Phenotypic Heterogeneity in Patients with Mutations in the Mitochondrial Complex I Assembly Gene NDUFAF5.

BACKGROUND: Rare mutations in NADH:ubiquinone oxidoreductase complex assembly factor 5 (NDUFAF5) are linked to Leigh syndrome. OBJECTIVE: We aimed to describe clinical characteristics and functional findings in a patient cohort with NDUFAF5 mutations. METHODS: Patients with biallelic NDUFAF5 mutations were recruited from multi-centers in Taiwan. Clinical, laboratory, radiological, and follow-up features were recorded and mitochondrial assays were performed in patients' skin fibroblasts. RESULTS: Nine patients from seven unrelated pedigrees were enrolled, eight homozygous for c.836 T > G (p.Met279Arg) in NDUFAF5 and one compound heterozygous for p.Met279Arg. Onset age had a bimodal distribution. The early-onset group (age <3 years) presented with psychomotor delay, seizure, respiratory failure, and hyponatremia. The late-onset group (age ≥5 years) presented with normal development, but slowly progressive dystonia. Combing 25 previously described patients, the p.Met279Arg variant was exclusively identified in Chinese ancestry. Compared with other groups, patients with late-onset homozygous p.Met279Arg were older at onset (P = 0.008), had less developmental delay (P = 0.01), less hyponatremia (P = 0.01), and better prognosis with preserved ambulatory function into early adulthood (P = 0.01). Bilateral basal ganglia necrosis was a common radiological feature, but brainstem and spinal cord involvement was more common with early-onset patients (P = 0.02). A modifier gene analysis showed higher concomitant mutation burden in early-versus late-onset p.Met279Arg homozygous cases (P = 0.04), consistent with more impaired mitochondrial function in fibroblasts from an early-onset case than a late-onset patient. CONCLUSIONS: The p.Met279Arg variant is a common mutation in our population with phenotypic heterogeneity and divergent prognosis based on age at onset. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Generation of a human induced pluripotent stem cell line NTUHi004-A from a patient with Leigh syndrome harboring a homozygous missense mutation c.836 T > G (p.Met279Arg) in NDUFAF5 gene.

Leigh syndrome is a rare autosomal recessive disorder showcasing a diverse range of neurological symptoms. Classical Leigh syndrome is associated with mitochondrial complex I deficiency, primarily resulting from biallelic mutations in the NDUFAF5 gene, encoding the NADH:ubiquinone oxidoreductase complex assembly factor 5. Using the Sendai virus delivery system, we generated an induced pluripotent stem cell line from peripheral blood mononuclear cells of a 47-years-old female patient who carried a homozygous NDUFAF5 c.836 T > G (p.Met279Arg) mutation. This cellular model serves as a tool for investigating the underlying pathogenic mechanisms and for the development of potential treatments for Leigh syndrome.

Survival of lung adenocarcinoma patients with malignant pleural effusion.

In the era of targeted therapy, the association between lung adenocarcinoma patient survival and malignant pleural effusions (MPEs) remains unclear. This study investigated the clinical characteristics, survival and epidermal growth factor receptor (EGFR) gene (EGFR) mutation status of lung adenocarcinoma patients with MPE. From June 2005 to December 2010, consecutive pleural effusions were collected prospectively. Patient clinical characteristics, EGFR mutation status, and overall survival were analysed. We collected MPEs from 448 patients in stage IV lung adenocarcinoma at initial diagnosis. Median overall survival for patients with MPEs at initial diagnosis and following disease progression were 14.3 months and 21.4 months, respectively (p=0.001). There were 296 (66.1%) patients harbouring EGFR mutations, the mutation rates among patients with an MPE at initial diagnosis and one following disease progression were 68.2% and 56.6%, respectively (p=0.044); the L858R mutation rate was also higher among the former (32.6% versus 18.1%; p=0.009). Multivariate analysis revealed that patients who: developed MPEs following disease progression, harboured EGFR mutations, and received EGFR-tyrosine kinase inhibitor therapy, had longer overall survival. Patients in stage IV lung adenocarcinoma with MPEs at initial diagnosis have shorter overall survival and higher EGFR mutation rate, especially for L858R, than patients who develop MPEs following disease progression.

Second-line pemetrexed treatment in Taiwanese patients with advanced nonsmall cell lung cancer: an open-label single-arm study.

BACKGROUND/PURPOSE: Although global and Asian studies on second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer have confirmed its efficacy and safety, a pivotal postcommitment study to consolidate the evidence regarding the Taiwanese population was warranted. This open-label single-arm study assessed the objective response rate to a tailored dose of single-agent pemetrexed in Taiwanese patients with advanced nonsmall cell lung cancer who had received prior chemotherapy. METHODS: Patients with stage IIIB/IV disease were treated with pemetrexed on day 1 of each 21-day cycle. A 500 mg/m(2) dose was administered in cycle 1. For cycle 2, the dose was increased to 1000 mg/m(2) (if there was no toxicity above predefined levels) or decreased to 375 mg/m(2). All patients received standard supplemental therapy. Patient follow-up continued until 18 months after the last patient was enrolled in this study or death. All patients were included in all analyses. RESULTS: Of the 33 patients who were enrolled, 25 (75.8%) received the 1000 mg/m(2) dose during cycle 2; 18 patients were dropped from the study, including 17 (51.5%) who had died by the time of analysis. The objective response and disease control rates were 18.2% (95% confidence limits [CI]: 7.0-35.5) and 54.5% (95% CI: 36.4-71.9), respectively. No patients exhibited a complete response. There were two serious drug-related adverse events (neutropenia and leukopenia) and two drug-related adverse events that resulted in removal from the study. Decreased neutrophil/granulocyte counts were the most frequently observed drug-related grade 3/4 events (9 patients, 24 treatment cycles). CONCLUSION: The objective response rate, disease control rate, and safety and tolerability profile in this population of Taiwanese patients were consistent with the published findings that were conducted using Asian and Western populations. These findings support the use of single-agent, second-line pemetrexed for the treatment of advanced nonsmall cell lung cancer in Taiwanese patients.

Factors impacting prognosis prediction in BCLC stage C and Child-Pugh class A hepatocellular carcinoma patients in prospective clinical trials of systemic therapy.

BACKGROUND: The purpose of this study was to determine the prognostic significance of clinical factors and staging systems for survival of hepatocellular carcinoma (HCC) patients who are candidates for therapeutic clinical trials. METHODS: From December 1990 to July 2005, 236 patients with unresectable HCC were enrolled into six published phase II trials assessing various therapeutic regimens. Of these, 156 chemotherapy-naive patients with Child-Pugh class A and Barcelona Clinic Liver Cancer stage C disease were included in this analysis. Twenty-seven relevant clinical characteristics were analyzed to identify prognostic factors of survival. Beyond these prognosticators, the predictive ability of eight staging systems (the tumor-node-metastasis, Okuda, Cancer of the Liver Italian Program [CLIP], Chinese University Prognostic Index, Japanese Integrated Staging, Tokyo, National Taiwan University Risk Estimation, and Advanced Liver Cancer Prognostic System [ALCPS] score) were compared using the Akaike information criteria. RESULTS: The median overall survival time was 129 days (95% confidence interval, 111-147 days). Significant predictors of a shorter overall survival time were an Eastern Cooperative Oncology Group performance status score ≥2, the presence of symptoms, ascites, an aspartate transaminase level more than two times the upper limit of normal, and regional lymph node involvement. The ALCPS and CLIP scores were superior to the other systems for predicting survival. CONCLUSIONS: The prognosis of patients with advanced HCC who are candidates for therapeutic clinical trials is affected by several factors related to the patient, liver function, and the tumor. The ALCPS and CLIP scores appear to be superior to the other systems for predicting survival.

Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma.

BACKGROUND: Previous, uncontrolled studies have suggested that first-line treatment with gefitinib would be efficacious in selected patients with non-small-cell lung cancer. METHODS: In this phase 3, open-label study, we randomly assigned previously untreated patients in East Asia who had advanced pulmonary adenocarcinoma and who were nonsmokers or former light smokers to receive gefitinib (250 mg per day) (609 patients) or carboplatin (at a dose calculated to produce an area under the curve of 5 or 6 mg per milliliter per minute) plus paclitaxel (200 mg per square meter of body-surface area) (608 patients). The primary end point was progression-free survival. RESULTS: The 12-month rates of progression-free survival were 24.9% with gefitinib and 6.7% with carboplatin-paclitaxel. The study met its primary objective of showing the noninferiority of gefitinib and also showed its superiority, as compared with carboplatin-paclitaxel, with respect to progression-free survival in the intention-to-treat population (hazard ratio for progression or death, 0.74; 95% confidence interval [CI], 0.65 to 0.85; P<0.001). In the subgroup of 261 patients who were positive for the epidermal growth factor receptor gene (EGFR) mutation, progression-free survival was significantly longer among those who received gefitinib than among those who received carboplatin-paclitaxel (hazard ratio for progression or death, 0.48; 95% CI, 0.36 to 0.64; P<0.001), whereas in the subgroup of 176 patients who were negative for the mutation, progression-free survival was significantly longer among those who received carboplatin-paclitaxel (hazard ratio for progression or death with gefitinib, 2.85; 95% CI, 2.05 to 3.98; P<0.001). The most common adverse events were rash or acne (in 66.2% of patients) and diarrhea (46.6%) in the gefitinib group and neurotoxic effects (69.9%), neutropenia (67.1%), and alopecia (58.4%) in the carboplatin-paclitaxel group. CONCLUSIONS: Gefitinib is superior to carboplatin-paclitaxel as an initial treatment for pulmonary adenocarcinoma among nonsmokers or former light smokers in East Asia. The presence in the tumor of a mutation of the EGFR gene is a strong predictor of a better outcome with gefitinib. (ClinicalTrials.gov number, NCT00322452.)

Advanced non-small cell lung cancer in patients aged 45 years or younger: outcomes and prognostic factors.

BACKGROUND: Lung cancer in young patients (less or equal to 45 years) is uncommon and has clinical characteristics different from that in older patients. We investigated the outcomes and prognostic factors of young patients with advanced non-small cell lung cancer (NSCLC). METHODS: From January 2000 to December 2009, we enrolled patients aged ≤45 years and diagnosed with stage IIIB or IV NSCLC. Their clinical data, including age, gender, performance status, histologic types, disease stages, laboratory data at diagnosis, treatment modalities, and survival were reviewed and analyzed. A Cox proportional hazard model was used to calculate the hazard ratio (HR) and its 95% confidence interval (CI). RESULTS: A total of 144 patients with advanced NSCLC were included. Female patients were more prevalent (n = 74, 51.4%). Adenocarcinoma was the most common histologic type (n = 119, 82.6%) in both genders (male, n = 54, 77.1%; female, n = 65, 87.8%). Epidermal growth factor receptor (EGFR) sequences were determined using tumor specimens from 58 patients, and 29 showed an EGFR mutation. No significant difference in median survival was found between patient groups with and without the EGFR mutation (798 vs. 708 days, p = 0.65). In multivariate analysis, male gender (HR, 1.70; 95% CI: 1.08-2.68), body mass index (BMI) less than 25 kg/m(2) (HR, 2.72; 95% CI: 1.39-5.30), stage IV disease (HR, 2.62; 95% CI: 1.50-4.57), and anemia (HR, 2.08; 95% CI: 1.15-3.77) were associated with a short survival time. CONCLUSIONS: Low BMI, stage IV disease, anemia at diagnosis, and male gender were the negative prognostic factors for young patients with advanced NSCLC.

Slug confers resistance to the epidermal growth factor receptor tyrosine kinase inhibitor.

RATIONALE: Non-small cell lung cancers carrying epidermal growth factor receptor (EGFR) mutations respond well to EGFR tyrosine kinase inhibitors (TKIs), but patients ultimately develop drug resistance and relapse. Although epithelial-mesenchymal transition (EMT) can predict resistance to EGFR TKIs, the molecular mechanisms are still unknown. OBJECTIVES: To examine the role of EMT regulators in resistance to gefitinib. METHODS: The expression level of EMT regulators in gefitinib-sensitive cells (PC9) and gefitinib-resistant cells (PC9/gef) was determined using quantitative real-time reverse transcription-polymerase chain reaction and Western blot analysis. Molecular manipulations (silencing or overexpression) were performed to investigate the effects of EMT regulators on gefitinib resistance in vitro, and a xenograft mouse model was used for in vivo confirmation. In addition, cancer cells from 44 patients with malignant pleural effusions of lung adenocarcinoma were collected for analysis of EMT regulator mRNA by quantitative real-time reverse transcription-polymerase chain reaction. MEASUREMENTS AND MAIN RESULTS: Slug expression, but not that of snail, twist, or zeb-1, was significantly increased in PC9/gef compared with PC9 cells. Slug knockdown in PC9/gef cells reversed resistance to gefitinib, and overexpression of Slug in PC9 cells protected cells from gefitinib-induced apoptosis. Silencing of Slug in gefitinib-resistant cells restored gefitinib-induced apoptosis primarily through Bim up-regulation and activation of caspase-9. Slug enhanced tumor growth in a xenograft mouse model, even with gefitinib treatment. In clinical samples, Slug expression was significantly higher in cancer cells with resistance to EGFR TKIs than in treatment-naive cancer cells. CONCLUSIONS: Slug contributes to the resistance to gefitinib and may be a potential therapeutic target for treating resistance to EGFR TKIs.

Generation of a human induced pluripotent stem cell line NTUHi002-A from a patient with aceruloplasminemia harboring a homozygous splicing mutation c.607+1 delG in CP gene.

Aceruloplasminemia is a rare autosomal recessive disorder caused by mutations in the CP gene, encoding the copper-binding protein ceruloplasmin. A mutation in the CP gene results in brain and systemic iron overload, which is classified as a rare subtype of neurodegeneration with brain iron accumulation (NBIA). Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells from peripheral blood mononuclear cells of a patient carrying the CP c.607+1 delG homozygous splicing mutation. The generated cell line retained the original genotype, expressed pluripotency markers, and differentiated into cells of the three germ layers.

Comparison of the quality of life between patients with non-small-cell lung cancer and healthy controls.

PURPOSE: We explored covariates of the quality of life (QOL) in non-small-cell lung cancer (NSCLC) patients and made a comparison with healthy controls. METHODS: We assessed the QOL of 220 consecutive NSCLC patients at a university hospital. The QOL data were measured by the brief version of the World Health Organization's Quality of Life and by utility using the standard gamble method. We selected demographically matched healthy controls from the 2001 National Health Interview Survey for comparison. Multiple linear regression models were constructed to explore significant factors of QOL after controlling for covariates. RESULTS: Patients with more advanced stages of NSCLC had poorer scores than did the healthy controls in the physical and psychological domains. Patients with disease duration of longer than 1 year tended to report higher physical and environment QOL than did those with NSCLC diagnosed for less than 1 year. Insight into one's own illness was associated with a higher utility, better social support, and improved financial resources. CONCLUSIONS: QOL was significantly associated with staging and duration of NSCLC. Disease insight appears to be a positive factor for operable NSCLC patients of the Taiwanese culture, which implies that clinicians should respect patient autonomy in diagnosis disclosure.

Generation of a human induced pluripotent stem cell (iPSC) line (IBMS-iPSC-070-02) from a patient with neurodegeneration with brain iron accumulation (NBIA) having compound heterozygous mutations in PANK2 gene.

Neurodegeneration with brain iron accumulation (NBIA) is a genetically and phenotypically heterogeneous group of inherited neurodegenerative disorder characterized by basal ganglia iron deposition. Mutations in Pantothenate Kinase 2 (PANK2) are major genetic causes for patients with NBIA. The location of PANK2 in the mitochondria suggests mutant PANK2 causing mitochondrial dysfunction in the pathogenesis of NBIA. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient having compound heterozygous mutations in PANK2. This cellular model could provide a platform for pathophysiological studies of NBIA in the future.

In vitro genome editing rescues parkinsonism phenotypes in induced pluripotent stem cells-derived dopaminergic neurons carrying LRRK2 p.G2019S mutation.

BACKGROUND: The c.G6055A (p.G2019S) mutation in leucine-rich repeat kinase 2 (LRRK2) is the most prevalent genetic cause of Parkinson's disease (PD). CRISPR/Cas9-mediated genome editing by homology-directed repair (HDR) has been applied to correct the mutation but may create small insertions and deletions (indels) due to double-strand DNA breaks. Adenine base editors (ABEs) could convert targeted A·T to G·C in genomic DNA without double-strand breaks. However, the correction efficiency of ABE in LRRK2 c.G6055A (p.G2019S) mutation remains unknown yet. This study aimed to compare the mutation correction efficiencies and off-target effects between HDR and ABEs in induced pluripotent stem cells (iPSCs) carrying LRRK2 c.G6055A (p.G2019S) mutation. METHODS: A set of mutation-corrected isogenic lines by editing the LRRK2 c.G6055A (p.G2019S) mutation in a PD patient-derived iPSC line using HDR or ABE were established. The mutation correction efficacies, off-target effects, and indels between HDR and ABE were compared. Comparative transcriptomic and proteomic analyses between the LRRK2 p.G2019S iPSCs and isogenic control cells were performed to identify novel molecular targets involved in LRRK2-parkinsonism pathways. RESULTS: ABE had a higher correction rate (13/53 clones, 24.5%) than HDR (3/47 clones, 6.4%). Twenty-seven HDR clones (57.4%), but no ABE clones, had deletions, though 14 ABE clones (26.4%) had off-target mutations. The corrected isogenic iPSC-derived dopaminergic neurons exhibited reduced LRRK2 kinase activity, decreased phospho-α-synuclein expression, and mitigated neurite shrinkage and apoptosis. Comparative transcriptomic and proteomic analysis identified different gene expression patterns in energy metabolism, protein degradation, and peroxisome proliferator-activated receptor pathways between the mutant and isogenic control cells. CONCLUSIONS: The results of this study envision that ABE could directly correct the pathogenic mutation in iPSCs for reversing disease-related phenotypes in neuropathology and exploring novel pathophysiological targets in PD.

Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer.

Gefitinib is effective as first-line therapy for advanced nonsmall cell lung cancer (NSCLC). However, after failure of gefitinib, it is unknown whether any second-line regimens could lead to better outcomes. To study the influence of different second-line antitumor regimens on the outcomes of patients with NSCLC after failure of first-line gefitinib, we carried out a retrospective study in a tertiary referral medical center to investigate the prognosis of patients with NSCLC receiving second-line antitumor treatment after gefitinib therapy. Clinical data and epidermal growth factor receptor (EGFR) mutational status of tumors were collected. A total of 195 patients with Stage IIIb or IV NSCLC receiving first-line gefitinib and at least 1 subsequent line therapy were identified. A second-line therapy with a platinum-based combination or taxane-containing regimen were associated with a higher therapy response, whereas a platinum-based combination was linked to better overall survival. Ninety-five patients had tumors with known EGFR mutation status; 61 had EGFR mutations and 34 had wild-type EGFR. A second-line therapy with a gemcitabine/platinum combination regimen resulted in better overall survival than erlotinib in patients with EGFR mutations (p = 0.035) but not in patients with wild-type EGFR (p = 0.785). The study suggested that, after failure of first-line gefitinib therapy, second-line platinum-based combination regimens were associated with a better overall survival than other regimens, including erlotinib. The survival benefit of platinum-based combination regimens existed in patients with mutant EGFR but not wild-type EGFR.

MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib.

In human lung adenocarcinomas harboring EGFR mutations, a second-site point mutation that substitutes methionine for threonine at position 790 (T790M) is associated with approximately half of cases of acquired resistance to the EGFR kinase inhibitors, gefitinib and erlotinib. To identify other potential mechanisms that contribute to disease progression, we used array-based comparative genomic hybridization (aCGH) to compare genomic profiles of EGFR mutant tumors from untreated patients with those from patients with acquired resistance. Among three loci demonstrating recurrent copy number alterations (CNAs) specific to the acquired resistance set, one contained the MET proto-oncogene. Collectively, analysis of tumor samples from multiple independent patient cohorts revealed that MET was amplified in tumors from 9 of 43 (21%) patients with acquired resistance but in only two tumors from 62 untreated patients (3%) (P = 0.007, Fisher's Exact test). Among 10 resistant tumors from the nine patients with MET amplification, 4 also harbored the EGFR(T790M) mutation. We also found that an existing EGFR mutant lung adenocarcinoma cell line, NCI-H820, harbors MET amplification in addition to a drug-sensitive EGFR mutation and the T790M change. Growth inhibition studies demonstrate that these cells are resistant to both erlotinib and an irreversible EGFR inhibitor (CL-387,785) but sensitive to a multikinase inhibitor (XL880) with potent activity against MET. Taken together, these data suggest that MET amplification occurs independently of EGFR(T790M) mutations and that MET may be a clinically relevant therapeutic target for some patients with acquired resistance to gefitinib or erlotinib.

Pemetrexed for heavily pretreated patients with advanced non-small cell lung cancer.

BACKGROUND/PURPOSE: The efficacy and safety of chemotherapy as third- or higher-line therapy for advanced non-small cell lung cancer (NSCLC) are unclear. The purpose of this study was to evaluate the efficacy and safety of pemetrexed for heavily pretreated, advanced NSCLC. METHODS: We retrospectively reviewed advanced NSCLC patients who received pemetrexed and more than two prior chemotherapy regimens. The tumor responses were evaluated by the Response Evaluation Criteria of Solid Tumors. Progression-free survival and overall survival were calculated by the Kaplan-Meier method. Toxicity was evaluated according to the Common Terminology Criteria for Adverse Events version 3.0. RESULTS: A total of 95 patients (53 men and 42 women) were included. The median age was 63 years (range, 29-83). Seventy (73.7%) patients had adenocarcinoma. The median number of prior systemic therapies was three (range, 2-7). The median number of cycles of pemetrexed therapy was four (range, 1-11). Seven (7.4%) patients achieved a partial response, and 33 (34.7%) had stable disease. The median progression-free survival was 11 6 days, and the median overall survival was 382 days. A trend toward increased progression-free survival was observed for patients who had non-squamous compared with squamous NSCLC. CONCLUSION: Pemetrexed has modest efficacy for heavily pretreated NSCLC patients.

Characteristics and risk factors of oxaliplatin-related hypersensitivity reactions.

BACKGROUND/PURPOSE: Hypersensitivity reactions during oxaliplatin infusion are a major problem associated with its use. In this study, we investigated the characteristics and risk factors of these events. METHODS: All patients who had received oxaliplatin in outpatient settings from January 2006 to March 2007 in a medical center were enrolled in this retrospective study. All the oxaliplatin infusions were reviewed. Manifestations of hypersensitivity reactions and clinicopathological variables were collected from medical records. RESULTS: Three hundred and eighty-three patients with 3648 oxaliplatin infusions were reviewed. Forty-seven patients (12.7%) developed hypersensitivity reactions, which occurred after a median of 10 infusions. The median time of onset from start of infusion was 40 minutes. Most presentations (90.7%) were mild to moderate, but rechallenge with oxaliplatin led to a high chance of further reactions (71.4%). Cutaneous symptoms were the most prevalent manifestation, followed by respiratory symptoms. With each repeated infusion, the incidence of hypersensitivity reactions increased. Higher oxaliplatin dose per infusion was an independent risk factor for such reactions. CONCLUSION: Patients treated with oxaliplatin for an extended period have a greater risk of oxaliplatin-related hypersensitivity reactions.

First-line systemic treatment of advanced stage non-small-cell lung cancer in Asia: consensus statement from the Asian Oncology Summit 2009.

Non-small-cell lung cancer (NSCLC) is an increasing global challenge, especially in low-income countries. Most guidelines for the management of advanced-stage NSCLC have limited effect in countries with resource constraints. Following a systematic literature search, we present an overview of the management of advanced-stage NSCLC in the first-line setting, discuss resources required for systemic therapy, and provide treatment recommendations stratified to four resources levels. Treatment guidelines appropriate for different resource levels offer a realistic approach to management of advanced-stage NSCLC, by recognising the limitations of a particular health-care system. Although there are many barriers to cancer control in low-resource countries, these can be overcome by using measures that are culturally appropriate, economically feasible, and evidence-based. Initiatives include strategic planning, tobacco control, training of health-care workers, access to therapeutic agents, acquisition of information, public education, and alliances with established institutions and international organisations.

Reprogramming of a human induced pluripotent stem cell (iPSC) line from a patient with neurodegeneration with brain iron accumulation (NBIA) harboring a novel frameshift mutation in C19orf12 gene.

Mutations in an open-reading frame on chromosome 19 (C19orf12) were identified as one of the causative genes for neurodegeneration with brain iron accumulation (NBIA). Because of the mitochondrial localization of the derived protein, this variant is referred to as mitochondrial membrane protein-associated neurodegeneration with brain iron accumulation (MPAN). Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a female patient with MPAN having a novel heterozygous frameshift mutation caused by an insertion, c.273_274insA (p.P92Tfs*9), in C19orf12. This cellular model could provide a platform for pathophysiological studies of MPAN.

Generation of a human induced pluripotent stem cell (iPSC) line (IBMS-iPSC-057-05) from a patient with familial parkinsonism and polyneuropathy having a heterozygous p.Y314S mutation in UQCRC1 gene.

A novel missense mutation, c.941A > C (p.Y314S), in mitochondrial ubiquinol-cytochrome c reductase core protein I (UQCRC1) gene, was recently identified in a family with autosomal-dominant late-onset parkinsonism and polyneuropathy. UQCRC1 encodes a mitochondria respiratory complex III protein. Mutant UQCRC1 cells showed decreased mitochondrial activity and neurite degeneration. Here, we used the Sendai virus delivery system to generate induced pluripotent stem cells (iPSCs) from peripheral blood mononuclear cells of a male patient having a heterozygous UQCRC1 p.Y314S mutation. The established iPSCs could differentiate into three germ layers in vivo. This cellular model provides a platform for further studies of UQCRC1-related parkinsonism and polyneuropathy.

Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response.

PURPOSE: Whole-brain radiation therapy (WBRT) has been applied to inoperable brain metastases in lung adenocarcinoma. Recently, an in vitro study showed reduced clonogenic survival of mutant epidermal growth factor receptor (EGFR) lung cancer cell lines in response to ionizing radiation compared with that of the wild type. To elucidate the role of EGFR mutations in radiation treatment, we evaluated the clinical response to WBRT and survival of lung adenocarcinoma patients with brain metastases. EXPERIMENTAL DESIGN: This was a retrospective analysis of 63 patients with brain metastases from lung adenocarcinoma who were treated with WBRT. Demographic data, EGFR mutation status, response to WBRT, and survival data were collected. Clinical response was assessed 1 month after the start of WBRT. Univariate and logistic regression models were used to test potential predictive factors associated with clinical response. Log-rank test and Cox regression were analyzed to identify factors that affected survival. RESULTS: Clinical response to WBRT was observed in 29 patients (46%), with 34 nonresponder patients (54%). Patients with EGFR mutations had higher response rates to WBRT compared with those with the wild-type (54% versus 24%; P = 0.045). Both the administration of EGFR tyrosine kinase inhibitor (P = 0.034) and EGFR mutation (P = 0.029) were independently associated with response to WBRT. In Cox regression analysis, WBRT responder (P = 0.010) and absence of extracranial metastases (P = 0.002) were associated with better survival. CONCLUSIONS: Both the EGFR mutations and the administration of EGFR TKI during WBRT were independent predictors of response to WBRT in brain metastases of lung adenocarcinoma.