Curr Opin Urol. 2023 Jun 29. doi: 10.1097/MOU.0000000000001109. Online ahead of print.

ABSTRACT

PURPOSE OF REVIEW: Penile cancer (PeCa) is an orphan disease due to its rare incidence in high-income countries. Traditional surgical options for clinical T1-2 disease, including partial and total penectomy, can dramatically affect patient's quality of life and mental health status. In selected patients, organ-sparing surgery (OSS) has the potential to remove the primary tumor with comparable oncologic outcomes while maintaining penile length, sexual and urinary function. In this review, we aim to discuss the indications, advantages, and outcomes of various OSSs currently available for men diagnosed with PeCa seeking an organ-preserving option.

RECENT FINDINGS: Patient survival largely depends on spotting and treating lymph node metastasis at an early stage. The required surgical and radiotherapy skill sets cannot be expected to be available in all centers. Consequently, patients should be referred to high-volume centers to receive the best available treatments for PeCa.

SUMMARY: OSS should be used for small and localized PeCa (T1-T2) as an alternative to partial penectomy to preserve patient's quality of life while maintaining sexual and urinary function and penile aesthetics. Overall, there are different techniques that can be used with different response and recurrence rates. In case of tumor recurrence, partial penectomy or radical penectomy is feasible, without impacting overall survival.

PMID:37377374 | DOI:10.1097/MOU.0000000000001109

Pharmaceuticals (Basel). 2023 May 31;16(6):822. doi: 10.3390/ph16060822.

ABSTRACT

Adenylosuccinic acid (ASA) is an orphan drug that was once investigated for clinical application in Duchenne muscular dystrophy (DMD). Endogenous ASA participates in purine recycling and energy homeostasis but might also be crucial for averting inflammation and other forms of cellular stress during intense energy demand and maintaining tissue biomass and glucose disposal. This article documents the known biological functions of ASA and explores its potential application for the treatment of neuromuscular and other chronic diseases.

PMID:37375769 | DOI:10.3390/ph16060822

EMBO Mol Med. 2023 Jul 10;15(7):e17159. doi: 10.15252/emmm.202217159. Epub 2023 Jun 27.

ABSTRACT

Rare diseases affect over 400 million people worldwide and less than 5% of rare diseases have an approved treatment. Fortunately, the number of underlying disease etiologies is far less than the number of diseases, because many rare diseases share a common molecular etiology. Moreover, many of these shared molecular etiologies are therapeutically actionable. Grouping rare disease patients for clinical trials based on the underlying molecular etiology, rather than the traditional, symptom-based definition of disease, has the potential to greatly increase the number of patients gaining access to clinical trials. Basket clinical trials based on a shared molecular drug target have become common in the field of oncology and have been accepted by regulatory agencies as a basis for drug approvals. Implementation of basket clinical trials in the field of rare diseases is seen by multiple stakeholders-patients, researchers, clinicians, industry, regulators, and funders-as a solution to accelerate the identification of new therapies and address patient's unmet needs.

PMID:37366158 | PMC:PMC10331571 | DOI:10.15252/emmm.202217159

J Biomed Inform. 2023 Jul;143:104429. doi: 10.1016/j.jbi.2023.104429. Epub 2023 Jun 22.

ABSTRACT

BACKGROUND: The diagnosis of rare genetic diseases is often challenging due to the complexity of the genetic underpinnings of these conditions and the limited availability of diagnostic tools. Machine learning (ML) algorithms have the potential to improve the accuracy and speed of diagnosis by analyzing large amounts of genomic data and identifying complex multiallelic patterns that may be associated with specific diseases. In this systematic review, we aimed to identify the methodological trends and the ML application areas in rare genetic diseases.

METHODS: We performed a systematic review of the literature following the PRISMA guidelines to search studies that used ML approaches to enhance the diagnosis of rare genetic diseases. Studies that used DNA-based sequencing data and a variety of ML algorithms were included, summarized, and analyzed using bibliometric methods, visualization tools, and a feature co-occurrence analysis.

FINDINGS: Our search identified 22 studies that met the inclusion criteria. We found that exome sequencing was the most frequently used sequencing technology (59%), and rare neoplastic diseases were the most prevalent disease scenario (59%). In rare neoplasms, the most frequent applications of ML models were the differential diagnosis or stratification of patients (38.5%) and the identification of somatic mutations (30.8%). In other rare diseases, the most frequent goals were the prioritization of rare variants or genes (55.5%) and the identification of biallelic or digenic inheritance (33.3%). The most employed method was the random forest algorithm (54.5%). In addition, the features of the datasets needed for training these algorithms were distinctive depending on the goal pursued, including the mutational load in each gene for the differential diagnosis of patients, or the combination of genotype features and sequence-derived features (such as GC-content) for the identification of somatic mutations.

CONCLUSIONS: ML algorithms based on sequencing data are mainly used for the diagnosis of rare neoplastic diseases, with random forest being the most common approach. We identified key features in the datasets used for training these ML models according to the objective pursued. These features can support the development of future ML models in the diagnosis of rare genetic diseases.

PMID:37352901 | DOI:10.1016/j.jbi.2023.104429

J Transl Med. 2023 Jun 23;21(1):410. doi: 10.1186/s12967-023-04183-7.

ABSTRACT

BACKGROUND: In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education.

METHODS: Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers.

RESULTS: Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1152 patients have been evaluated with an overall solved or likely solved rate of 17.5% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results.

CONCLUSION: Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

PMID:37353797 | PMC:PMC10288779 | DOI:10.1186/s12967-023-04183-7

Orphanet J Rare Dis. 2023 Jun 23;18(1):163. doi: 10.1186/s13023-023-02790-7.

ABSTRACT

BACKGROUND: Rare diseases affect more than 30 million Americans. The passage of the Orphan Drug Act (ODA) in the United States in 1983 represented a launching point for a rare disease drug development revolution for these patients. Financial incentives provided by the ODA through its Orphan Drug Designation Program, in addition to remarkable scientific advances over the past 40 years, have led to hundreds of drug approvals for rare diseases. Our research examines the rare diseases that have been targeted by orphan drug designations and subsequent approvals since the law was enacted.

METHODS: Using an internal FDA database, we classified and analyzed all orphan drug designations and approvals from 1983 to 2022 by disease and therapeutic area.

RESULTS: Over the 40 years of the ODA, 6,340 orphan drug designations were granted, representing drug development for 1,079 rare diseases. Additionally, 882 of those designations resulted in at least one FDA approval for use in 392 rare diseases. Much of this development has been concentrated in oncology as seven of the top ten most designated and approved diseases were rare cancers.

CONCLUSIONS: Researchers have estimated that there may be 7000-10,000 rare diseases that have been identified and described. Based on our study, we can conclude that around 5% of rare diseases have an FDA-approved drug and up to 15% of rare diseases have at least one drug that has been developed and shown promise in their treatment, diagnosis or prevention. Funding of basic and translational science for rare disease drug development should continue in order to bring therapies to the millions of affected patients who remain without treatment options.

PMID:37353796 | PMC:PMC10290406 | DOI:10.1186/s13023-023-02790-7

Korean J Gastroenterol. 2023 Jun 25;81(6):253-258. doi: 10.4166/kjg.2023.024.

ABSTRACT

BACKGROUND/AIMS: Gastrointestinal (GI) bezoars are relatively rare diseases with clinical characteristics and treatment modalities that depend on the location of the bezoars. This study evaluated the clinical characteristics and treatment outcomes in patients with GI bezoars.

METHODS: Seventy-five patients diagnosed with GI bezoars were enrolled in this study. Data were collected on the demographic and clinical characteristics and the characteristics of the bezoars, such as type, size, location, treatment modality, and clinical outcomes.

RESULTS: Among the 75 patients (mean age 71.2 years, 38 males), 32 (42.6%) had a history of intra-abdominal surgery. Hypertension (43%) and diabetes (30%) were common morbidities. The common location of the bezoars was the stomach in 33 (44%) and the small intestine in 33 (44%). Non-surgical management, including adequate hydration, chemical dissolution, and endoscopic removal, was successful in 2/2 patients with esophageal bezoars, 26/33 patients with gastric bezoars, 7/9 patients with duodenal bezoars, and 20/33 patients with small intestinal bezoars. The remaining patients had undergone surgical management.

CONCLUSIONS: The management of GI bezoars requires multidisciplinary approaches, including the appropriate correction of fluid and electrolyte imbalances, chemical dissolution, and endoscopic and surgical treatments.

PMID:37350520 | DOI:10.4166/kjg.2023.024

Int J Infect Dis. 2023 Jun 21:S1201-9712(23)00639-2. doi: 10.1016/j.ijid.2023.06.015. Online ahead of print.

ABSTRACT

OBJECTIVE: To investigate the challenges of patients with spinal muscular atrophy (SMA) during the Omicron variant pandemic.

DESIGN: A cross-sectional survey was conducted in China from January 2, 2023 to January 12, 2023 using a questionnaire that covered three aspects: (1) Demographic information; (2) SMA-related information; (3) COVID-19-related information. We recruited patients with SMA from 33 provinces. The prevalence, course and clinical manifestations of COVID-19 were calculated. The relationships between independent and outcome variables were investigated.

RESULTS: 677 patients (male: 349; female: 328) were included in this study (average age = 11.40 years); 534 (78.88%) suffered from COVID-19. The most common symptoms were fever (95.51%), cough (57.87%), and sputum (49.44%). Of the infected patients, 91.57% recovered from homecare and, 8.43% were hospitalized; 1.31% were admitted to intensive care unit (ICU). A positive correlation was observed between the SMA severity and hospitalization rate. The ICU stay rate in patients with SMA Type 1 was significantly higher than that in other SMA types.

CONCLUSIONS: This is the first large-sample survey to timely reveal the living situation of SMA patients under the pandemic of Omicron variant. Patients with SMA type 1 should be paid more attention in terms of hospitalization and ICU stay.

PMID:37352912 | DOI:10.1016/j.ijid.2023.06.015

Orphanet J Rare Dis. 2023 Jun 22;18(1):158. doi: 10.1186/s13023-023-02778-3.

ABSTRACT

BACKGROUND: Wilson disease (WD) is a genetic disorder of copper metabolism that leads to copper accumulation in various organs, primarily the liver and brain, resulting in heterogenous hepatic, neurologic, and psychiatric symptoms. Diagnosis can occur at any age, requiring lifelong treatment, which can involve liver transplantation. This qualitative study aims to understand the wider patient and physician experience of the diagnosis and management of WD in the US.

METHODS: Primary data were collected from 1:1 semi structured interviews with US-based patients and physicians and thematically analyzed with NVivo.

RESULTS: Twelve WD patients and 7 specialist WD physicians (hepatologists and neurologists) were interviewed. Analysis of the interviews revealed 18 themes, which were organized into 5 overarching categories: (1) Diagnosis journey, (2) Multidisciplinary approach, (3) Medication, (4) The role of insurance, and (5) Education, awareness, and support. Patients who presented with psychiatric or neurological symptoms reported longer diagnostic journeys (range 1 to 16 years) than those presenting with hepatic symptoms or through genetic screening (range 2 weeks to 3 years). All were also affected by geographical proximity to WD specialists and access to comprehensive insurance. Exploratory testing was often burdensome for patients, but receipt of a definitive diagnosis led to relief for some. Physicians emphasized the importance of multidisciplinary teams beyond hepatology, neurology, and psychiatry and recommended a combination of chelation, zinc, and a low-copper diet; however, only half the patients in this sample were on a chelator, and some struggled to access prescription zinc due to insurance issues. Caregivers often advocated for and supported adolescents with their medication and dietary regimen. Patients and physicians recommended more education and awareness for the healthcare community.

CONCLUSIONS: WD requires the coordination of care and medication among several specialists due to its complex nature, but many patients do not have access to multiple specialties due to geographical or insurance barriers. Because some patients cannot be treated in Centers of Excellence, easy access to reliable and up-to-date information is important to empower physicians, patients, and their caregivers in managing the condition, along with general community outreach programs.

PMID:37349760 | PMC:PMC10288732 | DOI:10.1186/s13023-023-02778-3

Orphanet J Rare Dis. 2023 Jun 22;18(1):159. doi: 10.1186/s13023-023-02767-6.

ABSTRACT

BACKGROUND: The economic burden of rare diseases on health systems is still not widely measured, with the generation of accurate information about the costs with medical care for subjects with rare diseases being crucial when defining health policies. Duchenne Muscular Dystrophy (DMD) is the most common form of muscular dystrophy, with new technologies recently being studied for its management. Information about the costs related to the disease in Latin America is scarce, and the objective of this study is to evaluate the annual hospital, home care and transportation costs per patient with DMD treatment in Brazil.

RESULTS: Data from 27 patients were included, the median annual cost per patient was R$ 17,121 (IQR R$ 6,786; 25,621). Home care expenditures accounted for 92% of the total costs, followed by hospital costs (6%) and transportation costs (2%). Medications and loss of family, and patient's productivity are among the most representative consumption items. When disease worsening due to loss of the ability to walk was incorporated to the analysis, it was shown that wheelchair users account for an incremental cost of 23% compared with non-wheelchair users.

CONCLUSIONS: This is an original study in Latin America to measure DMD costs using the micro-costing technique. Generating accurate information about costs is crucial to provide health managers with information that could help establish more sustainable policies when deciding upon rare diseases in emerging countries.

PMID:37349725 | PMC:PMC10288739 | DOI:10.1186/s13023-023-02767-6

BMC Oral Health. 2023 Jun 22;23(1):413. doi: 10.1186/s12903-023-03048-1.

ABSTRACT

BACKGROUND: Oral health is an inherent part of overall health as an important physiological crossroad of functions such as mastication, swallowing or phonation; and plays a central role in the life of relationships facilitating social and emotional expression.Our hypothesis was that in patients with rare diseases, access to dental care could be difficult because of the lack of professionals who know the diseases and accept to treat the patients, but also because some patients with cognitive and intellectual disabilities could not find adequate infrastructure to assist in managing their oral health.

METHODS: This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. The transcripts were reviewed to identify key themes and interviews were performed until the data were saturated and no further themes emerged.

RESULTS: Twenty-nine patients from 7 to 24 years old were included in the study of which 15 patients had an intellectual delay. The results show that access to care is complicated more by aspects concerning intellectual disability than by the fact that the disease is rare. Oral disorders are also an obstacle to the maintenance of their oral health.

CONCLUSION: The oral health of patients with rare diseases, can be greatly enhanced by a pooling of knowledge between health professionals in the various sectors around the patient's care. It is essential that this becomes a focus of national public health action that promotes transdisciplinary care for the benefit of these patients.

PMID:37349716 | PMC:PMC10286462 | DOI:10.1186/s12903-023-03048-1

N Engl J Med. 2023 Jun 22. doi: 10.1056/NEJMe2304147. Online ahead of print.

NO ABSTRACT

PMID:37345865 | DOI:10.1056/NEJMe2304147

Orphanet J Rare Dis. 2023 Jun 21;18(1):154. doi: 10.1186/s13023-023-02771-w.

ABSTRACT

BACKGROUND: During the COVID-19 pandemic people affected by rare diseases (RD) or caregiver of affected children have faced additional challenges. The pandemic has affected physical and mental health, social life and has led to financial consequences. Our objectives were to identify the impact of COVID-19 (1) on health care and (2) on daily life and participation of patients with RDs or caregivers from the perspective of representatives of patient organizations. Moreover, we explored their perspective on experiences of pandemic stress and resources during the pandemic.

RESULTS: We conducted 18 semi-structured interviews with representatives of patient organizations (e.g. chairperson, members of the steering committee), who were asked about the experiences of their members. The interviews were transcribed verbatim and analyzed using the framework approach. We contextualized our findings on the basis of the International Classification of Functioning, Disability and Health (ICF) model and adapted it according to identified subthemes. Patients and caregivers were confronted with aspects of pandemic stress such as lack of information, access and information regarding vaccination and being a risk group for COVID-19 infection. Physical and mental functioning was reported to be negatively impacted. Lock downs and contact restrictions led, e.g., to increasing lack of nursing services or lack of necessary informal support. Participation e.g. in social life and work was reduced. Health care services including medical care and supportive care as well as additional therapies were disrupted and greater effort was necessary to organize care. According to participants, central resources were informal support networks, digitalization, patient organizations and individual characteristics.

CONCLUSIONS: Our study highlights the consequences of the COVID-19 pandemic on the situation of people affected by RDs and caregivers. Contextualization of the results into the biopsychosocial model reinforces the impact of the pandemic on health care as well as daily life and participation. Major challenges and difficulties were experienced during lockdowns and contact restrictions. Depending on the risk of an infection with COVID-19, certain patient groups were still isolated and reduced social contacts or still followed strict hygienic measures (e.g., wearing medical masks). Future pandemic control measures, e.g. on lockdowns and closing facilities, should consider the challenges of people with RDs and caregivers of affected children.

PMID:37344904 | DOI:10.1186/s13023-023-02771-w

J Investig Med High Impact Case Rep. 2023 Jan-Dec;11:23247096231181856. doi: 10.1177/23247096231181856.

ABSTRACT

Porphyrias, particularly acute intermittent porphyria (AIP), are rare, inherited disorders of heme synthesis. On the other hand, systemic lupus erythematosus (SLE) is an uncommon autoimmune disease that affects women predominantly. The coexistence of AIP and SLE is rare. We report a case of concomitant diagnosis of AIP and SLE in a 21-year-old woman who presented with recurrent acute abdominal, chest, and back pain associated with nausea and vomiting, followed by arthralgia, multiple joint pain, and rash. Investigations revealed severe hyponatremia related to SIADH (syndrome of inappropriate antidiuretic hormone secretion) with a positive SLE antibody panel and a positive urine screen for porphobilinogen. Molecular test confirmed the diagnosis of AIP with a pathogenic mutation in the HMBS gene.

PMID:37341437 | DOI:10.1177/23247096231181856

Rev Med Suisse. 2023 Jun 21;19(832):1245-1249. doi: 10.53738/REVMED.2023.19.832.1245.

ABSTRACT

In nephrology, rare disorders are frequently encountered. In children, about 60% of the renal disorders are rare, with congenital abnormalities of the kidney and urinary tract disorders (CAKUT), being highly prevalent. In adults, about 22% of the disorders leading to renal replacement therapies are rare and include glomerulonephritis and genetic disorders. Rarity may preclude the rapid and extensive access to care for patients suffering of renal disorders, especially in Switzerland, which is small and fragmented. Only collaborative network and access to databases, shared resources and to specific competence may help patient management. Lausanne and Geneva University Hospitals have started specialized outpatient clinics for rare renal disorders several years ago and are part of national and international networks.

PMID:37341318 | DOI:10.53738/REVMED.2023.19.832.1245

Am J Bioeth. 2023 Jul;23(7):97-99. doi: 10.1080/15265161.2023.2208073.

NO ABSTRACT

PMID:37339318 | DOI:10.1080/15265161.2023.2208073

Am J Bioeth. 2023 Jul;23(7):100-102. doi: 10.1080/15265161.2023.2207514.

NO ABSTRACT

PMID:37339313 | DOI:10.1080/15265161.2023.2207514

Am J Bioeth. 2023 Jul;23(7):83-85. doi: 10.1080/15265161.2023.2207512.

NO ABSTRACT

PMID:37339309 | DOI:10.1080/15265161.2023.2207512

Am J Bioeth. 2023 Jul;23(7):94-96. doi: 10.1080/15265161.2023.2207511.

NO ABSTRACT

PMID:37339308 | DOI:10.1080/15265161.2023.2207511

Am J Bioeth. 2023 Jul;23(7):91-94. doi: 10.1080/15265161.2023.2207509.

NO ABSTRACT

PMID:37339297 | DOI:10.1080/15265161.2023.2207509