Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Infant high-grade gliomas appear clinically distinct from their counterparts in older
children, indicating that histopathologic grading may not accurately refl ect the
biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic
review, methylation profi ling, and custom panel, genome, or exome sequencing. After excluding tumors
representing other established entities or subgroups, we identifi ed 130 cases to be part of an “intrinsic” spectrum of disease specifi c to the infant population. These included those with targetable MAPK
alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK ( n = 31),
NTRK1/2/3 ( n = 21), ROS1 ( n = 9), and MET ( n = 4) as their driving alterations, with evidence of effi cacy
of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a
change in diagnostic practice and management. Infant high-grade gliomas in the cerebral hemispheres com..... READ ARTICLE

Cancer Discovery DOI:10.1158/2159-8290

Authors: Matthew Clarke, Alan Mackay, Britta Ismer, Jessica C. Pickles, Ruth G. Tatevossian, Scott Newman, Tejus A. Bale, Iris Stoler, Elisa Izquierdo, Sara Temelso, Diana M. Carvalho, Valeria Molinari, Anna Burford, Louise Howell, Alex Virasami, Amy R. Fairchild, Aimee Avery, Jane Chalker, Mark Kristiansen, Kelly Haupfear, James D. Dalton, Wilda Orisme, Ji Wen, Michael Hubank, Kathreena M. Kurian, Catherine Rowe, Mellissa Maybury, Stephen Crosier, Jeffrey Knipstein, Ulrich Schüller, Uwe Kordes, David E. Kram, Matija Snuderl, Leslie Bridges, Andrew J. Martin, Lawrence J. Doey, Safa Al-Sarraj, Christopher Chandler, Bassel Zebian, Claire Cairns, Rachael Natrajan, Jessica K.R. Boult, Simon P. Robinson, Martin Sill, Ira J. Dunkel, Stephen W. Gilheeney, Marc K. Rosenblum, Debbie Hughes, Paula Z. Proszek, Tobey J. Macdonald, Matthias Preusser, Christine Haberler, Irene Slavc, Roger Packer, Ho-Keung Ng, Shani Caspi, Mara Popović, Barbara Faganel Kotnik, Matthew D. Wood, Lissa Baird, Monika Ashok Davare, David A. Solomon, Thale Kristin Olsen, Petter Brandal, Michael Farrell, Jane B. Cryan, Michael Capra, Michael Karremann, Jens Schittenhelm, Martin U. Schuhmann, Martin Ebinger, Winand N.M. Dinjens, Kornelius Kerl, Simone Hettmer, Torsten Pietsch, Felipe Andreiuolo, Pablo Hernáiz Driever, Andrey Korshunov, Lotte Hiddingh, Barbara C. Worst, Dominik Sturm, Marc Zuckermann, Olaf Witt, Tabitha Bloom, Clare Mitchell, Evelina Miele, Giovanna Stefania Colafati, Francesca Diomedi-Camassei, Simon Bailey, Andrew S. Moore, Timothy E.G. Hassall, Stephen P. Lowis, Maria Tsoli, Mark J. Cowley, David S. Ziegler, Matthias A. Karajannis, Kristian Aquilina, Darren R. Hargrave, Fernando Carceller, Lynley V. Marshall, Andreas von Deimling, Christof M. Kramm, Stefan M. Pfister, Felix Sahm, Suzanne J. Baker, Angela Mastronuzzi, Andrea Carai, Maria Vinci, David Capper, Sergey Popov, David W. Ellison, Thomas S. Jacques, David T.W. Jones and Chris Jones

Review PaperKirk SmithApril 1, 2020infant high grade glioma, diagnostic practices

Pediatric low-grade glioma in the era of molecular diagnostics

Low grade gliomas are the most frequent brain tumors in children and encompass a spectrum of histologic entities which are currently assigned World Health Organisation grades I and II. They differ substantially from their adult counterparts in both their underlying genetic alterations and in the infrequency with which they transform to higher grade tumors. Nonetheless, children with low grade glioma are a therapeutic challenge due to the heterogeneity in their clinical behavior – in particular, those with incomplete surgical resection often suffer repeat progressions with resultant morbidity and, in some cases, mortality. The identification of up-regulation of the RAS–mitogen-activated protein kinase (RAS/MAPK) pathway as a near universal feature of these tumors has led to the development of targeted therapeutics aimed at improving responses while mitigating patient morbidity. Here, we review how molecular information can help to further define the entities which fall under the umbrell..... READ ARTICLE

Acta Neuropathologica Communications DOI:10.1186/s40478-020-00902-z

Authors: Scott Ryall, Uri Tabori & Cynthia Hawkins

Junction Location Identifier (JuLI): Accurate Detection of DNA Fusions in Clinical Sequencing for Precision Oncology

Accurate detection of genomic fusions by high-throughput sequencing in clinical samples with inadequate tumor purity and formalin-fixed, paraffin-embedded tissue is an essential task in precise oncology. We developed the fusion detection algorithm Junction Location Identifier (JuLI) for optimization of high-depth clinical sequencing... In clinical setting, although sensitivity is important, maintaining PPV is also essential to reduce the number of false positives. In particular, if the prevalence is relatively low, such as that of the ALK fusion in NSCLC (2% to 7%),29 several wrong decisions can be made when PPV is not guaranteed. Clinical decisions based on false test results are risky and may lead to inappropriate treatment strategies. Therefore, if the PPV cannot provide a sufficiently high confidence level, it will be difficult to use the method for diagnostic purposes. Because JuLI has better PPV relative to the existing algorithms, it is likely to deliver accurate fusion profil..... READ ARTICLE

The Journal of Molecular Diagnostics DOI:10.1016/j.jmoldx.2019.10.015

Authors: Hyun-Tae Shin, Nayoung K. D. Kim, Jae Won Yun, Boram Lee, Sungkyu Kyung, Ki-Wook Lee, Daeun Ryu, Jinho Kim, Joon Seol Bae, Donghyun Park, Yoon-La Choi, Se-Hoon Lee, Myung-Ju Ahn, Keunchil Park, Woong-Yang Park

Biomarkers in Lung Cancer

Key Points: Biomarkers can be used for risk assessment, detection, diagnosis, and prognosis and to personalize treatment in lung cancer. Clinically useful biomarkers for selection of high-risk patients for lung cancer screening and to differentiate early lung cancer from benign pulmonary nodules are needed. Biomarkers for nodule management and determination of high-risk groups for lung cancer screening are at all phases of development, from discovery to clinical utility studies. Current trends in lung cancer biomarker development include the integration of clinical and radiologic features with molecular biomarkers, the application of artificial intelligence to molecular and imaging biomarker development, the use highly sensitive technologies such as next-generation sequencing for molecular exploration, and a commitment to high-quality clinical validation and utility studies. READ ARTICLE

Clinics in Chest Medicine. DOI: 10.1016/j.ccm.2019.10.004

Authors: Catherine R. Sears, Peter J. Mazzone

Circulating Tumor DNA Analysis for Patients with Oncogene-Addicted NSCLC With Isolated Central Nervous System Progression

Introduction: In patients with oncogene-addicted NSCLC and isolated central nervous system progression (iCNS), tissue biopsy is challenging, and the clinical utility of plasma liquid biopsy (i.e., circulating tumor DNA [ctDNA]) is unknown... Conclusions: Although tagged amplicon-based next-generation sequencing has high detection rates of GA in plasma ctDNA in patients with NSCLC with extra-CNS disease, detection rate of GAs (52%) is lower in the subset of patients with iCNS disease. Complementary tests such as cerebrospinal fluid cell-free DNA may be useful. Further evidence would be beneficial to understand the genomic landscape in patients with NSCLC and iCNS. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.11.024

Authors: Mihaela Aldea, Lizza Hendriks, Laura Mezquita, Cécile Jovelet, David Planchard, Edouard Auclin, Jordi Remon, Karen Howarth, Jose Carlos Benitez, Anas Gazzah, Pernelle Lavaud, Charles Naltet, Ludovic Lacroix, Frankde Kievit, Clive Morris, Emma Green, Maud Ngo-Camus, Etienne Rouleau, … , Benjamin Besse

Review PaperKirk SmithMarch 1, 2020Liquid biopsy, ctDNA, NSCLC, Brain, Leptomeningeal

Catalog of 5’ Fusion Partners in ALK-positive NSCLC Circa 2020

Since the discovery of anaplastic lymphoma kinase fusion-positive (ALK+) NSCLC in 2007, the methods to detect ALK+ NSCLC have evolved and expanded from fluorescence in situ hybridization and immunohistochemistry to next-generation DNA sequencing, targeted RNA sequencing, and whole transcriptome sequencing. As such, the deep sequencing methods have resulted in the expansion of distinct fusion partners identified in ALK+ NSCLC to 90 (one variant PLEKHM2-ALK is found in small cell lung cancer but included in this catalog) by the end of January 2020; about 65 of them (since 2018) and most of the recent novel fusion partners were reported from China. Thirty-four of the distinct fusion partners are located on the short arm of chromosome 2; 28 of these 34 fusion partners are located on 2p21-25, in which ALK is located on 2p23.2-p23.1. Many of these new ALK+ NSCLC fusion variants have responded to ALK tyrosine kinase inhibitors (TKIs). Several of these novel ALK fusion variants were identified..... READ ARTICLE

Journal of Thoracic Oncology, Clinical and research reports DOI:10.1016/j.jtocrr.2020.100015

Authors: Sai-Hong IgnatiusOu, Viola W. Zhu and Misako Nagasaka

Efficacy of Crizotinib, Ceritinib, and Alectinib in ALK-Positive Non-Small Cell Lung Cancer Treatment: A Meta-Analysis of Clinical Trials

This study aimed to evaluate the efficacy of anaplastic lymphoma kinase (ALK)-inhibitors in the treatment of ALK-positive non-small cell lung cancer (NSCLC) by using a meta-analysis of clinical trials. We searched PubMed, EMBASE, Cochrane Library, and Clinicaltrials.gov by using keywords related to the topic in August 2018. The pooled effect sizes were calculated based on a random-effects model. We also performed subgroup meta-analysis by types of ALK inhibitors (crizotinib, ceritinib, and alectinib). A total of 20 clinical trials with 10 single-arm trials and 10 double-arm trials were included in the final meta-analysis. The median overall survival (OS), progression-free survival (PFS), overall response rate (ORR), disease control rate (DCR), 1 year survival rate, and 2 year survival rate were 19.14 months, 8.47 months, 62%, 78%, 74%, and 62%, respectively. ALK inhibitors showed a significantly superior efficacy compared with chemotherapy (hazard ratio (HR) for OS, 0.83; HR for PFS, 0..... READ ARTICLE

Cancers DOI:10.3390/cancers12030526

Authors: Hoang, T.; Myung, S.-K.; Pham, T.T.; Park, B.

Emerging Roles of ALK in Immunity and Insights for Immunotherapy

Anaplastic lymphoma kinase (ALK) is mostly known for its oncogenic role in several human cancers. Recent evidences clearly indicate new roles of ALK and its genetic aberrations (e.g. gene rearrangements and mutations) in immune evasion, innate and cell-mediated immunity. New ALK-related immunotherapy approaches are demonstrating both preclinical and clinical promises. Here, we provide a timely review on the most updated laboratory and patient-related findings on ALK and immunity, which would grant us important insights for the development of novel ALK immunotherapies for ALK-altered cancers. READ ARTICLE

Cancers DOI: 10.3390%2Fcancers12020426

Authors: Lan Wang and Vivian Wai Yan Lui

Review PaperKirk SmithFebruary 12, 2020ALK and aberrations in immunity, immunotherapies

Drug resistance to targeted therapeutic strategies in non-small cell lung cancer

Rapidly developing molecular biology techniques have been employed to identify cancer driver genes in specimens from patients with non-small cell lung cancer (NSCLC). Inhibitors and antibodies that specifically target driver gene-mediated signaling pathways to suppress tumor growth and progression are expected to extend the survival time and further improve the quality of life of patients. However, the health of patients with advanced and metastatic NSCLC presents significant challenges due to treatment resistance, mediated by cancer driver gene alteration, epigenetic alteration, and tumor heterogeneity. In this review, we discuss two different resistance mechanisms in NSCLC targeted therapies, namely changes in the targeted oncogenes (on-target resistance) and changes in other related signaling pathways (off-target resistance) in tumor cells. We highlight the conventional mechanisms of drug resistance elicited by the complex heterogeneous microenvironment of NSCLC during targeted ther..... READ ARTICLE

Pharmacology & Therapeutics DOI:10.1016/j.pharmthera.2019.107438

Authors: Wen-juan Liu, Yue Du, Ru Wen, Ming Yang, JianXu

Keratinocytes apoptosis contributes to crizotinib induced-erythroderma

Crizotinib is a multi-target receptor tyrosine kinase inhibitor which is of great importance for the management of ALK-rearranged non-small cell lung cancer (NSCLC) patients. Serious erythroderma and toxic epidermal necrolysis have been reported associated with crizotinib treatment. The underlying mechanisms have not been examined. In this study, we tested the toxicity of crizotinib on immortal human keratinocytes (HaCaT) and human primary keratinocytes. We found that crizotinib directly cause cytotoxic on these two cells, which could be the explanation of the clinical characteristic of pathology. Apoptosis was observed and Z-VAD-FMK, a pan-caspase inhibitor can almost totally reverse the apoptosis induction effect of crizotinib. However, mitochondrial dysfunction and DNA damage were not involved in crizotinib-induced apoptosis, indicating the intrinsic apoptosis pathway have no connection with this cutaneous toxicity. Further studies showed that crizotinib significantly increased clea..... READ ARTICLE

Toxicology Letters DOI:10.1016/j.toxlet.2019.11.007

Authors: Yuhuai Hu, Xiaochen Zhang, Ziying Zhao, Xueqin Chen, Ziye Zhou, Xiaochun Yang, Bo Yang, Qiaojun He, Peihua Luo

Review PaperKirk SmithFebruary 1, 2020Crizotinib, Cutaneous, toxicity, Erythroderma, Apoptosis, Cleaved-caspase-8

Clinical consequences of resistance to ALK inhibitors in non-small cell lung cancer

Introduction: ALK rearrangements are present in 2-7% of non-small cell lung cancer (NSCLC) cases, where the EML4-ALK fusion is the most frequent. Rearrangement of ALK with other fusion partners occurs only in ≈5% of NSCLC ALK-positive. These patients have benefited from ALK inhibitors, and currently, there are three generations of drugs as the standard of care. The first-generation ALK inhibitor crizotinib is approved in the front-line setting for the treatment of advanced NSCLC; unfortunately, these tumors may eventually develop resistance to this molecule. The Second-generation ALK inhibitors, ceritinib, alectinib, and brigatinib, are approved for patients recently diagnosed or in relapse. The third-generation inhibitor lorlatininb is approved for patients who have developed resistance to any ALK inhibitor. Expert opinion: Currently, there are a growing number of options of therapeutic agents against ALK+ NSCLC (approved and in development); however, adequate selection and sequencin..... READ ARTICLE

Expert Review of Respiratory Medicine DOI:10.1080/17476348.2020.1721285

Authors: Joseph A Pinto, Luis E Raez, Gelenis Domingo,

Targeted therapy of oncogenic-driven advanced non-small cell lung cancer: recent advances and new perspectives

The discovery of new actionable oncogenic drivers has led to the development of effective antineoplastic targeted agents in advanced non-small cell lung cancer (NSCLC). While the role of inhibitors of the epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), and ROS proto-oncogene 1 (ROS1) is widely acknowledged, other oncogenic drivers can be exploited as therapeutic targets. Areas covered: Our aim is to explore the therapeutic role of actionable oncogenic drivers, including well-established targets, such as EGFR, ALK, and ROS1, as well as less frequent drivers for which specific agents are at different stages of clinical development, such as MET, RET, BRAF, and NTRK. Expert opinion: Targeted agents have revolutionized the management of advanced NSCLC; in particular, novel agents and combinations targeting EGFR, ALK, ROS1, BRAF, and NTRK have become available and others are on their way. The molecularly driven approach to advanced NSCLC requires adequate tumor samples, as well as increasingly complex technologies designed to assess multiple targets on limited available tissue in an acceptable time-span. Furthermore, the role of other novel antineoplastic approaches, such as immunotherapy with immune checkpoint inhibitors, needs to be elucidated in the case of patients with oncogenic-driven NSCLC. READ ARTICLE

Expert Review of Respiratory Medicine DOI: 10.1080/17476348.2020.1714441

AUTHORS: Carlo Genova, Giovanni Rossi, Marco Tagliamento, Erika Rijavec, Federica Biello, Luigi Cerbone, Lodovica Zullo, Francesco Grossi

Review PaperKirk SmithJanuary 17, 2020Non-small cell lung cancer, targeted therapy, oncogenic drivers

Differences Between the East and the West in Managing Advanced-Stage Non-small Cell Lung Cancer

Lung cancer is a common cancer associated with high mortality rates worldwide. Unfortunately, it usually presents at a late stage, precluding the chance of curative therapy. The discovery of oncogenic driver mutations in patients with non-small cell lung cancer over the past 20 years has led to new molecular targeted therapies that have dramatically improved treatment efficacy and quality of life. New generations of therapy that target the drug-resistant mutations have also quickly evolved, benefiting patients who are refractory or intolerant to first-line targeted therapy. Eastern patients, from Southeast Asia, Japan and China, are known to have a higher incidence of epidermal growth factor receptor mutation. Therefore, compared with the West, more patients would benefit from these recent advances. In contrast, survival of patients without driver mutations has benefited from advances in novel therapeutics, including the immune checkpoint inhibitors. The current review aims to highligh..... READ ARTICLE

Clinical Oncology DOI:10.1016/j.clon.2019.07.014

Authors: V. H. F. Lee, T. S. K. Mok, Y. Goto, V. C. C. Hsue, L. Yang, Y. Jiang, D. K. C. Leung, K. S. Lau, P. Y. Tse

Life Threatening haemoptysis in primary lung cancer-signet ring cell carcinoma

Primary signet ring cell carcinoma of the lung is a rare non-small cell carcinoma of the lung with extremely aggressive features and poor prognosis. The diagnosis mainly required tissue biopsy with immunohistochemical analysis and gene mutation studies. We describe a unique case of primary signet ring cell carcinoma of the lung presenting with life threatening haemoptysis along with literature review of prognosis and management of this rare clinical entity. READ ARTICLE

Respiratory Medicine Case Reports DOI:10.1016/j.rmcr.2020.101195

Authors: Shamsuddin Anwar, Sudeep Acharya, Dany Elsayegh, Alisa Sokoloff, Maryam Rehan

Brain metastases from non-small cell lung cancer with EGFR or ALK mutations: A systematic review and meta-analysis of multidisciplinary approaches

Background and purpose: To analyze outcomes of non-small cell lung cancer (NSCLC) patients with brain metastases harboring EGFR or ALK mutations and examine for differences between tyrosine kinase inhibitors (TKIs) alone, radiotherapy (RT) alone (either whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS)), or combined TKIs and RT. Conclusion: NSCLC patients with brain metastases harboring EGFR or ALK mutations have superior OS compared to wild-type patients. No PFS or OS benefit was found with the addition of TKIs to RT. READ ARTICLE

Radiotherapy and Oncology. DOI: 10.1016/j.radonc.2019.11.010

Authors: Raj Singh, Eric J. Lehrer, Stephen Ko, Jennifer Peterson, Yanyan Lou, Alyx B. Porter, Rupesh Kotecha, Paul D. Brown, Nicholas G. Zaorsky, Daniel M. Trifiletti

Review PaperKirk SmithDecember 6, 2019Radiosurgery, ALK, EGFR, Mutated, Brain metastases

Brigatinib: New-generation ALK inhibitor for nonsmall cell lung cancer

Lung cancer, specifically nonsmall cell lung cancer (NSCLC) is the leading cause of death around the world. First-line therapies for metastatic NSCLC such as crizotinib, a tyrosine kinase inhibitor (TKI), have developed resistance due to a rearrangement of the anaplastic lymphoma kinase (ALK) gene. Brigatinib, approved in May 2016, is an ALK inhibitor specifically indicated for ALK-positive metastatic NSCLC in patients who have progressed on or resistant to crizotinib therapy. In several clinical trials, brigatinib has exhibited significant improvement in progression-free survival in patients that have experienced resistance to crizotinib therapy. The optimal dose of brigatinib was found to be 180 mg once daily and demonstrated greater efficacy as compared to its 90 mg once daily dose. Brigatinib was also found to be well tolerated. Although more studies are needed, the current data from these studies indicate brigatinib may be the most favorable therapeutic approach to treat NSCLC ALK..... READ ARTICLE

Current Problems in Cancer
DOI:10.1016/j.currproblcancer.2019.03.005

Authors: Stewart Umbela, Shahinaz Ghacha, Revika Matuknauth, Stacey Gause, Shrijana Joshee, Rahul R. Deshmukh

Review PaperKirk SmithDecember 1, 2019Brigatinib, Crizotinib-resistance, NSCLC, ALK, TKI

The Dandelion Dilemma Revisited for Oligoprogression: Treat the Whole Lawn or Weed Selectively?

When early-stage metastases appear, what is the evidence comparing the utility of systemic drug treatment versus focused radiation? "Oligoprogressive disease is a relatively new clinical concept describing progression at only a few sites of metastasis in patients with otherwise controlled widespread disease. Local ablative therapy for oligoprogressive disease may allow the continuation of systemic treatments by overcoming the few sub-clones that have developed resistance." READ ARTICLE

Clinical Oncology; DOI: 10.1016/j.clon.2019.05.015;

Authors: P.H. Patel, D. Palma, F. McDonald, A.C. Tree

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IV Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Stratégies thérapeutiques dans le cancer bronchique non à petites cellules ALK positif de stade IVTherapeutic strategies in advanced ALK positive non-small cell lung cancer. READ ARTICLE

Revue des Maladies Respiratoires DOI:Therapeutic strategies in advanced ALK positive non-small cell lung cancer

Authors: A. Tiotiu, Y. Billon, P. Vaillant, O. Menard, P. Hofman, C. Mascaux

Review PaperKirk SmithDecember 1, 2019ALK TKI, Therapeutic strategy, Rebiopsy, Resistance

ALK Mutation Status Before and After Alectinib Treatment in Locally Advanced or Metastatic ALK-Positive NSCLC: Pooled Analysis of Two Prospective Trials

Introduction: The effectiveness of ALK receptor tyrosine kinase (ALK) inhibitors can be limited by the development of ALK resistance mutations. This exploratory analysis assessed the efficacy of alectinib in patients with NSCLC and ALK point mutations using pooled data from two single-arm phase II studies. Conclusions: Alectinib appears clinically active against ALK rearrangements and mutations, as well as several ALK variants that can cause resistance to crizotinib. The use of cell-free DNA in plasma samples may be an alternative noninvasive method for monitoring resistance mutations during therapy. READ ARTICLE

Journal of Thoracic Oncology DOI:10.1016/j.jtho.2019.10.015

Authors: Johannes Noé, Alex Lovejoy, Sai-Hong Ignatius Ou, Stephanie J. Yaung, Walter Bordogna, Daniel M. Klass, Craig A. Cummings, Alice T. Shaw

Review PaperKirk SmithNovember 8, 2019Alectinib, ALK-positive, NSCLC, Mutation analysis, Resistance

20P - Detecting therapy-guiding aberrations in platelets and plasma at the transcriptome level in non-small-cell lung cancer

Background: The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma has become important for treating lung cancer patients. The aim of this study is to explore the feasibility of detecting therapy-guiding aberrations in RNA, isolated from platelet and plasma samples. Conclusions: In conclusion, the fraction of tumour-derived RNA transcripts in plasma and platelets appears to be very low or undetectable. Our data indicates that plasma and platelet-derived RNA is not a good source to identify tumour cell specific genomic aberrations. READ ARTICLE

Annals of Oncology DOI:10.1093/annonc/mdz413.025

Authors: P. Meng, A. A. Rybczynska, J. Wei, M. M. Terpstra, W. Timens, E. Schuuring, T. J. N. Hiltermann, H. J. M. Groen, K. Kok, A. J. Van der Wekken, A. Van den Berg