with deoxycholic acid (DCA), a therapy approved for adipolysis of submental fat. The patients experienced a reduction in tumor size with radiographic evidence as well as a notable reduction in symptoms.

PMID:37289681 | DOI:10.12788/cutis.0752

Orphanet J Rare Dis. 2023 Jun 7;18(1):140. doi: 10.1186/s13023-023-02667-9.

ABSTRACT

BACKGROUND: Rare diseases present a challenge to guideline implementation due to a low prevalence in the general population and the unfamiliarity of healthcare professionals. Existing literature in more common diseases references barriers and facilitators to guideline implementation. This systematic review aims to identify these barriers and facilitators in rare diseases from existing literature.

METHODS: A multi-stage strategy included searching MEDLINE PubMed, EMBASE Ovid, Web of Science and Cochrane library from the earliest date available to April 2021, Orphanet journal hand-search, a pearl-growing strategy from a primary source and reference/citation search was performed. The Integrated Checklist of Determinants of Practice which comprises of twelve checklists and taxonomies, informed by 57 potential determinants was selected as a screening tool to identify determinants that warrant further in-depth investigation to inform design of future implementation strategies.

RESULTS: Forty-four studies were included, most of which were conducted in the United States (54.5%). There were 168 barriers across 36 determinants (37 studies) and 52 facilitators across 22 determinants (22 studies). Fifteen diseases were included across eight WHO ICD-11 disease categories. Together individual health professional factors and guideline factors formed the majority of the reported determinants (59.5% of barriers and 53.8% of facilitators). Overall, the three most reported individual barriers were the awareness/familiarity with the recommendation, domain knowledge and feasibility. The three most reported individual facilitators were awareness/familiarity with the recommendation, agreement with the recommendation and ability to readily access the guidelines. Resource barriers to implementation included technology costs, ancillary staff costs and more cost-effective alternatives. There was a paucity of studies reporting influential people, patient advocacy groups or opinion leaders, or organisational factors influencing implementation.

CONCLUSIONS: Key barriers and facilitators to the implementation of clinical practice guidelines in the setting of rare diseases were at the individual health professional and guideline level. Influential people and organisational factors were relatively under-reported and warrant exploration, as does increasing the ability to access the guidelines as a potential intervention.

PMID:37286999 | PMC:PMC10246545 | DOI:10.1186/s13023-023-02667-9

Am J Hum Genet. 2023 Jun 1:S0002-9297(23)00164-7. doi: 10.1016/j.ajhg.2023.05.007. Online ahead of print.

ABSTRACT

Newborn genomic sequencing (NBSeq) to screen for medically important genetic information is of considerable interest but data characterizing the actionability of such findings, and the downstream medical efforts in response to discovery of unanticipated genetic risk variants, are lacking. From a clinical trial of comprehensive exome sequencing in 127 apparently healthy infants and 32 infants in intensive care, we previously identified 17 infants (10.7%) with unanticipated monogenic disease risks (uMDRs). In this analysis, we assessed actionability for each of these uMDRs with a modified ClinGen actionability semiquantitative metric (CASQM) and created radar plots representing degrees of penetrance of the condition, severity of the condition, effectiveness of intervention, and tolerability of intervention. In addition, we followed each of these infants for 3-5 years after disclosure and tracked the medical actions prompted by these findings. All 17 uMDR findings were scored as moderately or highly actionable on the CASQM (mean 9, range: 7-11 on a 0-12 scale) and several distinctive visual patterns emerged on the radar plots. In three infants, uMDRs revealed unsuspected genetic etiologies for existing phenotypes, and in the remaining 14 infants, uMDRs provided risk stratification for future medical surveillance. In 13 infants, uMDRs prompted screening for at-risk family members, three of whom underwent cancer-risk-reducing surgeries. Although assessments of clinical utility and cost-effectiveness will require larger datasets, these findings suggest that large-scale comprehensive sequencing of newborns will reveal numerous actionable uMDRs and precipitate substantial, and in some cases lifesaving, downstream medical care in newborns and their family members.

PMID:37279760 | DOI:10.1016/j.ajhg.2023.05.007

Orphanet J Rare Dis. 2023 Jun 6;18(1):138. doi: 10.1186/s13023-023-02733-2.

ABSTRACT

BACKGROUND: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited.

METHODS: We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients.

RESULTS: A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1-2 times, 32% 3-9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities.

CONCLUSIONS: This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures.

PMID:37280644 | DOI:10.1186/s13023-023-02733-2

Front Immunol. 2023 May 19;14:1186000. doi: 10.3389/fimmu.2023.1186000. eCollection 2023.

ABSTRACT

Coronavirus disease 2019 (COVID-19) is known to commonly induce a thrombotic diathesis, particularly in severely affected individuals. So far, this COVID-19-associated coagulopathy (CAC) has been partially explained by hyperactivated platelets as well as by the prothrombotic effects of neutrophil extracellular traps (NETs) released from neutrophils. However, precise insight into the bidirectional relationship between platelets and neutrophils in the pathophysiology of CAC still lags behind. Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare autoimmune disorder caused by auto-antibody formation in response to immunization with adenoviral vector vaccines. VITT is associated with life-threatening thromboembolic events and thus, high fatality rates. Our concept of the thrombophilia observed in VITT is relatively new, hence a better understanding could help in the management of such patients with the potential to also prevent VITT. In this review we aim to summarize the current knowledge on platelet-neutrophil interplay in COVID-19 and VITT.

PMID:37275917 | PMC:PMC10237318 | DOI:10.3389/fimmu.2023.1186000

F1000Res. 2023 Apr 11;11:175. doi: 10.12688/f1000research.76218.2. eCollection 2022.

ABSTRACT

Polygenic Risk Score (PRS) analysis is a method that predicts the genetic risk of an individual towards targeted traits. Even when there are no significant markers, it gives evidence of a genetic effect beyond the results of Genome-Wide Association Studies (GWAS). Moreover, it selects single nucleotide polymorphisms (SNPs) that contribute to the disease with low effect size making it more precise at individual level risk prediction. PRS analysis addresses the shortfall of GWAS by taking into account the SNPs/alleles with low effect size but play an indispensable role to the observed phenotypic/trait variance. PRS analysis has applications that investigate the genetic basis of several traits, which includes rare diseases. However, the accuracy of PRS analysis depends on the genomic data of the underlying population. For instance, several studies show that obtaining higher prediction power of PRS analysis is challenging for non-Europeans. In this manuscript, we review the conventional PRS methods and their application to sub-Saharan African communities. We conclude that lack of sufficient GWAS data and tools is the limiting factor of applying PRS analysis to sub-Saharan populations. We recommend developing Africa-specific PRS methods and tools for estimating and analyzing African population data for clinical evaluation of PRSs of interest and predicting rare diseases.

PMID:37273966 | PMC:PMC10233318 | DOI:10.12688/f1000research.76218.2

Ugeskr Laeger. 2023 May 15;185(20):V12220788.

ABSTRACT

Unilateral acute maculopathy is a rare inflammatory macular disorder believed to be caused by viral infection, especially Coxsackievirus. It most commonly affects young healthy adults. This is a case report of unilateral acute maculopathy in a 28-year-old man with concurrent hand, foot and mouth disease. Although the typical acute manifestation of the disease is sudden, severe, unilateral central vision loss, most patients achieve full visual recovery over the course of several weeks without therapy.

PMID:37264868

Clin Lymphoma Myeloma Leuk. 2023 May 12:S2152-2650(23)00157-X. doi: 10.1016/j.clml.2023.05.007. Online ahead of print.

NO ABSTRACT

PMID:37263876 | DOI:10.1016/j.clml.2023.05.007

Proc Natl Acad Sci U S A. 2023 Jun 6;120(23):e2300052120. doi: 10.1073/pnas.2300052120. Epub 2023 May 30.

ABSTRACT

Short trinucleotide expansions at the FMR1 locus are associated with the late-onset condition fragile X-associated tremor/ataxia syndrome (FXTAS), which shows very different clinical and pathological features from fragile X syndrome (associated with longer expansions), with no clear molecular explanation for these marked differences. One prevailing theory posits that the shorter, premutation expansion uniquely causes extreme neurotoxic increases in FMR1 mRNA (i.e., four to eightfold increases), but evidence to support this hypothesis is largely derived from analysis of peripheral blood. We applied single-nucleus RNA sequencing to postmortem frontal cortex and cerebellum from 7 individuals with premutation and matched controls (n = 6) to assess cell type-specific molecular neuropathology. We found only modest upregulation (~1.3-fold) of FMR1 in some glial populations associated with premutation expansions. In premutation cases, we also identified decreased astrocyte proportions in the cortex. Differential expression and gene ontology analysis demonstrated altered neuroregulatory roles of glia. Using network analyses, we identified cell type-specific and region-specific patterns of FMR1 protein target gene dysregulation unique to premutation cases, with notable network dysregulation in the cortical oligodendrocyte lineage. We used pseudotime trajectory analysis to determine how oligodendrocyte development was altered and identified differences in early gene expression in oligodendrocyte trajectories in premutation cases specifically, implicating early cortical glial developmental perturbations. These findings challenge dogma regarding extremely elevated FMR1 increases in FXTAS and implicate glial dysregulation as a critical facet of premutation pathophysiology, representing potential unique therapeutic targets directly derived from the human condition.

PMID:37252957 | DOI:10.1073/pnas.2300052120

Nat Methods. 2023 Jun;20(6):803-814. doi: 10.1038/s41592-023-01886-z. Epub 2023 May 29.

ABSTRACT

High-throughput profiling methods (such as genomics or imaging) have accelerated basic research and made deep molecular characterization of patient samples routine. These approaches provide a rich portrait of genes, molecular pathways and cell types involved in disease phenotypes. Machine learning (ML) can be a useful tool for extracting disease-relevant patterns from high-dimensional datasets. However, depending upon the complexity of the biological question, machine learning often requires many samples to identify recurrent and biologically meaningful patterns. Rare diseases are inherently limited in clinical cases, leading to few samples to study. In this Perspective, we outline the challenges and emerging solutions for using ML for small sample sets, specifically in rare diseases. Advances in ML methods for rare diseases are likely to be informative for applications beyond rare diseases for which few samples exist with high-dimensional data. We propose that the method community prioritize the development of ML techniques for rare disease research.

PMID:37248386 | DOI:10.1038/s41592-023-01886-z

Nat Commun. 2023 May 29;14(1):3090. doi: 10.1038/s41467-023-38782-1.

ABSTRACT

Long-read HiFi genome sequencing allows for accurate detection and direct phasing of single nucleotide variants, indels, and structural variants. Recent algorithmic development enables simultaneous detection of CpG methylation for analysis of regulatory element activity directly in HiFi reads. We present a comprehensive haplotype resolved 5-base HiFi genome sequencing dataset from a rare disease cohort of 276 samples in 152 families to identify rare (~0.5%) hypermethylation events. We find that 80% of these events are allele-specific and predicted to cause loss of regulatory element activity. We demonstrate heritability of extreme hypermethylation including rare cis variants associated with short (~200 bp) and large hypermethylation events (>1 kb), respectively. We identify repeat expansions in proximal promoters predicting allelic gene silencing via hypermethylation and demonstrate allelic transcriptional events downstream. On average 30-40 rare hypermethylation tiles overlap rare disease genes per patient, providing indications for variation prioritization including a previously undiagnosed pathogenic allele in DIP2B causing global developmental delay. We propose that use of HiFi genome sequencing in unsolved rare disease cases will allow detection of unconventional diseases alleles due to loss of regulatory element activity.

PMID:37248219 | PMC:PMC10226990 | DOI:10.1038/s41467-023-38782-1

Rev Infirm. 2023 May;72(291):1. doi: 10.1016/j.revinf.2023.04.001. Epub 2023 May 11.

NO ABSTRACT

PMID:37247978 | DOI:10.1016/j.revinf.2023.04.001

Isr Med Assoc J. 2023 May;25(5):369-371.

NO ABSTRACT

PMID:37245110

Mol Genet Metab. 2023 May 21;139(3):107612. doi: 10.1016/j.ymgme.2023.107612. Online ahead of print.

ABSTRACT

Clinical trial development in rare diseases poses significant study design and methodology challenges, such as disease heterogeneity and appropriate patient selection, identification and selection of key endpoints, decisions on study duration, choice of control groups, selection of appropriate statistical analyses, and patient recruitment. Therapeutic development in organic acidemias (OAs) shares many challenges with other inborn errors of metabolism, such as incomplete understanding of natural history, heterogenous disease presentations, requirement for sensitive outcome measures and difficulties recruiting a small sample of participants. Here, we review strategies for the successful development of a clinical trial to evaluate treatment response in propionic and methylmalonic acidemias. Specifically, we discuss crucial decisions that may significantly impact success of the study, including patient selection, identification and selection of endpoints, determination of the study duration, consideration of control groups including natural history controls, and selection of appropriate statistical analyses. The significant challenges associated with designing a clinical trial in rare disease can sometimes be successfully met through strategic engagement with experts in the rare disease, seeking regulatory and biostatistical guidance, and early involvement of patients and families.

PMID:37245378 | DOI:10.1016/j.ymgme.2023.107612