Myotonic dystrophy (DM) is considered a subgroup of myopathy and the most common type of muscular dystrophy that begins in adulthood. There are two major forms recognized based on clinical and molecular presentation: Myotonic dystrophy type I (DM1), known as Steinert disease, and myotonic dystrophy type II (DM2), or proximal myotonic myopathy which is a milder variety of DMI. These are progressive, multisystem genetic disorders. Clinical presentation is diverse and can range from asymptomatic electrical myotonia to severe weakness and disability, including cardiac conduction defects, infertility, cataracts, and insulin resistance. A congenital form of DM type 1 is associated with an apparent developmental disability. Myotonia is characterized by impaired relaxation of muscles after voluntary contraction due to repetitive depolarization of the muscle membrane. Myotonia, due to myotonic dystrophy, improves with repeated exercise and is worsened by exposure to cold.
Myotonias are inherited disorders acquired in an autosomal dominant fashion. Both DM1 and DM2 are caused by an expansion of DNA tandem repeats, which results in an RNA gain of function mutation. DM1 is caused by expansion of cytosine-thymine-guanine (CTG) repeat in the 3’-untranslated region of the DM1 protein kinase (DMPK) gene on chromosome 19q13.3. DM2 results from the expansion of cytosine-cytosine-thymine-guanine (CCTG) tetranucleotide repeat located in the intron of the CCHC-type zinc finger nucleic acid-binding protein (CNB or ZNF9) gene on chromosome 3q21.3.
The pathophysiology of DMI is related to the number of CTG repeats, with more repeats correlating with more severe disease. Those with less than 35 repeats are considered normal, and those that manifest with clinical symptoms typically have greater than 50. Maternal transmissions will often result in greater CTG expansion. Additionally, the newly expanded alleles have a bias for further expansions that leads to the genetic phenomenon of anticipation when transmitted from one generation to the next. The symptoms manifest at an earlier age with each successive generation due to this phenomenon. Secondly, new alleles with varied repeat sizes are continuously generated in non-dividing cells of skeletal muscle, heart, and brain. Skeletal muscles typically have more than 2,000 expansion repeats by age 20 and 4,000 by age 40, and a proposed mechanism of symptom progression is related to the age-dependent growth of the CTG repeats. In DM2, 75 or longer repeats are considered pathogenic. Unlike DM1, in DM2, there is no clear correlation between the length of the CCTG expansion and clinical severity. However, similar to DM1, CTG repeats continue with age.
Muscle biopsy demonstrates irregularity in muscle fiber size, rows of internal nuclei, muscle fibrosis, and myofibril orientation that is perpendicular to the muscle fiber. Type I fiber atrophy can be seen along with increased intrafusal fibers.
Myotonic dystrophy has a spectrum of clinical history and presentation, based on the number of CTG repeats present in the individual. This is a multisystem disorder that affects somatic and smooth muscles, and ophthalmological, cardiovascular, endocrine, and central nervous systems as well. It can range in presentation from lethal in infancy to being mild with the first presentation in late adulthood. DM1 is classically divided into three types: (1) congenital, (2) mild, and (3) classic. There is an additional subtype that typically presents in childhood, around the age of 10 as well. DM2 is a milder form than classic DM1.
Congenital Myotonic Dystrophy (CDM)
The congenital form presents in about 15% of cases, with fetal-onset involvement of muscle and the CNS and typically is seen in those with more than 1,000 repeats. Prenatal manifestations of CDM may include reductions in fetal movement and polyhydramnios. Additionally, equinovarus and ventriculomegaly can be appreciated on fetal ultrasound. The neonatal mortality rate is around 18%. Those who survive into childhood or adulthood typically exhibit a characteristic tented appearance of the upper lip that results from facial diplegia.  Other features include marked dysarthria and expressive aphasia. Hypotonia, rather than myotonia, is a hallmark of congenital DMI since myotonia or electrical myotonia are seldom present in the first year of life. Thus respiratory involvement is frequently seen and is the principal cause of death during this period.
Mild Myotonic Dystrophy
The mild form of DM1 or the oligosymptomatic form is associated with mild weakness, myotonia, and cataracts that begin between 20 to 70 years (typically after age 40 years). These patients usually have normal lifespans, and their CTG repeat size ranges between 50 and 150.
Classic Myotonic Dystrophy
The classic form of DM1 usually manifests during 2, 3, or 4 decades of life. Myotonia is the primary initial symptom. It is characterized by a “warm-up phenomenon” upon examination where it appears more pronounced after rest and improves with muscle activity. Distal muscle weakness is the predominant symptom in classic DM1. This leads to impairment of fine motor tasks involving the hands and impaired gait due to foot drop. The classic form also presents with the characteristic “myopathic face” or “hatchet face” due to weakness and wasting of the facial, levator palpebrae, and masticatory muscles. As opposed to DM2, hearing loss is not frequently encountered. Cardiac conduction abnormalities are often seen. Lifespan is reduced compared to average.
Childhood Myotonic Dystrophy
The childhood (infantile) subset of DM1 typically presents around age 10. It might even be undiagnosed due to a lack of neurological symptoms unless there is a prior positive family history of DM. Initial symptoms include learning difficulties and psychosocial problems. Dysarthria and hand muscle myotonia may be prominent features and might exacerbate learning difficulties. Cardiac conduction abnormalities may be diagnosed as early as age 10.
Myotonic Dystrophy Type II
DM2 typically manifests in adulthood (median age 48 years) and has a variable presentation. Some physical examination findings include early-onset cataracts (younger than 50 years), varying grip myotonia, proximal muscle weakness or stiffness, hearing loss, and myofascial pain. Weakness and/or myalgias are the most common initial presenting symptom and are seen in 50% of patients. DM2 presents mostly with axial and proximal muscle weakness that affects the neck flexors, long finger flexors, hip flexors, and hip extensors in contrast to DM1 that typically manifests as distal muscle weakness. Pain is one of the primary complaints in DM2 and is described as abdominal, musculoskeletal, and exercise-related pain. It typically fluctuates and is sometimes misdiagnosed as fibromyalgia.
Myotonic dystrophy should be suspected in patients with symptoms of weakness, a suspected family history DM, and characteristic physical exam findings. Genetic testing for CTG repeats has replaced other modalities in the diagnosis of DM. Other diagnostic testing modalities may often be obtained prior to genetic testing and involves serum creatinine kinase, hepatobiliary function testing, muscle biopsies, and electrocardiographic findings for cardiomyopathy.
Genetic testing is performed to reveal the presence of an expanded CTG repeat in the dystrophia myotonica protein kinase (DMPK) gene and establish a definitive diagnosis. Alleles containing 5 to 34 CTG repeats are normal, and between 35 and 50 are mutable normal alleles (permutation alleles). Demonstrating full penetrance alleles of greater than 50 CTG repeats confirms the diagnosis associated with clinical manifestations. If this testing is negative and clinical suspicion is high, genetic testing specific for CCTG repeat in the ZNF9 (CNBP- Cellular nucleic acid-binding protein) gene should be pursued. CCTG repeats over 75 is typical for clinical manifestation of DM2.
Serum Creatine Kinase
In patients with mild disease, it may be mildly elevated but is typically normal.
Elevations in the hepatobiliary enzymes alkaline phosphatase, gamma-glutamyl transferase (GGT), serum aspartate aminotransferase, and serum alanine aminotransferase can be seen in 30% to 50% of patients. Elevations do not correlate with the severity of muscle weakness, disease duration, or serum levels of creatine kinase.
Electrodiagnostic (EDX) testing has been the modality of choice for diagnosis prior to molecular testing. It has the capability to diagnose patients who are clinically asymptomatic or have subtle findings. Motor nerve conduction studies (NCS) show decreased amplitude with normal latency and normal conduction velocities. Sensory nerve conduction studies are typically normal. Electromyography (EMG) typically has normal insertional activity. Early recruitment with short duration and small amplitudes motor unit potentials are observed. Myotonic discharges are highly specific and consist of spontaneous discharges that have a waxing and waning of amplitude and frequency, typically from around 150/second to 20/second. It is shown that evaluating distal muscles is more sensitive for detecting myotonic discharges than proximal muscles.
Overview of Electrodiagnostic Findings of Myotonia
Muscle biopsy typically reveals a morphological picture of a myopathy. The majority of biopsy findings are seen in proximal muscle groups, most notably in the biceps brachii and tibialis anterior muscles. Type I fiber atrophy can be seen in early disease, along with type II fiber hypertrophy. Additional findings include irregularity in muscle fiber size, rows of internal nuclei, muscle fibrosis, and myofibril orientation that is perpendicular to the muscle fiber.
There is no curative treatment for DM. Thus, maximizing health and functional independence is the goal of supportive management. This is geared towards monitoring and treating all the medical issues associated with DM.
Cardiovascular: Cardiac monitoring with a 12-lead electrocardiogram should be performed in all patients once diagnosed with DM and annually to monitor cardiac conduction disturbances. Baseline cardiac imaging should be performed and serially every 1 to 5 years thereafter.
Pulmonary: Obtaining a baseline and serial pulmonary function testing to monitor for neuromuscular respiratory failure.
Daytime somnolence and obstructive sleep apnea: Evaluate for sleep apnea and prescribe continuous positive airway pressure (CPAP) if required. Neurostimulants such as methylphenidate can be considered for excessive sleepiness.
Ocular involvement: Annual eye exam that includes slit-lamp examination is recommended annually. Surgical removal of cataracts that impair vision and function.
Obstetrics and gynecology care: A high-risk obstetrics evaluation is indicated for patients who are pregnant or considering pregnancy due to the risk of miscarriage, preterm delivery, and respiratory difficulties during pregnancy.
Endocrine issues: These patients are at increased risk of diabetes mellitus from insulin resistance; thus, a baseline and annual fasting blood glucose and hemoglobin A1C are recommended. Screening for hypothyroidism is also required. Since primary hypogonadism and erectile dysfunction are commonly seen in men with DM1, questioning about erectile dysfunction is suggested and accordingly treated if low testosterone is detected on further testing.
Myotonia: Medications that reduce sustained myotonia are used and include sodium channel blockers such as mexiletine, tricyclic antidepressants, benzodiazepines, or calcium antagonists. Sodium channel blockers are contraindicated in those with second and third-degree heart block.
Physical and occupational therapy is recommended for strengthening weakened muscles, evaluation for orthotics, and durable medical equipment needs. Speech-language pathology (SLP) is required for dysphagia and swallowing studies or dysarthria as indicated. SLP is also utilized for intellectual disabilities and learning strategies.
This is a rare condition caused by a loss of function mutation of the heparan sulfate proteoglycan 2 gene (HSPG2). Unlike DM, there is no warm-up phenomenon of the myotonia. Additionally, during nerve conduction studies, the myotonic discharges lack the waxing and waning in amplitude and frequency.
Hyperkalemic Periodic Paralysis (HPP)
HPP is an autosomal dominant muscle sodium channelopathy that is illustrated by episodic attacks of muscle weakness. It is due to a mutation of the SCN4A protein of skeletal muscle sodium channels located on chromosome 17q23. The attacks characteristically manifest during the first decade of life and typically last less than one hour. Skipping meals, foods with high potassium content, cold temperatures, or resting post-exercise can exacerbate the attacks. Administering 2 to 10 g of potassium under supervision can be done while performing serial strength examinations every 10 to 20 minutes, which should elicit an attack of weakness.
Paramyotonia Congenita (PC)
PC presents with paradoxical myotonia, which is made worse by repetitive muscle contractions and exercise. It also demonstrates increased myotonia with decreased muscle temperature. The etiology is due to mutations in the sodium voltage-gated channel alpha subunit 4 gene (SCN4A). PC typically presents during the first decade of life and commonly affects the facial and upper extremities muscles, with the lower extremities less affected.
Myotonia congenita is an inheritable disorder of the chloride voltage-gated channel 1 gene (CLCN1) on chromosome 7q35, which encodes the chloride channel within human skeletal muscle. It has an autosomal recessive (Becker disease) and autosomal dominant (Thomsen disease) inheritance pattern. The autosomal form tends to be more severe.
Conditions with Electrical Myotonia without Clinical Myotonia
The prognosis of myotonic dystrophy correlates with the age of onset and the size of expansion of CTG repeats. Earlier age of onset of symptoms and a greater number of CTG repeats are linked with poorer functional outcomes and reduced survival rates. Up to 50% of individuals with DM1 tend to be partially or wheelchair dependent prior to death. Those with DM2 have a milder course and are typically independent of durable medical equipment or assistive devices for mobility. The leading cause of mortality in DM is neuromuscular-associated respiratory failure, followed by cardiovascular complications.
The CTG expansions of DM affect multiple organ systems in addition to the musculoskeletal system and is associated with several complications.
Central Nervous System
Neurology and Physical Medicine and Rehabilitation
High-Risk Obstetrics and Gynecology
Physical, Occupational Therapy, and Speech-Language Pathology (SLP)
Patients should be educated on the importance of maintaining strength and coping strategies to mitigate myotonic episodes. Education should also be performed to counsel individuals with DM on fertility strategies (if male) and the inheritance pattern of DM for those wishing to have children.
The optimal management of patients with myotonic dystrophy requires an interprofessional approach. Members of the team should include a primary care provider or pediatrician if onset is before 18 years of age, a neurologist, and a physiatrist. Supplementary medical providers may include a cardiologist or ophthalmologist for associated cardiac arrhythmias or early-onset cataracts, respectively. Appropriate consultants should be involved whenever necessary to manage and treat these patients optimally. Other team members include physical therapists, occupational therapists, and speech-language pathologists to optimize function and assist with durable medical equipment evaluation. For pediatric patients, providing a structured and educational environment that is adapted to the intellectual disability with home health service staff well versed in neuroscience and rehabilitation is necessary. Unfortunately, at this time, there is no cure for DM, and treatment is aimed at monitoring and treating associated conditions while maximizing functional independence. Consensus-based care recommendations for adults with myotonic dystrophy type 1 and 2 should be followed to reduce morbidity and mortality. [Level 5]
|||Hahn C,Salajegheh MK, Myotonic disorders: A review article. Iranian journal of neurology. 2016 Jan 5; [PubMed PMID: 27141276]|
|||Brook JD,McCurrach ME,Harley HG,Buckler AJ,Church D,Aburatani H,Hunter K,Stanton VP,Thirion JP,Hudson T, Molecular basis of myotonic dystrophy: expansion of a trinucleotide (CTG) repeat at the 3' end of a transcript encoding a protein kinase family member. Cell. 1992 Feb 21; [PubMed PMID: 1310900]|
|||Ranum LP,Rasmussen PF,Benzow KA,Koob MD,Day JW, Genetic mapping of a second myotonic dystrophy locus. Nature genetics. 1998 Jun; [PubMed PMID: 9620781]|
|||Thornton CA, Myotonic dystrophy. Neurologic clinics. 2014 Aug; [PubMed PMID: 25037086]|
|||Mahadevan M,Tsilfidis C,Sabourin L,Shutler G,Amemiya C,Jansen G,Neville C,Narang M,Barceló J,O'Hoy K, Myotonic dystrophy mutation: an unstable CTG repeat in the 3' untranslated region of the gene. Science (New York, N.Y.). 1992 Mar 6; [PubMed PMID: 1546325]|
|||Turner C,Hilton-Jones D, The myotonic dystrophies: diagnosis and management. Journal of neurology, neurosurgery, and psychiatry. 2010 Apr; [PubMed PMID: 20176601]|
|||Yotova V,Labuda D,Zietkiewicz E,Gehl D,Lovell A,Lefebvre JF,Bourgeois S,Lemieux-Blanchard E,Labuda M,Vézina H,Houde L,Tremblay M,Toupance B,Heyer E,Hudson TJ,Laberge C, Anatomy of a founder effect: myotonic dystrophy in Northeastern Quebec. Human genetics. 2005 Jul; [PubMed PMID: 15883838]|
|||Schoser B,Montagnese F,Bassez G,Fossati B,Gamez J,Heatwole C,Hilbert J,Kornblum C,Kostera-Pruszczyk A,Krahe R,Lusakowska A,Meola G,Moxley R 3rd,Thornton C,Udd B,Formaker P, Consensus-based care recommendations for adults with myotonic dystrophy type 2. Neurology. Clinical practice. 2019 Aug; [PubMed PMID: 31583190]|
|||Zaki M,Boyd PA,Impey L,Roberts A,Chamberlain P, Congenital myotonic dystrophy: prenatal ultrasound findings and pregnancy outcome. Ultrasound in obstetrics [PubMed PMID: 17238150]|
|||Echenne B,Bassez G, Congenital and infantile myotonic dystrophy. Handbook of clinical neurology. 2013 [PubMed PMID: 23622362]|
|||Logigian EL,Blood CL,Dilek N,Martens WB,Moxley RT 4th,Wiegner AW,Thornton CA,Moxley RT 3rd, Quantitative analysis of the [PubMed PMID: 15880468]|
|||Wenninger S,Montagnese F,Schoser B, Core Clinical Phenotypes in Myotonic Dystrophies. Frontiers in neurology. 2018; [PubMed PMID: 29770119]|
|||Callus E,Bertoldo EG,Beretta M,Boveri S,Cardani R,Fossati B,Brigonzi E,Meola G, Neuropsychological and Psychological Functioning Aspects in Myotonic Dystrophy Type 1 Patients in Italy. Frontiers in neurology. 2018; [PubMed PMID: 30298045]|
|||Meola G,Cardani R, Myotonic Dystrophy Type 2: An Update on Clinical Aspects, Genetic and Pathomolecular Mechanism. Journal of neuromuscular diseases. 2015 Jul 22; [PubMed PMID: 27858759]|
|||Ricker K,Koch MC,Lehmann-Horn F,Pongratz D,Otto M,Heine R,Moxley RT 3rd, Proximal myotonic myopathy: a new dominant disorder with myotonia, muscle weakness, and cataracts. Neurology. 1994 Aug; [PubMed PMID: 8058147]|
|||Auvinen S,Suominen T,Hannonen P,Bachinski LL,Krahe R,Udd B, Myotonic dystrophy type 2 found in two of sixty-three persons diagnosed as having fibromyalgia. Arthritis and rheumatism. 2008 Nov [PubMed PMID: 18975316]|
|||Schoser B, Myotonic Dystrophy Type 2 . 1993 [PubMed PMID: 20301639]|
|||Achiron A,Barak Y,Magal N,Shohat M,Cohen M,Barar R,Gadoth N, Abnormal liver test results in myotonic dystrophy. Journal of clinical gastroenterology. 1998 Jun; [PubMed PMID: 9649014]|
|||Khoshbakht R,Soltanzadeh A,Zamani B,Abdi S,Gharagozli K,Kahrizi K,Khoshbakht R,Nafissi S, Correlation between distribution of muscle weakness, electrophysiological findings and CTG expansion in myotonic dystrophy. Journal of clinical neuroscience : official journal of the Neurosurgical Society of Australasia. 2014 Jul; [PubMed PMID: 24417793]|
|||Nojszewska M,Lusakowska A,Gawel M,Sierdzinski J,Sulek A,Krysa W,Elert-Dobkowska E,Seroka A,Kaminska AM,Kostera-Pruszczyk A, The needle EMG findings in myotonia congenita. Journal of electromyography and kinesiology : official journal of the International Society of Electrophysiological Kinesiology. 2019 Dec; [PubMed PMID: 31610484]|
|||Burakgazi AZ, Electrodiagnostic findings in myotonic dystrophy: A study on 12 patients. Neurology international. 2019 Nov 29; [PubMed PMID: 31871599]|
|||Pongratz D,Schultz D,Koppenwallner C,Hübner G, [Diagnostic value of muscle biopsy findings in myotonic dystrophy (Curschmann-Steinert) (author's transl)]. Klinische Wochenschrift. 1979 Mar 1; [PubMed PMID: 431031]|
|||McNally EM,Mann DL,Pinto Y,Bhakta D,Tomaselli G,Nazarian S,Groh WJ,Tamura T,Duboc D,Itoh H,Hellerstein L,Mammen PPA, Clinical Care Recommendations for Cardiologists Treating Adults With Myotonic Dystrophy. Journal of the American Heart Association. 2020 Feb 18; [PubMed PMID: 32067592]|
|||Ashizawa T,Gagnon C,Groh WJ,Gutmann L,Johnson NE,Meola G,Moxley R 3rd,Pandya S,Rogers MT,Simpson E,Angeard N,Bassez G,Berggren KN,Bhakta D,Bozzali M,Broderick A,Byrne JLB,Campbell C,Cup E,Day JW,De Mattia E,Duboc D,Duong T,Eichinger K,Ekstrom AB,van Engelen B,Esparis B,Eymard B,Ferschl M,Gadalla SM,Gallais B,Goodglick T,Heatwole C,Hilbert J,Holland V,Kierkegaard M,Koopman WJ,Lane K,Maas D,Mankodi A,Mathews KD,Monckton DG,Moser D,Nazarian S,Nguyen L,Nopoulos P,Petty R,Phetteplace J,Puymirat J,Raman S,Richer L,Roma E,Sampson J,Sansone V,Schoser B,Sterling L,Statland J,Subramony SH,Tian C,Trujillo C,Tomaselli G,Turner C,Venance S,Verma A,White M,Winblad S, Consensus-based care recommendations for adults with myotonic dystrophy type 1. Neurology. Clinical practice. 2018 Dec; [PubMed PMID: 30588381]|
|||Arikawa-Hirasawa E,Le AH,Nishino I,Nonaka I,Ho NC,Francomano CA,Govindraj P,Hassell JR,Devaney JM,Spranger J,Stevenson RE,Iannaccone S,Dalakas MC,Yamada Y, Structural and functional mutations of the perlecan gene cause Schwartz-Jampel syndrome, with myotonic myopathy and chondrodysplasia. American journal of human genetics. 2002 May; [PubMed PMID: 11941538]|
|||Charles G,Zheng C,Lehmann-Horn F,Jurkat-Rott K,Levitt J, Characterization of hyperkalemic periodic paralysis: a survey of genetically diagnosed individuals. Journal of neurology. 2013 Oct; [PubMed PMID: 23884711]|
|||Miller TM, Differential diagnosis of myotonic disorders. Muscle [PubMed PMID: 18067134]|
|||Burke D,Skuse NF,Lethlean AK, An analysis of myotonia in paramyotonia congenita. Journal of neurology, neurosurgery, and psychiatry. 1974 Aug; [PubMed PMID: 4422263]|
|||Ørstavik K,Wallace SC,Torbergsen T,Abicht A,Erik Tangsrud S,Kerty E,Rasmussen M, A de novo Mutation in the SCN4A Gene Causing Sodium Channel Myotonia. Journal of neuromuscular diseases. 2015 Jun 4; [PubMed PMID: 27858731]|
|||Liu XL,Huang XJ,Shen JY,Zhou HY,Luan XH,Wang T,Chen SD,Wang Y,Tang HD,Cao L, Myotonia congenita: novel mutations in CLCN1 gene. Channels (Austin, Tex.). 2015; [PubMed PMID: 26260254]|
|||Groh WJ,Groh MR,Shen C,Monckton DG,Bodkin CL,Pascuzzi RM, Survival and CTG repeat expansion in adults with myotonic dystrophy type 1. Muscle [PubMed PMID: 21484823]|
|||de Die-Smulders CE,Höweler CJ,Thijs C,Mirandolle JF,Anten HB,Smeets HJ,Chandler KE,Geraedts JP, Age and causes of death in adult-onset myotonic dystrophy. Brain : a journal of neurology. 1998 Aug; [PubMed PMID: 9712016]|
|||Benhayon D,Lugo R,Patel R,Carballeira L,Elman L,Cooper JM, Long-term arrhythmia follow-up of patients with myotonic dystrophy. Journal of cardiovascular electrophysiology. 2015 Mar; [PubMed PMID: 25546341]|
|||Chaudhry SP,Frishman WH, Myotonic dystrophies and the heart. Cardiology in review. 2012 Jan-Feb; [PubMed PMID: 22143278]|
|||Petri H,Ahtarovski KA,Vejlstrup N,Vissing J,Witting N,Køber L,Bundgaard H, Myocardial fibrosis in patients with myotonic dystrophy type 1: a cardiovascular magnetic resonance study. Journal of cardiovascular magnetic resonance : official journal of the Society for Cardiovascular Magnetic Resonance. 2014 Aug 1; [PubMed PMID: 25086734]|
|||Gupta N,N Saxena K,Kumar Panda A,Anand R,Mishra A, Myotonic dystrophy: an anaesthetic dilemma. Indian journal of anaesthesia. 2009 Dec; [PubMed PMID: 20640098]|
|||Wang Y,Pfeiffer RM,Alsaggaf R,Meeraus W,Gage JC,Anderson LA,Bremer RC,Nikolenko N,Lochmuller H,Greene MH,Gadalla SM, Risk of skin cancer among patients with myotonic dystrophy type 1 based on primary care physician data from the U.K. Clinical Practice Research Datalink. International journal of cancer. 2018 Mar 15; [PubMed PMID: 29114849]|