Wakayama Medical University

Abstract Somatic mutations in cancer genomes are caused by multiple mutational processes, each of which generates a characteristic mutational signature 1 . Here, as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium 2 of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), we characterized mutational signatures using 84,729,690 somatic mutations from 4,645 whole-genome and 19,184 exome sequences that encompass most types of cancer. We identified 49 single-base-substitution, 11 doublet-base-substitution, 4 clustered-base-substitution and 17 small insertion-and-deletion signatures. The substantial size of our dataset, compared with previous analyses 3–15 , enabled the discovery of new signatures, the separation of overlapping signatures and the decomposition of signatures into components that may represent associated—but distinct—DNA damage, repair and/or replication mechanisms. By estimating the contribution of each signature to the mutational catalogues of individual cancer genomes, we revealed associations of signatures to exogenous or endogenous exposures, as well as to defective DNA-maintenance processes. However, many signatures are of unknown cause. This analysis provides a systematic perspective on the repertoire of mutational processes that contribute to the development of human cancer.

BACKGROUND: Osimertinib is an epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that is selective for both EGFR-TKI sensitizing and T790M resistance mutations in patients with non-small-cell lung cancer. The efficacy of osimertinib as compared with platinum-based therapy plus pemetrexed in such patients is unknown. METHODS: In this randomized, international, open-label, phase 3 trial, we assigned 419 patients with T790M-positive advanced non-small-cell lung cancer, who had disease progression after first-line EGFR-TKI therapy, in a 2:1 ratio to receive either oral osimertinib (at a dose of 80 mg once daily) or intravenous pemetrexed (500 mg per square meter of body-surface area) plus either carboplatin (target area under the curve, 5 [AUC5]) or cisplatin (75 mg per square meter) every 3 weeks for up to six cycles; maintenance pemetrexed was allowed. In all the patients, disease had progressed during receipt of first-line EGFR-TKI therapy. The primary end point was investigator-assessed progression-free survival. RESULTS: The median duration of progression-free survival was significantly longer with osimertinib than with platinum therapy plus pemetrexed (10.1 months vs. 4.4 months; hazard ratio; 0.30; 95% confidence interval [CI], 0.23 to 0.41; P<0.001). The objective response rate was significantly better with osimertinib (71%; 95% CI, 65 to 76) than with platinum therapy plus pemetrexed (31%; 95% CI, 24 to 40) (odds ratio for objective response, 5.39; 95% CI, 3.47 to 8.48; P<0.001). Among 144 patients with metastases to the central nervous system (CNS), the median duration of progression-free survival was longer among patients receiving osimertinib than among those receiving platinum therapy plus pemetrexed (8.5 months vs. 4.2 months; hazard ratio, 0.32; 95% CI, 0.21 to 0.49). The proportion of patients with adverse events of grade 3 or higher was lower with osimertinib (23%) than with platinum therapy plus pemetrexed (47%). CONCLUSIONS: Osimertinib had significantly greater efficacy than platinum therapy plus pemetrexed in patients with T790M-positive advanced non-small-cell lung cancer (including those with CNS metastases) in whom disease had progressed during first-line EGFR-TKI therapy. (Funded by AstraZeneca; AURA3 ClinicalTrials.gov number, NCT02151981 .).

Abstract Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale 1–3 . Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4–5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter 4 ; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation 5,6 ; analyses timings and patterns of tumour evolution 7 ; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity 8,9 ; and evaluates a range of more-specialized features of cancer genomes 8,10–18 .

OBJECTIVES: The purpose of this document is to make the output of the International Working Group for Intravascular Optical Coherence Tomography (IWG-IVOCT) Standardization and Validation available to medical and scientific communities, through a peer-reviewed publication, in the interest of improving the diagnosis and treatment of patients with atherosclerosis, including coronary artery disease. BACKGROUND: Intravascular optical coherence tomography (IVOCT) is a catheter-based modality that acquires images at a resolution of ~10 μm, enabling visualization of blood vessel wall microstructure in vivo at an unprecedented level of detail. IVOCT devices are now commercially available worldwide, there is an active user base, and the interest in using this technology is growing. Incorporation of IVOCT in research and daily clinical practice can be facilitated by the development of uniform terminology and consensus-based standards on use of the technology, interpretation of the images, and reporting of IVOCT results. METHODS: The IWG-IVOCT, comprising more than 260 academic and industry members from Asia, Europe, and the United States, formed in 2008 and convened on the topic of IVOCT standardization through a series of 9 national and international meetings. RESULTS: Knowledge and recommendations from this group on key areas within the IVOCT field were assembled to generate this consensus document, authored by the Writing Committee, composed of academicians who have participated in meetings and/or writing of the text. CONCLUSIONS: This document may be broadly used as a standard reference regarding the current state of the IVOCT imaging modality, intended for researchers and clinicians who use IVOCT and analyze IVOCT data.

Concept of Diabetes Mellitus: Diabetes mellitus is a group of diseases associated with various metabolic disorders, the main feature of which is chronic hyperglycemia due to insufficient insulin action. Its pathogenesis involves both genetic and environmental factors. The long-term persistence of metabolic disorders can cause susceptibility to specific complications and also foster arteriosclerosis. Diabetes mellitus is associated with a broad range of clinical presentations, from being asymptomatic to ketoacidosis or coma, depending on the degree of metabolic disorder. Classification (Tables 1 and 2, and Figure 1): Table 1. Etiological classification of diabetes mellitus and glucose metabolism disorders I. Type 1 (destruction of pancreatic β-cells, usually leading to absolute insulin deficiency) A. Autoimmune B. Idiopathic II. Type 2 (ranging from predominantly insulin secretory defect, to predominantly insulin resistance with varying degrees of insulin secretory defect) III. Due to other specific mechanisms or diseases (see Table 2 for details) A. Those in which specific mutations have been identified as a cause of genetic susceptibility (1) Genetic abnormalities of pancreatic β-cell function (2) Genetic abnormalities of insulin action B. Those associated with other diseases or conditions (1) Diseases of exocrine pancreas (2) Endocrine diseases (3) Liver disease (4) Drug- or chemical-induced (5) Infections (6) Rare forms of immune-mediated diabetes (7) Various genetic syndromes often associated with diabetes IV. Gestational diabetes mellitus Note: Those that cannot at present be classified as any of the above are called unclassifiable. The occurrence of diabetes-specific complications has not been confirmed in some of these conditions. Table 2. Diabetes mellitus and glucose metabolism disorders due to other specific mechanisms and diseases A. Those in which specific mutations have been identified as a cause of genetic susceptibility B. Those associated with other diseases or conditions (1) Genetic abnormalities of pancreatic β-cell functionInsulin gene (abnormal insulinemia, abnormal proinsulinemia, neonatal diabetes mellitus) HNF 4α gene (MODY1) Glucokinase gene (MODY2) HNF 1α gene (MODY3) IPF-1 gene (MODY4) HNF 1β gene (MODY5) Mitochondria DNA (MIDD) NeuroD1 gene (MODY6) Kir6.2 gene (neonatal diabetes mellitus) SUR1 gene (neonatal diabetes mellitus) AmylinOthers(2) Genetic abnormalities of insulin actionInsulin receptor gene (type A insulin resistance, leprechaunism, Rabson–Mendenhall syndrome etc.) Others (1) Diseases of exocrine pancreasPancreatitisTrauma/pancreatectomyNeoplasmHemochromatosisOthers(2) Endocrine diseasesCushing’s syndromeAcromegalyPheochromocytomaGlucagonomaAldosteronismHyperthyroidismSomatostatinomaOthers(3) Liver diseaseChronic hepatitisLiver cirrhosis Others(4) Drug- or chemical-inducedGlucocorticoidsInterferonOthers(5) InfectionsCongenital rubellaCytomegalovirusOthers(6) Rare forms of immune-mediated diabetesAnti-insulin receptor antibodiesStiffman syndromeInsulin autoimmune syndromeOthers(7) Various genetic syndromes often associated with diabetesDown syndromePrader-Willi syndromeTurner syndromeKlinefelter syndromeWerner syndromeWolfram syndromeCeruloplasmin deficiencyLipoatrophic diabetes mellitusMyotonic dystrophyFriedreich ataxiaLaurence-Moon-Biedl syndromeOthers The occurrence of diabetes-specific complications has not been confirmed in some of these conditions. Figure 1Open in figure viewerPowerPoint A scheme of the relationship between etiology (mechanism) and patho-physiological stages (states) of diabetes mellitus. Arrows pointing right represent worsening of glucose metabolism disorders (including onset of diabetes mellitus). Among the arrow lines, indicates the condition classified as ‘diabetes mellitus’. Arrows pointing left represent improvement in the glucose metabolism disorder. The broken lines indicate events of low frequency. For example, in type 2 diabetes mellitus, infection can lead to ketoacidosis and require temporary insulin treatment for survival. Also, once diabetes mellitus has developed, it is treated as diabetes mellitus regardless of improvement in glucose metabolism, therefore, the arrow lines pointing left are filled in black. In such cases, a broken line is used, because complete normalization of glucose metabolism is rare. The classification of glucose metabolism disorders is principally derived from etiology, and includes staging of pathophysiology based on the degree of deficiency of insulin action. These disorders are classified into four groups: (i) type 1 diabetes mellitus; (ii) type 2 diabetes mellitus; (iii) diabetes mellitus due to other specific mechanisms or diseases; and (iv) gestational diabetes mellitus. Type 1 diabetes is characterized by destruction of pancreatic β-cells. Type 2 diabetes is characterized by combinations of decreased insulin secretion and decreased insulin sensitivity (insulin resistance). Glucose metabolism disorders in category (iii) are divided into two subgroups; subgroup A is diabetes in which a genetic abnormality has been identified, and subgroup B is diabetes associated with other pathologic disorders or clinical conditions. The staging of glucose metabolism includes normal, borderline and diabetic stages depending on the degree of hyperglycemia occurring as a result of the lack of insulin action or clinical condition. The diabetic stage is then subdivided into three substages: non-insulin- requiring, insulin-requiring for glycemic control, and insulin-dependent for survival. The two former conditions are called non-insulin-dependent diabetes and the latter is known as insulin-dependent diabetes. In each individual, these stages may vary according to the deterioration or the improvement of the metabolic state, either spontaneously or by treatment. Diagnosis (Tables 3–7 and Figure 2): Table 3. Criteria of fasting plasma glucose levels and 75 g oral glucose tolerance test 2-h value Normal range Diabetic range Fasting value <110 mg/dL (6.1 mmol/L) ≥126 mg/dL (7.0 mmol/L) 75 g OGTT 2-h value <140 mg/dL (7.8 mmol/L) ≥200 mg/dL (11.1 mmol/L) Evaluation of OGTT Normal type: If both values belong to normal range *Diabetic type: If any of the two values falls into diabetic range Borderline typeNeither normal nor diabetic types *Casual plasma glucose ≥200 mg/dL (≥11.1 mmol/L) and HbA1c≥6.5% are also regarded as to indicate diabetic type. Even for normal type, if 1-h value is 180 mg/dL (10.0 mmol/L), the risk of progression to diabetes mellitus is greater than for <180 mg/dL (10.0 mmol/L) and should be treated as with borderline type (follow-up observation, etc.). Fasting plasma glucose level of 100–109 mg/dL (5.5–6.0 mmol/L) is called ‘high-normal’: within the range of normal fasting plasma glucose. Plasma glucose level after glucose load in oral glucose tolerance test (OGTT) is not included in casual plasma glucose levels. The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Table 4. Procedures for diagnosing diabetes mellitus Clinical diagnosis (1) At initial examination, a ‘diabetic type’ is diagnosed if any of the following criteria are met: (i) fasting plasma glucose level ≥126 mg/dL (7.0 mmol/L), (ii) 75 g OGTT 2-h value ≥200 mg/dL (11.1 mmol/L), (iii) casual plasma glucose level ≥200 mg/dL (11.1 mmol/L) or (iv) *HbA1c≥6.5%. Re-examination is carried out at another date and diabetes mellitus is diagnosed if ‘diabetic type’ is confirmed again**. However, diagnosis cannot be made on the basis of a repeated HbA1c test alone. If the same blood sample is confirmed to be diabetic type by both plasma glucose and HbA1c levels (any of [i] to [iii] plus [iv]), then diabetes mellitus can be diagnosed from the initial test (2) If plasma glucose level shows diabetic type (any of [i] to [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination• The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss)• The presence of definite diabetic retinopathy (3) If it can be confirmed that either of the above conditions 1 or 2 existed in the past, diabetes mellitus must be diagnosed or suspected even if present test values do not meet the above conditions (4) If diabetes mellitus is suspected but the diagnosis cannot be made by the above (1) to (3), the patient should be followed-up (5) The following points should be kept in mind when selecting the method of determination in initial examination and re-examination• If HbA1c is used at initial examination, another method of determination is required for diagnosis at re-examination. As a rule, both plasma glucose level and HbA1c should be measured• If casual plasma glucose level is ≥200 mg/dL (11.1 mmol/L) at the initial test, a different test method is desirable for re-examination• In the case of disorders and conditions in which HbA1c may be inappropriately low, plasma glucose level should be used for diagnosis (Table 5) Epidemiological study For the purpose of estimating the frequency of diabetes mellitus, determination of ‘diabetic type’ from a single test can be considered to represent ‘diabetes mellitus’. Whenever possible, the criteria to be used are HbA1c≥6.5% or OGTT 2-h value ≥200 mg/dL (11.1 mmol/L) Health screening It is important to detect diabetes mellitus and identify high risk groups without overlooking anyone. Therefore, besides measuring plasma glucose and HbA1c, clinical information such as family history and obesity should be referred *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). **Hyperglycemia must be confirmed in a non-stressful condition. OGTT, oral glucose tolerance test. Table 5. Disorders and conditions associated with low HbA1c values Anemia Liver disease Dialysis Major hemorrhage Blood transfusion Chronic malaria Hemoglobinopathy Others Table 6. Situations where a 75-g oral glucose tolerance test is recommended Strongly recommended (suspicion of present diabetes mellitus cannot be ruled out) Fasting plasma glucose level is 110–125 mg/dL (6.1–6.9 mmol/L) Casual plasma glucose level is 140–199 mg/dL (7.8–11.0 mmol/L) *HbA1c is 6.0–6.4% (excluding those having overt symptoms of diabetes mellitus) Testing is desirable (high risk of developing diabetes mellitus in the future;Testing is especially advisable for patients with risk factors for arteriosclerosis such as hypertension, dyslipidemia and obesity.) Fasting plasma glucose level is 100–109 mg/dL (5.5–6.0 mmol/L) *HbA1c is 5.6–5.9% Strong family history of diabetes mellitus or present obesity regardless of above criteria *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Table 7. Definition and diagnostic criteria of gestational diabetes mellitus Definition of gestational diabetes mellitus Glucose metabolism disorder with first recognition or onset during pregnancy, but that has not developed into diabetes mellitus Diagnostic criteria of gestational diabetes mellitus Diagnosed if one or more of the following criteria is met in a 75 g OGTT Fasting plasma glucose ≥92 mg/dL (5.1 mmol/L) 1-h value ≥180 mg/dL (10.0 mmol/L) 2-h value ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed according to ‘Clinical diagnosis’ outlined in Table 4 is excluded from gestational diabetes mellitus (IADPSG Consensus Panel, Reference 42, partly modified with permission of Diabetes Care). Figure 2Open in figure viewerPowerPoint Flow chart outlining steps in the clinical diagnosis of diabetes mellitus. *The value for HbA1c (%) is indicated with 0.4% added to HbA1c (JDS) (%). Categories of the State of Glycemia: Confirmation of chronic hyperglycemia is essential for the diagnosis of diabetes mellitus. When plasma glucose levels are used to determine the categories of glycemia, patients are classified as having a diabetic type if they meet one of the following criteria: (i) fasting plasma glucose level of ≥126 mg/dL (≥7.0 mmol/L); (ii) 2-h value of ≥200 mg/dL (≥11.1 mmol/L) in 75 g oral glucose tolerance test (OGTT); or (iii) casual plasma glucose level of ≥200 mg/dL (≥11.1 mmol/L). Normal type is defined as fasting plasma glucose level of <110 mg/dL (<6.1 mmol/L) and 2-h value of <140 mg/dL (<7.8 mmol/L) in OGTT. Borderline type (neither diabetic nor normal type) is defined as falling between the diabetic and normal values. According to the current revision, in addition to the earlier listed plasma glucose values, hemoglobin A1c (HbA1c) has been given a more prominent position as one of the diagnostic criteria. That is, (iv) HbA1c≥6.5% is now also considered to indicate diabetic type. The value of HbA1c, which is equivalent to the internationally used HbA1c (%) (HbA1c [NGSP]) defined by the NGSP (National Glycohemoglobin Standardization Program), is expressed by adding 0.4% to the HbA1c (JDS) (%) defined by the Japan Diabetes Society (JDS). Subjects with borderline type have a high rate of developing diabetes mellitus, and correspond to the combination of impaired fasting glucose (IFG) and impaired glucose tolerance (IGT) noted by the American Diabetes Association (ADA) and WHO. Although borderline cases show few of the specific complications of diabetes mellitus, the risk of arteriosclerosis is higher than those of normal type. When HbA1c is 6.0–6.4%, suspected diabetes mellitus cannot be excluded, and when HbA1c of 5.6–5.9% is included, it forms a group with a high risk for developing diabetes mellitus in the future, even if they do not have it currently. Clinical Diagnosis: 1 If any of the criteria for diabetic type (i) through to (iv) is observed at the initial examination, the patient is judged to be ‘diabetic type’. Re-examination is conducted on another day, and if ‘diabetic type’ is reconfirmed, diabetes mellitus is diagnosed. However, a diagnosis cannot be made only by the re-examination of HbA1c alone. Moreover, if the plasma glucose values (any of criteria [i], [ii], or [iii]) and the HbA1c (criterion [iv]) in the same blood sample both indicate diabetic type, diabetes mellitus is diagnosed based on the initial examination alone. If HbA1c is used, it is essential that the plasma glucose level (criteria [i], [ii] or [iii]) also indicates diabetic type for a diagnosis of diabetes mellitus. When diabetes mellitus is suspected, HbA1c should be measured at the same time as examination for plasma glucose. 2 If the plasma glucose level indicates diabetic type (any of [i], [ii], or [iii]) and either of the following conditions exists, diabetes mellitus can be diagnosed immediately at the initial examination. • The presence of typical symptoms of diabetes mellitus (thirst, polydipsia, polyuria, weight loss) • The presence of definite diabetic retinopathy 3 If it can be confirmed that the above conditions 1 or 2 existed in the past, diabetes mellitus can be diagnosed or suspected regardless of the current test results. 4 If the diagnosis of diabetes cannot be established by these procedures, the patient is followed up and re-examined after an appropriate interval. 5 The physician should assess not only the presence or absence of diabetes, but also its etiology and glycemic stage, and the presence and absence of diabetic complications or associated conditions. Epidemiological Study: For the purpose of estimating the frequency of diabetes mellitus, ‘diabetes mellitus’ can be substituted for the determination of ‘diabetic type’ from a single examination. In this case, HbA1c≥6.5% alone can be defined as ‘diabetes mellitus’. Health Screening: It is important not to misdiagnose diabetes mellitus, and thus clinical information such as family history and obesity should be referred to at the time of screening in addition to an index for plasma glucose level. Gestational Diabetes Mellitus: There are two hyperglycemic disorders in pregnancy: (i) gestational diabetes mellitus (GDM); and (ii) diabetes mellitus. GDM is diagnosed if one or more of the following criteria is met in a 75 g OGTT during pregnancy: 1 Fasting plasma glucose level of ≥92 mg/dL (5.1 mmol/L) 2 1-h value of ≥180 mg/dL (10.0 mmol/L) 3 2-h value of ≥153 mg/dL (8.5 mmol/L) However, diabetes mellitus that is diagnosed by the clinical diagnosis of diabetes mellitus defined earlier is excluded from GDM. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2010.00074.x, 2010)

Takotsubo syndrome (TTS) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that TTS may be associated with severe clinical complications including death and that its prevalence is probably underestimated. Since current guidelines on TTS are lacking, it appears timely and important to provide an expert consensus statement on TTS. The clinical expert consensus document part I summarizes the current state of knowledge on clinical presentation and characteristics of TTS and agrees on controversies surrounding TTS such as nomenclature, different TTS types, role of coronary artery disease, and etiology. This consensus also proposes new diagnostic criteria based on current knowledge to improve diagnostic accuracy.

Abstract Cancer develops through a process of somatic evolution 1,2 . Sequencing data from a single biopsy represent a snapshot of this process that can reveal the timing of specific genomic aberrations and the changing influence of mutational processes 3 . Here, by whole-genome sequencing analysis of 2,658 cancers as part of the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) 4 , we reconstruct the life history and evolution of mutational processes and driver mutation sequences of 38 types of cancer. Early oncogenesis is characterized by mutations in a constrained set of driver genes, and specific copy number gains, such as trisomy 7 in glioblastoma and isochromosome 17q in medulloblastoma. The mutational spectrum changes significantly throughout tumour evolution in 40% of samples. A nearly fourfold diversification of driver genes and increased genomic instability are features of later stages. Copy number alterations often occur in mitotic crises, and lead to simultaneous gains of chromosomal segments. Timing analyses suggest that driver mutations often precede diagnosis by many years, if not decades. Together, these results determine the evolutionary trajectories of cancer, and highlight opportunities for early cancer detection.

&lt;b&gt;&lt;i&gt;Background/Aims:&lt;/i&gt;&lt;/b&gt; Our previous study confirmed that &lt;i&gt;Aloe&lt;/i&gt; sterol stimulates collagen and hyaluronic acid production in human dermal fibroblasts. This study aims to investigate whether &lt;i&gt;Aloe&lt;/i&gt; sterol intake affects skin conditions. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We performed a 12-week, randomized, double-blind, placebo-controlled study to evaluate the effects of oral &lt;i&gt;Aloe&lt;/i&gt; sterol supplementation on skin elasticity, hydration, and the collagen score in 64 healthy women (age range 30-59 years; average 44.3 years) who were randomly assigned to receive either a placebo or an &lt;i&gt;Aloe&lt;/i&gt; sterol-supplemented yogurt. Skin parameters were measured and ultrasound analysis of the forearm was performed. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; ANCOVA revealed statistical differences in skin moisture, transepidermal water loss, skin elasticity, and collagen score between the &lt;i&gt;Aloe&lt;/i&gt; sterol and placebo groups. The gross elasticity (R2), net elasticity (R5), and biological elasticity (R7) scores of the &lt;i&gt;Aloe&lt;/i&gt; sterol group significantly increased with time. In addition, skin fatigue area F3, which is known to decrease with age and fatigue, also increased with &lt;i&gt;Aloe&lt;/i&gt; sterol intake. Ultrasound echogenicity revealed that the collagen content in the dermis increased with &lt;i&gt;Aloe&lt;/i&gt; sterol intake. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; The results suggest that continued &lt;i&gt;Aloe&lt;/i&gt; sterol ingestion contributes to maintaining healthy skin.

BACKGROUND: Patients with advanced biliary tract cancer have a poor prognosis, and first-line standard of care (gemcitabine plus cisplatin) has remained unchanged for more than 10 years. The TOPAZ-1 trial evaluated durvalumab plus chemotherapy for patients with advanced biliary tract cancer. METHODS: In this double-blind, placebo-controlled, phase 3 study, we randomly assigned patients with previously untreated unresectable or metastatic biliary tract cancer or with recurrent disease 1:1 to receive durvalumab or placebo in combination with gemcitabine plus cisplatin for up to eight cycles, followed by durvalumab or placebo monotherapy until disease progression or unacceptable toxicity. The primary objective was to assess overall survival. Secondary end points included progression-free survival, objective response rate, and safety. RESULTS: Overall, 685 patients were randomly assigned to durvalumab (n=341) or placebo (n=344) with chemotherapy. As of data cutoff, 198 patients (58.1%) in the durvalumab group and 226 patients (65.7%) in the placebo group had died. The hazard ratio for overall survival was 0.80 (95% confidence interval [CI], 0.66 to 0.97; P=0.021). The estimated 24-month overall survival rate was 24.9% (95% CI, 17.9 to 32.5) for durvalumab and 10.4% (95% CI, 4.7 to 18.8) for placebo. The hazard ratio for progression-free survival was 0.75 (95% CI, 0.63 to 0.89; P=0.001). Objective response rates were 26.7% with durvalumab and 18.7% with placebo. The incidences of grade 3 or 4 adverse events were 75.7% and 77.8% with durvalumab and placebo, respectively. CONCLUSIONS: Durvalumab plus chemotherapy significantly improved overall survival versus placebo plus chemotherapy and showed improvements versus placebo plus chemotherapy in prespecified secondary end points including progression-free survival and objective response rate. The safety profiles of the two treatment groups were similar. (Funded by AstraZeneca; ClinicalTrials.gov number, NCT03875235.)

A. Khosroshahi, Z. S. Wallace, J. L. Crowe, T. Akamizu, A. Azumi, M. N. Carruthers, S. T. Chari, E. Della-Torre, L. Frulloni, H. Goto, P. A. Hart, T. Kamisawa, S. Kawa, M. Kawano, M. H. Kim, Y. Kodama, K. Kubota, M. M. Lerch, M. L€ ohr, Y. Masaki, S. Matsui, T. Mimori, S. Nakamura, T. Nakazawa, H. Ohara, K. Okazaki, J. H. Ryu, T. Saeki, N. Schleinitz, A. Shimatsu, T. Shimosegawa, H. Takahashi, M. Takahira, A. Tanaka, M. Topazian, H. Umehara, G. J. Webster, T. E. Witzig, M. Yamamoto, W. Zhang, T. Chiba, and J. H. Stone

Transcatheter hepatic artery embolization was performed in 120 patients with unresectable hepatoma. The cumulative one-year survival rate was 44%. In most cases follow-up angiography revealed the selective disappearance of tumor vessels, and computed tomography demonstrated a marked decrease in tumor density without any changes in the surrounding liver parenchyma. Histologic examination in 14 cases confirmed these findings.

Abstract A key mutational process in cancer is structural variation, in which rearrangements delete, amplify or reorder genomic segments that range in size from kilobases to whole chromosomes 1–7 . Here we develop methods to group, classify and describe somatic structural variants, using data from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA), which aggregated whole-genome sequencing data from 2,658 cancers across 38 tumour types 8 . Sixteen signatures of structural variation emerged. Deletions have a multimodal size distribution, assort unevenly across tumour types and patients, are enriched in late-replicating regions and correlate with inversions. Tandem duplications also have a multimodal size distribution, but are enriched in early-replicating regions—as are unbalanced translocations. Replication-based mechanisms of rearrangement generate varied chromosomal structures with low-level copy-number gains and frequent inverted rearrangements. One prominent structure consists of 2–7 templates copied from distinct regions of the genome strung together within one locus. Such cycles of templated insertions correlate with tandem duplications, and—in liver cancer—frequently activate the telomerase gene TERT . A wide variety of rearrangement processes are active in cancer, which generate complex configurations of the genome upon which selection can act.

In 1999, the Japan Diabetes Society (JDS) launched the previous version of the diagnostic criteria of diabetes mellitus, in which JDS took initiative in adopting glycated hemoglobin (HbA1c) as an adjunct to the diagnosis of diabetes. In contrast, in 2009 the International Expert Committee composed of the members of the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) manifested the recommendation regarding the use of HbA1c in diagnosing diabetes mellitus as an alternative to glucose measurements based on the updated evidence showing that HbA1c has several advantages as a marker of chronic hyperglycemia2–4. The JDS extensively evaluated the usefulness and feasibility of more extended use of HbA1c in the diagnosis of diabetes based on Japanese epidemiological data, and then the ‘Report of the Committee on the Classification and Diagnostic Criteria of Diabetes Mellitus’ was published in the Journal of Diabetes Investigation5 and Diabetology International6. The new diagnostic criterion in Japan came into effect on 1 July 2010. According to the new version of the criteria, HbA1c (JDS) ≥6.1% is now considered to indicate a diabetic type, but the previous diagnosis criteria of high plasma glucose (PG) levels to diagnose diabetes mellitus also need to be confirmed. Those are as follows: (i) FPG ≥126 mg/dL (7.0 mmol/L); (ii) 2-h PG ≥200 mg/dL (11.1 mmol/L) during an oral glucose tolerance test; or (iii) casual PG ≥200 mg/dL (11.1 mmol/L). If both PG criteria and HbA1c in patients have met the diabetic type, those patients are immediately diagnosed to have diabetes mellitus5,6. In the report, the HbA1c measurements in Japan are well calibrated with Japanese-Clinical-Laboratory-Use Certified Reference Material (JCCRM). The certified values are determined by a high-resolution type ion-exchange high performance liquid chromatography (HPLC) (KO 500 method) and certified using the designated comparison method (DCM) of the Japan Society of Clinical Chemistry (JSCC) and the JDS. After incorporating a proportional bias correction to the value anchored to the peptide mapping method of the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC), the DCM actually measures β-N-mono-deoxyfructosyl hemoglobin and has an intercept approximately equal to zero against the peptide mapping method of IFCC in measuring fresh raw human blood samples. Furthermore, standardization of HbA1c in Japan was initiated in 1993, and the serial reference materials from JDS Lot 1 to JDS Lot 4 are well certified using the DCM until now. In the new diagnosis criteria5,6, the new cut-point of HbA1c (JDS) for diagnosis of diabetes mellitus is 6.1%, which is equivalent to the internationally-used HbA1c (National Glycohemoglobin Standardization Program [NGSP]) 6.5%, as HbA1c (NGSP)(%) is reported to be equivalent to 1.019 × HbA1c (JDS)% + 0.3%, which is reasonably estimated by the equation of HbA1c (JDS)% + 0.4%, as the difference between the two equations is within error of HbA1c measurements (2∼3%). However, on 1 October 2011, the Reference Material Institute for Clinical Chemistry Standards (ReCCS, Kanagawa, Japan) was certified as an Asian Secondary Reference Laboratory (ASRL) using the KO 500 method and the reference materials JCCRM411-2 (JDS Lot 4) after successful completion of NGSP network laboratory certification. Therefore, the HbA1c unit is now traceable to the Diabetes Control and Complications Trial (DCCT) reference method. The comparison was carried out with the Central Primary Reference Laboratory (CPRL) in the University of Missouri School of Medicine. The conversion equation from HbA1c (JDS) to HbA1c (NGSP) units is officially certified as follows: NGSP (%) = 1.02 × JDS (%) + 0.25%; conversely, JDS (%) = 0.980 × NGSP (%) – 0.245%. Based on this equation, in the range of JDS values ≤4.9%, NGSP (%) = JDS (%) + 0.3%; in the range of JDS 5.0∼9.9%, NGSP (%) = JDS (%) + 0.4%; and in the range of JDS 10∼14.9%, NGSP (%) = JDS (%) + 0.5%. These results show that the previous equation of NGSP (%) = JDS (%) + 0.4% is also confirmed in the present equation, considering a 2∼3% error of HbA1c measurements. The council meeting of the JDS finally decided to use HbA1c (NGSP) values in clinical practice from 1 April 2012, although HbA1c (JDS) values will be included until people become familiar with the new expression. Finally, it is also important to emphasize that the new HbA1c (NGSP) values can be directly measured and printed out from 1 April 2012. However, both new diagnostic reference values and target values of glycemic control have been adjusted to those equivalent values of HbA1c (JDS), as shown in the Table 1.

In this study, we questioned whether in vivo probucol could prevent the progression of atherosclerosis in homozygous Watanabe heritable hyperlipidemic (WHHL) rabbits, an animal model for familial hypercholesterolemia. At 2 months of age, eight WHHL rabbits were divided into two groups. Group A (n = 4) was fed standard rabbit chow for 6 months. Group B (n = 4) was fed standard rabbit chow containing 1% probucol for 6 months. At the end of the experiments, average plasma concentrations of cholesterol were 704 +/- 121 mg/dl in group A and 584 +/- 61 mg/dl in group B, respectively. The percentage of surface area of total thoracic aorta with visible plaques in group A versus group B was 54.2% +/- 18.8% versus 7.0% +/- 6.3%, respectively. What was noteworthy was that the percentage of plaque in the descending thoracic aorta was almost negligible (0.2% +/- 0.2%) in group B rabbits compared to that in group A rabbits (41.1% +/- 20.2%). Low density lipoproteins (LDL) isolated from WHHL rabbits under treatment with probucol (group B) were shown to be highly resistant to oxidative modification by cupric ion and to be minimally recognized by macrophages. On the contrary, LDL from group A rabbits incubated with cupric ion showed a 7.4-fold increase in peroxides (thiobarbituric acid-reactive substances) and a 4.3-fold increase in the synthesis of cholesteryl ester in macrophages compared to those of LDL from group B rabbits. Thus, probucol could definitely prevent the progression of atherosclerosis in homozygous WHHL rabbits in vivo by limiting oxidative LDL modification and foam cell transformation of macrophages.

Optical coherence tomography (OCT) is a novel intravascular imaging modality, based on infrared light emission, that enables a high resolution arterial wall imaging, in the range of 10-20 microns. This feature of OCT allows the visualization of specific components of the atherosclerotic plaques. The aim of the present Expert Review Document is to address the methodology, terminology and clinical applications of OCT for qualitative and quantitative assessment of coronary arteries and atherosclerosis.

The clinical expert consensus statement on takotsubo syndrome (TTS) part II focuses on the diagnostic workup, outcome, and management. The recommendations are based on interpretation of the limited clinical trial data currently available and experience of international TTS experts. It summarizes the diagnostic approach, which may facilitate correct and timely diagnosis. Furthermore, the document covers areas where controversies still exist in risk stratification and management of TTS. Based on available data the document provides recommendations on optimal care of such patients for practising physicians.

The inflammatory bowel disease ulcerative colitis (UC) frequently progresses to colon cancer. To understand the mechanisms by which UC patients develop colon carcinomas, we used a mouse model of the disease whereby administration of azoxymethane (AOM) followed by repeated dextran sulfate sodium (DSS) ingestion causes severe colonic inflammation and the subsequent development of multiple tumors. We found that treating WT mice with AOM and DSS increased TNF-alpha expression and the number of infiltrating leukocytes expressing its major receptor, p55 (TNF-Rp55), in the lamina propria and submucosal regions of the colon. This was followed by the development of multiple colonic tumors. Mice lacking TNF-Rp55 and treated with AOM and DSS showed reduced mucosal damage, reduced infiltration of macrophages and neutrophils, and attenuated subsequent tumor formation. WT mice transplanted with TNF-Rp55-deficient bone marrow also developed significantly fewer tumors after AOM and DSS treatment than either WT mice or TNF-Rp55-deficient mice transplanted with WT bone marrow. Furthermore, administration of etanercept, a specific antagonist of TNF-alpha, to WT mice after treatment with AOM and DSS markedly reduced the number and size of tumors and reduced colonic infiltration by neutrophils and macrophages. These observations identify TNF-alpha as a crucial mediator of the initiation and progression of colitis-associated colon carcinogenesis and suggest that targeting TNF-alpha may be useful in treating colon cancer in individuals with UC.

Tubulointerstitial fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. Transforming growth factor-beta (TGF-beta) is reportedly upregulated in response to injurious stimuli such as unilateral ureteral obstruction (UUO), causing renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. We now show that mice lacking Smad3 (Smad3ex8/ex8), a key signaling intermediate downstream of the TGF-beta receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation. Culture of primary renal tubular epithelial cells from wild-type or Smad3-null mice confirms that the Smad3 pathway is essential for TGF-beta1-induced EMT and autoinduction of TGF-beta1. Moreover, mechanical stretch of the cultured epithelial cells, mimicking renal tubular distention due to accumulation of urine after UUO, induces EMT following Smad3-mediated upregulation of TGF-beta1. Exogenous bone marrow monocytes accelerate EMT of the cultured epithelial cells and renal tubules in the obstructed kidney after UUO dependent on Smad3 signaling. Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy.

Tubulointerstitial fibrosis is the final common result of a variety of progressive injuries leading to chronic renal failure. Transforming growth factor-β (TGF-β) is reportedly upregulated in response to injurious stimuli such as unilateral ureteral obstruction (UUO), causing renal fibrosis associated with epithelial-mesenchymal transition (EMT) of the renal tubules and synthesis of extracellular matrix. We now show that mice lacking Smad3 (Smad3ex8/ex8), a key signaling intermediate downstream of the TGF-β receptors, are protected against tubulointerstitial fibrosis following UUO as evidenced by blocking of EMT and abrogation of monocyte influx and collagen accumulation. Culture of primary renal tubular epithelial cells from wild-type or Smad3-null mice confirms that the Smad3 pathway is essential for TGF-β1–induced EMT and autoinduction of TGF-β1. Moreover, mechanical stretch of the cultured epithelial cells, mimicking renal tubular distention due to accumulation of urine after UUO, induces EMT following Smad3-mediated upregulation of TGF-β1. Exogenous bone marrow monocytes accelerate EMT of the cultured epithelial cells and renal tubules in the obstructed kidney after UUO dependent on Smad3 signaling. Together the data demonstrate that the Smad3 pathway is central to the pathogenesis of interstitial fibrosis and suggest that inhibitors of this pathway may have clinical application in the treatment of obstructive nephropathy.

Neoadjuvant or adjuvant immunotherapy can improve outcomes in patients with resectable non–small-cell lung cancer (NSCLC). Perioperative regimens may combine benefits of both to improve long-term outcomes. Download a PDF of the Research Summary. We randomly assigned patients with resectable NSCLC (stage II to IIIB [N2 node stage] according to the eighth edition of the AJCC Cancer Staging Manual) to receive platinum-based chemotherapy plus durvalumab or placebo administered intravenously every 3 weeks for 4 cycles before surgery, followed by adjuvant durvalumab or placebo intravenously every 4 weeks for 12 cycles. Randomization was stratified according to disease stage (II or III) and programmed death ligand 1 (PD-L1) expression (≥1% or <1%). Primary end points were event-free survival (defined as the time to the earliest occurrence of progressive disease that precluded surgery or prevented completion of surgery, disease recurrence [assessed in a blinded fashion by independent central review], or death from any cause) and pathological complete response (evaluated centrally). A total of 802 patients were randomly assigned to receive durvalumab (400 patients) or placebo (402 patients). The duration of event-free survival was significantly longer with durvalumab than with placebo; the stratified hazard ratio for disease progression, recurrence, or death was 0.68 (95% confidence interval [CI], 0.53 to 0.88; P=0.004) at the first interim analysis. At the 12-month landmark analysis, event-free survival was observed in 73.4% of the patients who received durvalumab (95% CI, 67.9 to 78.1), as compared with 64.5% of the patients who received placebo (95% CI, 58.8 to 69.6). The incidence of pathological complete response was significantly greater with durvalumab than with placebo (17.2% vs. 4.3% at the final analysis; difference, 13.0 percentage points; 95% CI, 8.7 to 17.6; P<0.001 at interim analysis of data from 402 patients). Event-free survival and pathological complete response benefit were observed regardless of stage and PD-L1 expression. Adverse events of maximum grade 3 or 4 occurred in 42.4% of patients with durvalumab and in 43.2% with placebo. Data from 62 patients with documented EGFR or ALK alterations were excluded from the efficacy analyses in the modified intention-to-treat population. In patients with resectable NSCLC, perioperative durvalumab plus neoadjuvant chemotherapy was associated with significantly greater event-free survival and pathological complete response than neoadjuvant chemotherapy alone, with a safety profile that was consistent with the individual agents. (Funded by AstraZeneca; AEGEAN ClinicalTrials.gov number, NCT03800134.) QUICK TAKE VIDEO SUMMARYPerioperative Chemoimmunotherapy in Lung Cancer 02:08