Anti-CD19 Chimeric Antigen Receptor T-Cell Therapy for Richter Transformation: An International, Multicenter, Retrospective Study.

PURPOSE: Outcomes for Richter transformation (RT) are poor with current therapies. The efficacy and safety of anti-CD19 chimeric antigen receptor T-cell therapy (CAR-T) for RT are not established. METHODS: We performed an international multicenter retrospective study of patients with RT who received CAR-T. Patient, disease, and treatment characteristics were summarized using descriptive statistics, and modeling analyses were used to determine association with progression-free survival (PFS) and overall survival (OS). PFS and OS were estimated from the date of CAR-T infusion. RESULTS: Sixty-nine patients were identified. The median age at CAR-T infusion was 64 years (range, 27-80). Patients had a median of four (range, 1-15) previous lines of therapy for CLL and/or RT, including previous Bruton tyrosine kinase inhibitor and/or BCL2 inhibitor therapy in 58 (84%) patients. The CAR-T product administered was axicabtagene ciloleucel in 44 patients (64%), tisagenlecleucel in 17 patients (25%), lisocabtagene maraleucel in seven patients (10%), and brexucabtagene autoleucel in one patient (1%). Eleven patients (16%) and 25 patients (37%) experienced grade ≥3 cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, respectively. The overall response rate was 63%, with 46% attaining a complete response (CR). After a median follow-up of 24 months, the median PFS was 4.7 months (95% CI, 2.0 to 6.9); the 2-year PFS was 29% (95% CI, 18 to 41). The median OS was 8.5 months (95% CI, 5.1 to 25.4); the 2-year OS was 38% (95% CI, 26 to 50). The median duration of response was 27.6 months (95% CI, 14.5 to not reached) for patients achieving CR. CONCLUSION: CAR-T demonstrates clinical efficacy for patients with RT.

Clinical phenotyping and genetic diagnosis of a large cohort of Sudanese families with hereditary spinocerebellar degenerations.

Hereditary spinocerebellar degenerations (SCDs) is an umbrella term that covers a group of monogenic conditions that share common pathogenic mechanisms and include hereditary spastic paraplegia (HSP), cerebellar ataxia, and spinocerebellar ataxia. They are often complicated with axonal neuropathy and/or intellectual impairment and overlap with many neurological conditions, including neurodevelopmental disorders. More than 200 genes and loci inherited through all modes of Mendelian inheritance are known. Autosomal recessive inheritance predominates in consanguineous communities; however, autosomal dominant and X-linked inheritance can also occur. Sudan is inhabited by genetically diverse populations, yet it has high consanguinity rates. We used next-generation sequencing, genotyping, bioinformatics analysis, and candidate gene approaches to study 90 affected patients from 38 unrelated Sudanese families segregating multiple forms of SCDs. The age-at-onset in our cohort ranged from birth to 35 years; however, most patients manifested childhood-onset diseases (the mean and median ages at onset were 7.5 and 3 years, respectively). We reached the genetic diagnosis in 63% and possibly up to 73% of the studied families when considering variants of unknown significance. Combining the present data with our previous analysis of 25 Sudanese HSP families, the success rate reached 52-59% (31-35/59 families). In this article we report candidate variants in genes previously known to be associated with SCDs or other phenotypically related monogenic disorders. We also highlight the genetic and clinical heterogeneity of SCDs in Sudan, as we did not identify a major causative gene in our cohort, and the potential for discovering novel SCD genes in this population.

Reversal of life-threatening bleeding with protamine sulfate in a patient with plasma cell leukemia.

Plasma cell disorders, such as multiple myeloma, can cause numerous derangements of hemostasis. In this case report, we present a life-threatening coagulopathy in a patient with progressing multiple myeloma in which the antibody-producing heparin-like activity is a free light chain. The patient's bleeding was successfully treated using protamine sulfate, which then allowed treatment of her plasma cell leukemia. In the literature, other authors have reported similar patients who have responded to protamine sulphate either in vitro or in vivo , providing further evidence for the role of protamine sulfate in the reversal of coagulopathy and resolution of bleeding diathesis. Standard treatments of transfusion with fresh frozen plasma and cryoprecipitate are likely to be ineffective in life-threatening bleeding related to this mechanism (heparin-like effect), and it is essential that treating physicians are aware of this potential mechanism of bleeding in their patients.

Genetic diagnosis in Sudanese and Tunisian families with syndromic intellectual disability through exome sequencing.

BACKGROUND: Intellectual disability is a form of neurodevelopmental disorders that begin in childhood and is characterized by substantial intellectual difficulties as well as difficulties in conceptual, social, and practical areas of living. Several genetic and nongenetic factors contribute to its development; however, its most severe forms are generally attributed to single-gene defects. High-throughput technologies and data sharing contributed to the diagnosis of hundreds of single-gene intellectual disability subtypes. METHOD: We applied exome sequencing to identify potential variants causing syndromic intellectual disability in six Sudanese patients from four unrelated families. Data sharing through the Varsome portal corroborated the diagnosis of one of these patients and a Tunisian patient investigated through exome sequencing. Sanger sequencing validated the identified variants and their segregation with the phenotypes in the five studied families. RESULT: We identified three pathogenic/likely pathogenic variants in CCDC82, ADAT3, and HUWE1 and variants of uncertain significance in HERC2 and ATP2B3. The patients with the CCDC82 variants had microcephaly and spasticity, two signs absent in the two previously reported families with CCDC82-related intellectual disability. CONCLUSION: In conclusion, we report new patients with pathogenic mutations in the genes CCDC82, ADAT3, and HUWE1. We also highlight the possibility of extending the CCDC82-linked phenotype to include spastic paraplegia and microcephaly.

Operationalization of patients' rights in Sudan: Quantifying nurses' knowledge.

BACKGROUND: Promoting patients' rights is essential for defining the standards of clinical services within a country. Given their responsibilities, nurses can be the primary target for research to investigate the issue of patients' rights within a healthcare system. As such, assessing the knowledge of nurses about patients' rights is an essential step toward improving the quality of healthcare in limited resource settings like Sudan. OBJECTIVES: We aimed to assess the level of knowledge about patients' rights among the nursing staff at Friendship Teaching Hospital in Sudan. METHODS: This hospital-based cross-sectional study was carried out at the Friendship Teaching Hospital in Sudan. We surveyed the totality of nurses (95) at the hospital using an amended survey. The data were analyzed in SPSS software using descriptive and inferential statistics. ETHICAL CONSIDERATION: The study was approved by the Research Unit of Khartoum Ministry of Health and the Hospital administration. All respondents gave verbal consent prior to participating in the study. RESULTS: Only 48.4% of the participants knew about the existence of the Sudanese Charter of patients' rights. Nonetheless, our analysis found that 65.8% of nurses had acceptable level of knowledge (scored more than 75% of the total knowledge score) of patients' rights, and none of the participant scored less than 50% of the total knowledge score. Finally, we found no statistical association between the knowledge score and demographic data, educational level, whether the participant knows about the existence of the Charter or not and a number of other factors. CONCLUSION: Nurses' lack of knowledge about the existence of the Sudanese Charter of patients' rights adopted in 2009 rights confirms the need for further efforts by Ministry of Health to promote the document. Furthermore, further research is needed to investigate the disconnect between nurses' lack of knowledge about the existence of the charter and their awareness of the rights within the charter as well as the actual implementation of rights.

Hereditary spastic paraplegias: identification of a novel SPG57 variant affecting TFG oligomerization and description of HSP subtypes in Sudan.

Hereditary spastic paraplegias (HSP) are the second most common type of motor neuron disease recognized worldwide. We investigated a total of 25 consanguineous families from Sudan. We used next-generation sequencing to screen 74 HSP-related genes in 23 families. Linkage analysis and candidate gene sequencing was performed in two other families. We established a genetic diagnosis in six families with autosomal recessive HSP (SPG11 in three families and TFG/SPG57, SACS and ALS2 in one family each). A heterozygous mutation in a gene involved in an autosomal dominant HSP (ATL1/SPG3A) was also identified in one additional family. Six out of seven identified variants were novel. The c.64C>T (p.(Arg22Trp)) TFG/SPG57 variant (PB1 domain) is the second identified that underlies HSP, and we demonstrated its impact on TFG oligomerization in vitro. Patients did not present with visual impairment as observed in a previously reported SPG57 family (c.316C>T (p.(Arg106Cys)) in coiled-coil domain), suggesting unique contributions of the PB1 and coiled-coil domains in TFG complex formation/function and a possible phenotype correlation to variant location. Some families manifested marked phenotypic variations implying the possibility of modifier factors complicated by high inbreeding. Finally, additional genetic heterogeneity is expected in HSP Sudanese families. The remaining families might unravel new genes or uncommon modes of inheritance.

Validity and reliability of Arabic MOS social support survey.

We aimed to generate a valid reliable Arabic version of MOS social support survey (MOS-SSS). We did a cross sectional study in medical students of Faculty of Medicine in Khartoum, Sudan. We did a clustered random sampling in 500 students of which 487 were suitable for analysis. We followed the standard translation process for translating the MOS-SSS. We accomplished factor analysis to assess construct validity, and generated item-scales correlations to evaluate the convergent and discriminant validity. We extracted the Cronbach's α and Spearman Brown coefficient of spit half method to determine internal consistency. We measured stability by correlation between the scores of the MOS survey taken at two different occasions with ten days apart in 252 participants. All items correlated highly (0.788 or greater) with their hypothesized scales. All items in subscales correlated higher by two standard errors with their own scale than with any other scale. Principle component analysis with varimax rotation was conducted on the 19 items and examination of scree plot graphically suggested 4 predominant factors that account for 72 % of variance. It showed high loadings, ranging from 0.720 to 0.84 for items of emotional support, 0.699-0.845 for tangible support, 0.518-0.823 for affectionate support, and 0.740-0.816 for positive social interaction. Cronbach's alpha for overall MOS scale and subscales indicated high internal consistency. The test-retest correlation showed weak correlation between the test and retest (ranges from 0.04 to 0.104). The Arabic MOS-SSS had high validity and internal consistency.