Translation and Validation of the Indonesian MD Anderson Dysphagia Inventory (MDADI) in Head and Neck Cancer Patients with Swallowing Disorders

Abstract Introduction Dysphagia is common in head and neck cancer patients; it is associated with significant morbidity, including quality of life. Several instruments can be used to assess the quality of life of dysphagia patients, including the M.D Anderson dysphagia inventory (MDADI) questionnaire, which is sufficiently valid and reliable to improve the quality of life of patients with neurological disorders and head and neck cancer. Objective The purpose of the present study is to perform adaptation, cultural translation, and validation of the MDADI questionnaire for the Indonesian language. Methods This cross-sectional study assessed the validity and reliability of the MDADI Indonesian adaptation instrument in head and neck cancer patients with swallowing disorders in the Otorhinolaryngology clinic of the Dr. Sardjito hospital, Yogyakarta, from May to August 2019. Results There were 40 study subjects, including 31 men and 9 women. The MDADI instrument adapted to Indonesian is valid and reliable as an instrument for assessing the quality of life of patients with head and neck cancer with swallowing disorders, with r-values ranging from 0.314 to 0.939. Internal consistency shows that Cronbach's α is 0.915, and test-retest reliability (intra-class correlation) ranges from 0.919 to 0.985. Conclusion The translation and validation of the Indonesian MDADI instrument were performed as an instrument for assessing the quality of life of head and neck cancer patients with swallowing disorders.

Translation and Validation of the Indonesian MD Anderson Dysphagia Inventory (MDADI) in Head and Neck Cancer Patients with Swallowing Disorders.

Introduction Dysphagia is common in head and neck cancer patients; it is associated with significant morbidity, including quality of life. Several instruments can be used to assess the quality of life of dysphagia patients, including the M.D Anderson dysphagia inventory (MDADI) questionnaire, which is sufficiently valid and reliable to improve the quality of life of patients with neurological disorders and head and neck cancer. Objective The purpose of the present study is to perform adaptation, cultural translation, and validation of the MDADI questionnaire for the Indonesian language. Methods This cross-sectional study assessed the validity and reliability of the MDADI Indonesian adaptation instrument in head and neck cancer patients with swallowing disorders in the Otorhinolaryngology clinic of the Dr. Sardjito hospital, Yogyakarta, from May to August 2019. Results There were 40 study subjects, including 31 men and 9 women. The MDADI instrument adapted to Indonesian is valid and reliable as an instrument for assessing the quality of life of patients with head and neck cancer with swallowing disorders, with r-values ranging from 0.314 to 0.939. Internal consistency shows that Cronbach's α is 0.915, and test-retest reliability (intra-class correlation) ranges from 0.919 to 0.985. Conclusion The translation and validation of the Indonesian MDADI instrument were performed as an instrument for assessing the quality of life of head and neck cancer patients with swallowing disorders.

The Role of Mannose-Binding Lectin Serum Level in Tubotympanic Chronic Suppurative Otitis Media.

BACKGROUND: Chronic suppurative otitis media (CSOM) is a common public health problem worldwide and a major cause of hearing impairment especially in developing countries. The role of Mannose-Binding Lectin (MBL), a component of innate immunity, in CSOM has not been studied. The aim of the study was to examine whether MBL deficiency was more frequently present in cases group of tubotympanic CSOM patients rather than healthy subjects. MATERIAL AND METHODS: This was an analytic observational study. Subjects were enrolled in the Otorhinolaryngology Clinic at Margono Soekarjo Hospital, Purwokerto, Indonesia. An independent t-test was used to compare the mean of MBL serum concentration between tubotympanic CSOM subjects and control. RESULTS: From 36 tubotympanic CSOM patients, there were 8 (22.22%) patients with MBL deficiency (MBL level < 100 ng/ml), while no deficiency was found in the control group. The mean of MBL level in cases group was 354.88 ng/ml, with the lowest level being 0.001 ng/ml and the highest level 690.24 ng/ml, while in the control group MBL level mean was 376.27 with the lowest level being 188.71 and the highest level 794.54 ng/ml. CONCLUSION: There was no significant difference of MBL serum level between tubotympanic CSOM and control group. However, the presence of subjects with MBL deficiency in the tubotympanic CSOM group might be considered as playing a role in the tubotympanic CSOM.

Detection of Epstein-Barr and Human Papilloma Viruses in the Middle Ear Squamous Cell Carcinoma.

The uncommon ear tumor of middle ear squamous cell carcinoma (MESCC) is thought to be associated with the history of long-term chronic otitis media in the most cases. The main etiologic factor of MESCC is still unclear and may be multifactorial. Infections of Epstein-Barr virus (EBV) and Human Papillomavirus (HPV) are considered as one of the etiologic factor of MESCC. Previous studies have shown that the EBV and HPV have been detected in MESCC. Although the EBV and HPV have been implicated in human malignancies, their roles in pathogenesis of MESCC have not been elucidated. There has never been report on the presence of EBV and HPV in Indonesian MESCC. This study aimed to determine the presence of EBV and HPV in MESCC. Seven paraffin-embedded tissues of speciment from biopsy were analyzed for the presence of EBV and HPV by immunohistochemistry, stained using polyclonal antibody anti EBNA1 and anti HPV. The samples consisted of 4 (57 %) males and 3 (43 %) females with age range of 26-87 years old. Immunohistochemistry result demonstrated that EBV was detected in three of seven (43 %) and HPV in two of seven (29 %) samples. Coexistence of the presence of EBV and HPV were found in one of seven (14 %) sample. The presence of EBV and HPV in MESCC suggests that viral infection may play an important etiologic role in the carcinogenesis of middle ear.

Hypoxia-Inducible Factor-1α Expression in Indonesian Laryngeal Squamous Cell Carcinoma Patients.

Objectives. This research aimed to determine the association between hypoxia-inducible factor-1α (HIF-1α) expression and laryngeal squamous cell carcinoma clinical stage. Methods. We retrospectively analyzed paraffin-embedded tissue from 47 laryngeal squamous cell carcinoma (LSCC) patients from 2011 to 2014. HIF-1α expression was analyzed by immunohistochemistry using an anti-HIF-1α mouse monoclonal antibody. The association between HIF-1α expression and clinical stage was analyzed using the chi square test. Results. The glottis was the predominant site of laryngeal squamous cell carcinoma occurrence, and 43/47 (91.5%) patients presented at an advanced stage. Of the advanced stage patients, 27/43 stained positive for HIF-1α expression and 16/43 stained negative. Of the early stage patients, 2/4 stained positive for HIF-1α expression and 2/4 stained negative. Statistical analysis did not demonstrate significant association of HIF-1α expression. Conclusion. There was no statistically significant association between HIF-1α expression and the clinical stage or histological differentiation of LSCC.

A G-to-A transition at the fifth position of intron-32 of the dystrophin gene inactivates a splice-donor site both in vivo and in vitro.

The splicing pattern of pre-mRNA is unpredictable in genes harboring a single-nucleotide change within the consensus sequence of a splice-donor site. In the dystrophin gene, a transition from G to A at the fifth position of intron-32 (4518+5G > A) has been reported as a polymorphism within the consensus sequence or a mutation identified in Duchenne muscular dystrophy (DMD). Here, we report both in vivo and in vitro evidence that shows inactivation of the splice-donor site caused by this mutation. In one Japanese DMD case, two novel dystrophin mRNAs were identified in the patient's lymphocytes, one with a 98 bp deletion of the 3' end of exon-32 (dys32-98) and the other with a 28 bp intron retained between exons 32 and 33 (dys32 + 28). Genomic sequencing disclosed a single-nucleotide change from G to A at the fifth position of intron-32 (4518+5G > A). To demonstrate in vitro the inactivation of this splice-donor site by this nucleotide change, mini-dystrophin genes comprising three exons harboring either normal or mutant intron-32 sequences were expressed in HeLa cells, and the splicing products were analyzed by reverse-transcription PCR amplification. A normal transcript consisting of three exons was obtained from the normal construct. From the mutant, we obtained one product containing a 98 bp deletion at the 3' end of exon-32, indicating complete inactivation of the native splice-donor site. Thus, both in vivo and in vitro experiments demonstrate that 4518+5G > A causes a splicing error leading to transcript termination; it did not behave like a silent polymorphism. Our results indicate that the in vitro splicing system is a powerful tool for determining the underlying mechanism of a disease-causing mutation in a splicing consensus sequence.

Chimeric RNA/ethylene-bridged nucleic acids promote dystrophin expression in myocytes of duchenne muscular dystrophy by inducing skipping of the nonsense mutation-encoding exon.

Editing of dystrophin mRNA by induction of exon skipping, using antisense oligonucleotides, has been proposed as one way to generate dystrophin expression in Duchenne muscular dystrophy (DMD) patients. Here, antisense chimeric oligonucleotides consisting of RNA and a new modified nucleic acid are tested for activity to induce skipping of an exon containing a nonsense mutation. In a Japanese DMD case, a nonsense mutation (R1967X) due to a single nucleotide change in exon 41 of the dystrophin gene (C5899T) was identified. Oligonucleotides consisting of 2'-O-methyl RNA and a new 2'-O,4'-C-ethylene-bridged nucleic acid (ENA) were designed to bind the mutation site of exon 41, and their ability to induce exon 41 skipping in dystrophin mRNA was evaluated. Finally, among the specific oligonucleotides tested, an 18-mer RNA/ENA chimera was found to have the strongest activity, inducing exon 41 skipping in nearly 90% of dystrophin mRNA. Accordingly, nearly 90% of cultured myocytes were shown to be dystrophin positive by immunohistochemical analysis. Western blot analysis disclosed the presence of nearly normal-sized dystrophin up to 1 week after the transfection. Our results suggest that an RNA/ENA chimera can be used to express dystrophin in DMD.

Novel double-deletion mutations of the OFD1 gene creating multiple novel transcripts.

Oral-facial-digital syndrome type 1 (OFD1) is an X-linked dominant disease characterized by malformations of the face, oral cavity, and digits. Thus far, 18 small mutations in the OFD1 gene have been reported. Here, we describe, in one Japanese sporadic female OFD1 case, the presence of a novel pair of deletion mutations: a 4,094-bp deletion encompassing exon 7 to intron 9, and a 14-bp deletion in intron 9, both of which are present in her paternal X-chromosome. The first deletion, the largest known to affect OFD1, was revealed by identifying four novel transcripts that all lacked exons 7-9. The most likely cause of the double deletion is two unequal recombinations between homologous sequences. Identification of the 4,094-bp deletion was made possible only by analyzing OFD1 mRNA, underscoring the utility of mRNA analysis in the mutational analysis of OFD1.

Chimeric RNA and 2'-O, 4'-C-ethylene-bridged nucleic acids have stronger activity than phosphorothioate oligodeoxynucleotides in induction of exon 19 skipping in dystrophin mRNA.

Antisense phosphorothioate oligodeoxynucleotides against exon 19 of the dystrophin gene have been shown to induce exon 19 skipping and promote the expression of internally deleted dystrophin by correcting the translational reading frame. Because phosphorothioate oligonucleotides are associated with a variety of toxic nonantisense effects, several modifications of nucleic acid have been introduced to alleviate this toxicity. Recently, a 2'-O, 4'-C-ethylene-bridged nucleic acid (ENA trade mark, Sankyo Lifetech Co., Ltd., Tokyo, Japan) was reported to have high affinity to complementary RNA strands and be resistant to nuclease digestion. Here, we examined the ability of this modified nucleic acid to induce exon skipping. Oligonucleotides having the same sequence as the phosphorothioate oligonucleotides but with some stretches of modified backbone (2'-O-methyl RNA with an ENA5-mer at the 5'-end and 3'-end) (RNA/ENA chimera) were transfected into myocytes, and the expressed dystrophin mRNA was analyzed. The RNA/ENA chimera induced exon 19 skipping in a dose-dependent and time-dependent manner. Remarkably, the exon 19-skipping activity of the RNA/ENA chimera was more than 40 times stronger than that of the corresponding conventional phosphorothioate oligodeoxynucleotide. This is the first report of such strong activity of an RNA/ENA chimera in the induction of exon skipping in the dystrophin gene. This new technology will allow the development of less toxic antisense drugs, making long-term therapy possible.

Design of 2'-O-Me RNA/ENA chimera oligonucleotides to induce exon skipping in dystrophin pre-mRNA.

2'-O-Me RNA/ENA chimera oligonucleotides complementary to exon 45 and 46 of the dystrophin gene induced exon 45 and 46 skipping of the dystrophin pre-mRNA, respectively. The induction of exon skipping by the most effective 2'-O-Me RNA/ENA chimeras led to the expression of dystrophin in dystrophin-deficient myocytes by correcting the translational reading frames. Also, in the process of 2'-O-Me RNA/ENA chimera optimization to induce exon skipping in several exons, it was found that the optimized target sequences of the chimeras included guanosine- or adenosine-rich sequences that might function as spiking enhancer sequences (SES).