Case Report: Identification of a CARD8 variant in all three patients with PFAPA syndrome complicated with Kawasaki disease.

Background: Periodic fever, aphthous stomatitis, pharyngitis, and cervical adenitis (PFAPA syndrome), and Kawasaki disease (KD) are both considered to be disorders of the innate immune system, and the potential role of inflammasome activation in the immunopathogenesis of both diseases has been previously described. Case presentation: Herein, we report the clinical courses of three patients who presented a rare combination of PFAPA syndrome and KD. Two patients who presented KD later developed the PFAPA syndrome, of whom one developed recurrent KD 2 years after the initial diagnosis. The third patient developed KD one year after the onset of PFAPA syndrome. The presence of both of these conditions within individual patients, combined with the knowledge that inflammasome activation is involved in both PFAPA syndrome and KD, suggests a shared background of inflammatory dysregulation. To elucidate the mechanism underlying shared inflammatory dysregulation, we investigated the roles of Nod-like receptors (NLRs) and their downstream inflammasome-related genes. All the patients had a frameshift variant in CARD8 (CARD8-FS). A previous study demonstrated a higher frequency of CARD8-FS, whose product loses CARD8 activity and activates the NLRP3 inflammasome, in patients with the PFAPA syndrome. Additionally, the NLRP3 inflammasome is known to be activated in patients with KD. Together, these results suggest that the CARD8-FS variant may also be essential in KD pathogenesis. As such, we analyzed the CARD8 variants among patients with KD. However, we found no difference in the variant frequency between patients with KD and the general Japanese population. Conclusions: We report the clinical courses of three patients with a rare combination of PFAPA syndrome and KD. All the patients had the CARD8-FS variant. However, we could not find a difference in the variant frequency between patients with KD and the general Japanese population. As the frequency of KD is much higher than that of PFAPA among Japanese patients, and the cause of KD is multifactorial, it is possible that only a small portion of patients with KD harbor CARD8-FS as a causative gene.

Cancer cell immunity-related protein co-expression networks are associated with early-stage solid-predominant lung adenocarcinoma.

Background: Solid-predominant lung adenocarcinoma (SPA), which is one of the high-risk subtypes with poor prognosis and unsatisfactory response to chemotherapy and targeted therapy in lung adenocarcinoma, remains molecular profile unclarified. Weighted correlation network analysis (WGCNA) was used for data mining, especially for studying biological networks based on pairwise correlations between variables. This study aimed to identify disease-related protein co-expression networks associated with early-stage SPA. Methods: We assessed cancerous cells laser-microdissected from formalin-fixed paraffin-embedded (FFPE) tissues of a SPA group (n = 5), referencing a low-risk subtype, a lepidic predominant subtype group (LPA) (n = 4), and another high-risk subtype, micropapillary predominant subtype (MPA) group (n = 3) and performed mass spectrometry-based proteomic analysis. Disease-related co-expression networks associated with the SPA subtype were identified by WGCNA and their upstream regulators and causal networks were predicted by Ingenuity Pathway Analysis. Results: Among the forty WGCNA network modules identified, two network modules were found to be associated significantly with the SPA subtype. Canonical enriched pathways were highly associated with cellular growth, proliferation, and immune response. Upregulated HLA class I molecules HLA-G and HLA-B implicated high mutation burden and T cell activation in the SPA subtype. Upstream analysis implicated the involvement of highly activated oncogenic regulators, MYC, MLXIPL, MYCN, the redox master regulator NFE2L2, and the highly inhibited LARP1, leading to oncogenic IRES-dependent translation, and also regulators of the adaptive immune response, including highly activated IFNG, TCRD, CD3-TCR, CD8A, CD8B, CD3, CD80/CD86, and highly inhibited LILRB2. Interestingly, the immune checkpoint molecule HLA-G, which is the counterpart of LILRB2, was highly expressed characteristically in the SPA subtype and might be associated with antitumor immunity. Conclusion: Our findings provide a disease molecular profile based on protein co-expression networks identified for the high-risk solid predominant adenocarcinoma, which will help develop future therapeutic strategies.

Short-term clinical results of bicruciate-retaining total knee arthroplasty using personalized alignment.

BACKGROUND: Bicruciate-retaining (BCR) prosthesis has been introduced to recreate normal knee movement by preserving both the anterior and posterior cruciate ligaments. However, the use of BCR total knee arthroplasty (TKA) is still debatable because of several disappointing reports. We have been performing BCR TKAs with personalized alignment (PA). This study aimed to reveal the limb alignment and soft tissue balance of FA-BCR TKAs and compare the clinical outcomes of FA-BCR TKAs with those of unicompartmental knee arthroplasty (UKA). METHODS: Fifty BCR TKAs and 58 UKAs were included in this study. The joint component gaps of BCR TKA were evaluated intraoperatively and the postoperative hip-knee-ankle (HKA) angle, medial proximal tibial angle (MPTA), and lateral distal femoral angle (LDFA) were measured using full-length standing radiography. The short-term clinical outcomes of BCR TKAs were compared with those of UKA using the scoring system of 2011 Knee Society Scoring (KSS) and the knee injury and osteoarthritis outcome score (KOOS) at an average of 2 years postoperatively (1-4yeras). RESULTS: The coronal alignment values of PA-BCR TKA were as follows: HKA angle, 177.9° ± 2.3°; MPTA, 85.4° ± 1.9°; and LDFA, 87.5° ± 1.9°. The joint component gaps at flexion angles of 10°, 30°, 60°, and 90° were 11.1 ± 1.2, 10.9 ± 1.4, 10.7 ± 1.3, and 11.2 ± 1.4 mm for the medial compartment and 12.9 ± 1.5, 12.6 ± 1.8, 12.5 ± 1.8 and 12.5 ± 1.7 mm for the lateral compartment, respectively. The patient expectation score and maximum extension angle of PA-BCR TKA were significantly better than those of UKAs. CONCLUSIONS: The short-term clinical outcomes of PA-BCR TKA were comparable or a slightly superior to those of UKAs.

Figure-4 Patient Positioning Increases Medial Meniscus Extrusion on Ultrasound in Patients With Posterior Medial Meniscus Root Tears of the Knee.

Purpose: To compare the degree of medial meniscal extrusion (MME) between knees with medial meniscus posterior root tear (MMPRT) and degenerative tears of the medial meniscus using ultrasonography (US) in different limb positions and to identify the findings characteristic of MMPRT. Methods: The study group comprised 25 subjects with MMPRT (group RT), 25 subjects with degenerative medial meniscal tears (group D), and 25 knees with no abnormalities of the medial meniscus (MM) on magnetic resonance imaging (MRI) (group C) whose age was ≥40 years. MME was evaluated using US in the supine, figure-4, feet-dangling, and standing positions. The MME was evaluated by the actual measurement values and the relative values to the MME in the supine position. The differences in the MME among the 3 groups in each limb position were analyzed using one-way analysis of variance. P < .05 was considered significant. Results: The actual MME values were largest in group RT in all 4 limb positions. When changing the limb position from the supine to the figure-4, the actual MME increased from 3.8 ± 0.8 mm to 5.5 ± 1.3 mm in group RT, whereas it decreased from 3.4 ± 1.1 mm to 1.8 ± 1.2 mm in group D, showing the most significant difference in MME of the figure-4 position between the 2 groups (P < .001). In group RT, 88% of knees had the maximum MME in the figure-4 position. In group D, 60% of knees had the maximum MME in the standing position and only 2 knees (8%) had the maximum MME in the figure-4 position. Conclusions: The increase in MME from the supine to the figure-4 position was a characteristic finding of MMPRT but not degenerative tears. Level of Evidence: Level III, case-control study.

Neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis: A case report with a novel missense variant of SCN1A.

Variants of SCN1A represent the archetypal channelopathy associated with several epilepsy syndromes. The clinical phenotypes have recently expanded from Dravet syndrome. CASE REPORT: We present a female patient with the de novo SCN1A missense variant, c.5340G > A (p. Met1780Ile). The patient had various clinical features with neonatal onset SCN1A epileptic encephalopathy, arthrogryposis multiplex congenita, thoracic hypoplasia, thoracic scoliosis, and hyperekplexia. CONCLUSION: Our findings are compatible with neonatal developmental and epileptic encephalopathy with movement disorders and arthrogryposis; the most severe phenotype probably caused by gain-of-function variant of SCN1A. The efficacy of sodium channel blocker was also discussed. Further exploration of the phenotype-genotype relationship of SCN1A variants may lead to better pharmacological treatments and family guidance.

Incidental Hyperferritinemia in Very Young Infants with Mild Symptoms of COVID-19 Disease.

BACKGROUND: The number of children infected with novel coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has increased during the outbreak of the Omicron strain. Hyperferritinemia has been reported in severe cases of COVID-19, and in children or neonates with multisystem inflammatory syndrome (MIS). Hyperferritinemia is considered to be one of the signs of MIS, but thus far, there have been few summarized reports on it. We retrospectively analyzed four infants less than 3 months of age with SARS-CoV-2 infections treated in our institution during the outbreak of the Omicron strain. RESULTS: most patients were in good condition, but hyperferritinemia was observed in all of four cases. CONCLUSIONS: Hyperferritinemia can be observed in infantile COVID-19 patients even with mild symptoms. It is necessary to carefully monitor their clinical course and monitor the patients.

Minichromosome maintenance 2 is an independent predictor of survival in patients with lung adenocarcinoma.

Minichromosome maintenance (MCM) protein deregulation is associated with tumor formation, progression and malignant transformation. MCM2 is frequently expressed during premalignant lung cell proliferation and is a sensitive marker for the early detection of pulmonary malignant lesions. The present study was undertaken to investigate whether MCM2 expression is of clinical and prognostic value in patients who have undergone lung adenocarcinoma resection. Between January 2009 and December 2010, 102 consecutive patients underwent complete pulmonary resection (involving lobectomy or more extensive resection) for lung adenocarcinoma at St. Marianna Medical University Hospital (Kanagawa, Japan). Among those, 73 patients, who had a final pathological diagnosis of lung adenocarcinoma measuring ≥10 mm, were enrolled in the present study. High MCM2 expression was found in 35 patients (48.0%). Univariate analysis of the overall survival (OS) revealed that pathological stage and MCM2 expression were significant prognostic factors in lung adenocarcinoma (P<0.001 and P<0.002, respectively). Univariate analysis of the recurrence-free survival (RFS), the significant prognostic factors included pathological stage, EGFR mutation status and MCM2 expression (P<0.001, P<0.034 and P<0.003, respectively). On multivariate survival analysis, high MCM2 expression and pathological stage II-III were identified as independent strong prognostic factors (OS: HR=5.084, 95% CI: 1.715-15.080, P=0.003; RFS: HR=2.761, 95% CI: 1.090-6.998, P=0.032). Therefore, the findings of the present study demonstrated that MCM2 may serve as a potential biomarker and therapeutic target for lung adenocarcinoma.

Protein co-expression network-based profiles revealed from laser-microdissected cancerous cells of lung squamous-cell carcinomas.

No therapeutic targets have been identified for lung squamous cell cancer (SqCC) which is the second most prevalent lung cancer because its molecular profiles remain unclear. This study aimed to unveil disease-related protein networks by proteomic and bioinformatic assessment of laser-microdissected cancerous cells from seven SqCCs compared with eight representative lung adenocarcinomas. We identified three network modules significant to lung SqCC using weighted gene co-expression network analysis. One module was intrinsically annotated to keratinization and cell proliferation of SqCC, accompanied by hypoxia-induced aerobic glycolysis, in which key regulators were activated (HIF1A, ROCK2, EFNA1-5) and highly suppressed (KMT2D). The other two modules were significant for translational initiation, nonsense-mediated mRNA decay, inhibited cell death, and interestingly, eIF2 signaling, in which key regulators, MYC and MLXIPL, were highly activated. Another key regulator LARP1, the master regulator in cap-dependent translation, was highly suppressed although upregulations were observed for hub proteins including EIF3F and LARP1 targeted ribosomal proteins, among which PS25 is the key ribosomal protein in IRES-dependent translation. Our results suggest an underlying progression mechanism largely caused by switching to the cap-independent, IRES-dependent translation of mRNA subsets encoding oncogenic proteins. Our findings may help to develop therapeutic strategies to improve patient outcomes.

Mutant Proteomics of Lung Adenocarcinomas Harboring Different EGFR Mutations.

Epidermal growth factor receptor EGFR major driver mutations may affect downstream molecular networks and pathways, which would influence treatment outcomes of non-small cell lung cancer (NSCLC). This study aimed to unveil profiles of mutant proteins expressed in lung adenocarcinomas of 36 patients harboring representative driver EGFR mutations (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Surprisingly, the orthogonal partial least squares discriminant analysis performed for identified mutant proteins demonstrated the profound differences in distance among the different EGFR mutation groups, suggesting that cancer cells harboring L858R or Ex19del emerge from cellular origins different from L858R/Ex19del-negative cells. Weighted gene coexpression network analysis, together with over-representative analysis, identified 18 coexpressed modules and their eigen proteins. Pathways enriched differentially for both the L858R and Ex19del mutations included carboxylic acid metabolic process, cell cycle, developmental biology, cellular responses to stress, mitotic prophase, cell proliferation, growth, epithelial to mesenchymal transition (EMT), and immune system. The IPA causal network analysis identified the highly activated networks of PARPBP, HOXA1, and APH1 under the L858R mutation, whereas those of ASGR1, APEX1, BUB1, and MAPK10 were highly activated under the Ex19del mutation. Interestingly, the downregulated causal network of osimertinib intervention showed the highest significance in overlap p-value among most causal networks predicted under the L858R mutation. We also identified the causal network of MAPK interacting serine/threonine kinase 1/2 (MNK1/2) highly activated differentially under the L858R mutation. Tumor-suppressor AMOT, a component of the Hippo pathways, was highly inhibited commonly under both L858R and Ex19del mutations. Our results could identify disease-related protein molecular networks from the landscape of single amino acid variants. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

A proteogenomic profile of early lung adenocarcinomas by protein co-expression network and genomic alteration analysis.

The tumourigenesis of early lung adenocarcinomas, including adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and lepidic predominant invasive adenocarcinoma (LPA), remains unclear. This study aimed to capture disease-related molecular networks characterising each subtype and tumorigenesis by assessing 14 lung adenocarcinomas (AIS, five; MIA, five; LPA, four). Protein-protein interaction networks significant to the three subtypes were elucidated by weighted gene co-expression network analysis and pairwise G-statistics based analysis. Pathway enrichment analysis for AIS involved extracellular matrix proteoglycans and neutrophil degranulation pathway relating to tumour growth and angiogenesis. Whereas no direct networks were found for MIA, proteins significant to MIA were involved in oncogenic transformation, epithelial-mesenchymal transition, and detoxification in the lung. LPA was associated with pathways of HSF1-mediated heat shock response regulation, DNA damage repair, cell cycle regulation, and mitosis. Genomic alteration analysis suggested that LPA had both somatic mutations with loss of function and copy number gains more frequent than MIA. Oncogenic drivers were detected in both MIA and LPA, and also LPA had a higher degree of copy number loss than MIA. Our findings may help identifying potential therapeutic targets and developing therapeutic strategies to improve patient outcomes.

Disease-related cellular protein networks differentially affected under different EGFR mutations in lung adenocarcinoma.

It is unclear how epidermal growth factor receptor EGFR major driver mutations (L858R or Ex19del) affect downstream molecular networks and pathways. This study aimed to provide information on the influences of these mutations. The study assessed 36 protein expression profiles of lung adenocarcinoma (Ex19del, nine; L858R, nine; no Ex19del/L858R, 18). Weighted gene co-expression network analysis together with analysis of variance-based screening identified 13 co-expressed modules and their eigen proteins. Pathway enrichment analysis for the Ex19del mutation demonstrated involvement of SUMOylation, epithelial and mesenchymal transition, ERK/mitogen-activated protein kinase signalling via phosphorylation and Hippo signalling. Additionally, analysis for the L858R mutation identified various pathways related to cancer cell survival and death. With regard to the Ex19del mutation, ROCK, RPS6KA1, ARF1, IL2RA and several ErbB pathways were upregulated, whereas AURK and GSKIP were downregulated. With regard to the L858R mutation, RB1, TSC22D3 and DOCK1 were downregulated, whereas various networks, including VEGFA, were moderately upregulated. In all mutation types, CD80/CD86 (B7), MHC, CIITA and IFGN were activated, whereas CD37 and SAFB were inhibited. Costimulatory immune-checkpoint pathways by B7/CD28 were mainly activated, whereas those by PD-1/PD-L1 were inhibited. Our findings may help identify potential therapeutic targets and develop therapeutic strategies to improve patient outcomes.

Survival outcomes of adjuvant chemotherapy with modified weekly nab-paclitaxel and carboplatin for completely resected nonsmall cell lung cancer: FAST-nab.

The relatively low toxicity profile of nab-paclitaxel plus carboplatin and its feasibility as an adjuvant administration was reported previously. This study aimed to evaluate the survival efficacy for completely resected patients with stage IB, II, and IIIA nonsmall cell lung cancer (NSCLC). Twenty-nine eligible patients with NSCLC who received surgical resection for pathological stage IB, II, or IIIA, followed by postoperative adjuvant chemotherapy with modified 3-week cycles of either nab-paclitaxel (nab-P) (100 mg/m) on days 1 and 8 followed by carboplatin area (area under the curve = 6) on day 1 were prospectively enrolled and assessed for survival outcomes against patients with the same stages who received other postoperative adjuvant chemotherapy regimens during the same period. There were no significant differences in clinicopathological features, including age, gender, smoking status, performance status, surgical procedures, tumor histology, and pathological stage between the two groups. The cumulative overall survival (OS) rates at 5 years of the experimental and control groups in pathological stage IB-IIIA were 85.4% and 63.9%, respectively (P = 0.598), while recurrence-free survival (RFS) rates in these groups at 5 years were 65.2% and 34.8%, respectively (P = 0.344). Moreover, the cumulative OS rates of the experimental and control groups in pathological stage II-IIIA were 83.6% and 63.6%, respectively (P = 0.970), while RFS rates in these groups at 5 years were 61.1% and 37.3%, respectively (P = 0.460). This new regimen was considered an attractive alternative postoperative adjuvant chemotherapy option with relatively low toxicity and moderate survival outcomes for completely resected NSCLC.

Current status of clinical proteogenomics in lung cancer.

Introduction: Lung cancer is the leading cause of cancer death worldwide. Proteogenomics, a way to integrate genomics, transcriptomics, and proteomics, have emerged as a way to understand molecular causes in cancer tumorigenesis. This understanding will help identify therapeutic targets that are urgently needed to improve individual patient outcomes. Areas covered: To explore underlying molecular mechanisms of lung cancer subtypes, several efforts have used proteogenomic approaches that integrate next generation sequencing (NGS) and mass spectrometry (MS)-based technologies. Expert opinion: A large-scale, MS-based, proteomic analysis, together with both NGS-based genomic data and clinicopathological information, will facilitate establishing extensive databases for lung cancer subtypes that can be used for further proteogenomic analyzes. Proteogenomic strategies will further be understanding of how major driver mutations affect downstream molecular networks, resulting in lung cancer progression and malignancy, and how therapy-resistant cancers resistant are molecularly structured. These strategies require advanced bioinformatics based on a dynamic theory of network systems, rather than statistics, to accurately identify mutant proteins and their affected key networks.

Identification of key modules and hub genes for small-cell lung carcinoma and large-cell neuroendocrine lung carcinoma by weighted gene co-expression network analysis of clinical tissue-proteomes.

Small-cell lung carcinoma (SCLC) and large-cell neuroendocrine lung carcinoma (LCNEC) are high-grade lung neuroendocrine tumors (NET). However, comparative protein expression within SCLC and LCNEC remains unclear. Here, protein expression profiles were obtained via mass spectrometry-based proteomic analysis. Weighted gene co-expression network analysis (WGCNA) identified co-expressed modules and hub genes. Of 34 identified modules, six were significant and selected for protein-protein interaction (PPI) network analysis and pathway enrichment. Within the six modules, the activation of cellular processes and complexes, such as alternative mRNA splicing, translation initiation, nucleosome remodeling and deacetylase (NuRD) complex, SWItch/Sucrose Non-Fermentable (SWI/SNF) superfamily-type complex, chromatin remodeling pathway, and mRNA metabolic processes, were significant to SCLC. Modules enriched in processes, including signal recognition particle (SRP)-dependent co-translational protein targeting to membrane, nuclear-transcribed mRNA catabolic process of nonsense-mediated decay (NMD), and cellular macromolecule catabolic process, were characteristically activated in LCNEC. Novel high-degree hub genes were identified for each module. Master and upstream regulators were predicted via causal network analysis. This study provides an understanding of the molecular differences in tumorigenesis and malignancy between SCLC and LCNEC and may help identify potential therapeutic targets.

PD-L1 Expression in Non-Small-Cell Lung Cancer Including Various Adenocarcinoma Subtypes.

PURPOSE: Knowledge regarding programmed death-ligand 1 (PD-L1) expression in lung cancer is limited. We aim to clarify PD-L1-positive expression in non-small-cell lung cancer (NSCLC), including adenocarcinoma subtypes. METHODS: In all, 90 NSCLC specimens containing various adenocarcinoma subtypes, in addition to squamous cell carcinoma and large-cell carcinoma were selected. PD-L1 was immunohistochemically stained by murine monoclonal antibody clone 22C3. RESULTS: When PD-L1-positive expression was defined by tumor proportion score (TPS) ≥1%, the positive cases were 0/11 in adenocarcinoma in situ, 0/12 in minimally invasive adenocarcinoma, 1/10 in lepidic predominant adenocarcinoma, 1/13 in papillary predominant adenocarcinoma, 8/14 in acinar predominant adenocarcinoma, 6/11 in solid predominant adenocarcinoma, 0/3 in micropapillary predominant adenocarcinoma, 0/4 in invasive mucinous adenocarcinoma, 4/9 in squamous cell carcinoma, and 2/3 in large-cell carcinoma. PD-L1 positivity was higher in males, smokers, advanced pathologic stages, positive vessel invasion, and positive lymphatic invasion. Postoperative survival analysis revealed that PD-L1-positive expression was a significantly worse prognostic factor in univariate analysis for recurrence-free survival (RFS). CONCLUSION: PD-L1-positive tumors were frequent in acinar predominant adenocarcinoma and solid predominant adenocarcinoma than other adenocarcinoma subtypes. PD-L1 expression seemed to increase according to pathologic tumor progression, suggesting a worse postoperative prognosis in NSCLC patients.

Differential Proteomic Analysis between Small Cell Lung Carcinoma (SCLC) and Pulmonary Carcinoid Tumors Reveals Molecular Signatures for Malignancy in Lung Cancer.

PURPOSE: The molecular underpinnings that may prognosticate survival and increase our understanding of tumor development and progression are still poorly understood. This study aimed to define the molecular signatures for malignancy in small cell lung carcinoma (SCLC), which is known for its highly aggressive clinical features and poor prognosis. EXPERIMENTAL DESIGN: Using clinical specimens, the authors perform a comparative proteomic analysis of high-grade SCLCs and low-grade pulmonary carcinoid tumors (PCTs), both of which are types of neuroendocrine tumors. A label-free LC-MS-based quantitative proteomic analysis is applied to tumor cells laser-microdissected from their formalin-fixed paraffin-embedded (FFPE) tissues obtained from six patients each. RESULTS: Overall, 1991 proteins are identified from tumor cells in the FFPE tissues. Through the protein-protein interaction network analysis of 201 proteins significantly, the authors find that SCLC is functionally characterized by activation of molecular pathways for spliceosome, RNA transport, and DNA replication and cell cycle. Particularly, 11 proteins involved in tumor proliferation (MCM2, 4, 6, 7, and MSH2), metastasis (RCC2, CORO1C, CHD4, and IPO9), and cancer metabolism (PHGDH and TYMP) are identified as SCLC-specific proteins. Furthermore, their prognostic significances are demonstrated by online Kaplan-Meier survival analysis. CONCLUSIONS AND CLINICAL RELEVANCE: These clinical tissue proteomic approach for SCLC reveals the proteins associated with aggressiveness and poor prognosis. The identified SCLC-specific proteins represent potential therapeutic targets. Moreover, MCMs and PHGDH can be poor prognostic factors for lung cancer.

Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation.

Numerous genetic syndromes that include intellectual disability (ID) have been reported. Recently, HECW2 mutations were detected in patients with ID and growth development disorders. Four de novo missense mutations have been reported. Here, we report a Japanese girl with Rett-like symptoms of severe ID, hypotonia, refractory epilepsy, and stereotypical hand movement (hand tapping, flapping, and wringing) after the age of 1 year. Characteristically, she had cortical visual impairment. She had difficulty swallowing since the age of 4 years, and diminished activity was noticeable since the age of 12 years, suggesting neurodevelopmental regression. She has no acquired microcephaly, and brain magnetic resonance imaging showed non-specific mild cerebral and cerebellar atrophy without progression over time. Genetic analyses of MECP2, CDKL5, and FOXG1 were negative. Whole-exome sequencing analysis revealed a known de novo mutation (c.3988C > T) in HECW2. The characteristics of her clinical symptoms are severe cortical visual impairment and Rett-like phenotype such as involuntary movements and regression. This is the first report that patients with HECW2 mutation could show Rett-like feature.

Survival significance of coexisting chronic obstructive pulmonary disease in patients with early lung cancer after curative surgery.

BACKGROUND: The impact of chronic obstructive pulmonary disease (COPD) severity on survival after curative resection of early-stage lung cancer (NSCLC) has not been sufficiently elucidated. METHODS: We retrospectively reviewed 250 consecutive patients who underwent lobectomy with lymph nodal dissection for pathological stage I-II NSCLC. RESULTS: Among the COPD patients, 28 were classified as Global Initiative for Chronic Obstructive Lung Disease (GOLD) 1, 21 as GOLD 2, and one as GOLD 3. The cumulative overall survival (OS) of the non-COPD, GOLD 1, and GOLD 2-3 groups at five years was 90.7%, 85.7%, and 55.3%, respectively, (P < 0.0001), while recurrence-free survival (RFS) between the groups at five years was 84.7%, 80.7%, and 72.9%, respectively. Although RFS in the GOLD 2-3 group tended to indicate a poor prognosis, there was no statistical difference between the groups (P = 0.385). In multivariate analysis, age ≥75 years, pN1, and GOLD 2-3 COPD were independent factors for a poor prognosis (P = 0.034, P = 0.010, and P = 0.030, respectively). CONCLUSIONS: Our results indicate that early stage NSCLC patients with COPD had a significantly increased risk of poorer OS and potentially an increased risk of poor RFS.