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While 44-83% of children with steroid-resistant nephrotic syndrome (SRNS) without a proven genetic cause respond to treatment with a calcineurin inhibitor (CNI), current guidelines recommend against the use of immunosuppression in monogenic SRNS. This is despite existing evidence suggesting that remission with CNI treatment is possible and can improve prognosis in some cases of monogenic SRNS. Herein, our retrospective study assessed response frequency, predictors of response and kidney function outcomes among children with monogenic SRNS treated with a CNI for at least three months. Data from 203 cases (age 0-18 years) were collected from 37 pediatric nephrology centers. Variant pathogenicity was reviewed by a geneticist, and 122 patients with a pathogenic and 19 with a possible pathogenic genotype were included in the analysis. After six months of treatment and at last visit, 27.6% and 22.5% of all patients respectively, demonstrated partial or full response. Achievement of at least partial response at six months of treatment conferred a significant reduction in kidney failure risk at last follow-up compared to no response (hazard ratio [95% confidence interval] 0.25, [0.10-0.62]). Moreover, risk of kidney failure was significantly lower when only those with a follow-up longer than two years were considered (hazard ratio 0.35, [0.14-0.91]). Higher serum albumin level at CNI initiation was the only factor related to increased likelihood of significant remission at six months (odds ratio [95% confidence interval] 1.16, [1.08-1.24]). Thus, our findings justify a treatment trial with a CNI also in children with monogenic SRNS., (Copyright © 2023 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Background: The Treatment of Brain Arteriovenous Malformations Study (TOBAS) is an all-inclusive pragmatic study comprising 2 randomized clinical trials (RCTs). Patients excluded from the RCTs are followed in parallel treatment and observation registries, allowing a comparison between RCT and registry patients., Methods: The first randomized clinical trial (RCT-1) offers 1:1 randomized allocation of intervention versus conservative management for patients with arteriovenous malformation (AVM). The second randomized clinical trial (RCT-2) allocates 1:1 pre-embolization or no pre-embolization to surgery or radiosurgery patients judged treatable with or without embolization. Characteristics of RCT patients are reported and compared to registry patients., Results: From June 2014 to May 2021, 1010 patients with AVM were recruited; 498 patients were observed and 373 were included in the treatment registries. Randomized allocation in RCT-1 was applied to 139 (26%) of the 512 patients (including 127 of 222 [57%] with unruptured AVMs) considered for curative treatment. RCT-1 AVM patients differed (in rupture status, Spetzler-Martin grade and baseline modified Rankin Score) from those in the observation or treatment registries (P < 0.001). Most patients had small (<3 cm; 71%) low-grade (Spetzler-Martin I-II; 64%) unruptured (91%) AVMs. The allocated management was conservative (n = 71) or curative (n = 68), using surgery (n = 39), embolization (n = 16), or stereotactic radiosurgery (n = 13). Pre-embolization was considered for 179/309 (58%) patients allocated/assigned to surgery or stereotactic radiosurgery; 87/179 (49%) were included in RCT-2. RCT-2 patient AVMs differed in size, eloquence and grade from patients of the pre-embolization registry (P < 0.01). Most had small (<3 cm in 82%) low-grade (83%) AVMs in non-eloquent brain (64%)., Conclusions: Patients included in the RCTs differ significantly from registry patients. Meaningful results can be obtained if multiple centers actively participate in the TOBAS RCTs., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Introduction: Clinically distinguishing patients with the inherited salt-losing tubulopathies (SLTs), Gitelman or Bartter syndrome (GS or BS) from other causes of hypokalemia (LK) patients is difficult, and genotyping is costly. We decided to identify clinical characteristics that differentiate SLTs from LK., Methods: A total of 66 hypokalemic patients with possible SLTs were recruited to a prospective observational cohort study at the University College London Renal Tubular Clinic, London. All patients were genotyped for pathogenic variants in genes which cause SLTs; 39 patients had pathogenic variants in genes causing SLTs. We obtained similar data sets from cohorts in Taipei and Kobe, as follows: the combined data set comprised 419 patients; 291 had genetically confirmed SLT. London and Taipei data sets were combined to train machine learning (ML) algorithms, which were then tested on the Kobe data set., Results: Single biochemical variables (e.g., plasma renin) were significantly, but inconsistently, different between SLTs and LK in all cohorts. A decision table algorithm using serum bicarbonate and urinary sodium excretion (FE Na ) achieved a classification accuracy of 74%. This was superior to all the single biochemical variables identified previously., Conclusion: ML algorithms can differentiate true SLT in the context of a specialist clinic with some accuracy. However, based on routine biochemistry, the accuracy is insufficient to make genotyping redundant., (© 2022 International Society of Nephrology. Published by Elsevier Inc.)

Objectives: The Comprehensive Aneurysm Management (CAM) study is a pragmatic trial designed to manage unruptured intracranial aneurysm (UIA) patients within a care research framework., Methods: CAM is an all-inclusive study. Management options are allocated according to an algorithm combining pre-randomization and clinical judgment. Eligible patients are offered 1:1 randomized allocation of intervention versus conservative management and 1:1 randomization allocation of surgical versus endovascular treatment. Ineligible patients are registered. The primary outcome is survival without dependency (modified Rankin Scale score <3) at 10 years. All UIA patients at 1 center are reported., Results: Between February 2020 and July 2021, 403 UIA patients were recruited: 179 (44%) in one of the randomized controlled trials (RCTs) and 224 (56%) in one of the registries. Conservative management was recommended for 205 of 403 patients (51%); of 198 (49%) patients considered for curative treatment, 159 (80%) were randomly allocated conservative (n = 81) or curative treatment (n = 78). These patients were younger and had larger aneurysms than those in the observation registry (P = 0.004). In 39 of 198 patients (20%), conservative management was not considered reasonable (17 patients were recommended endovascular, 2 surgery, and 20 the RCT comparing endovascular with surgical treatment). In total, 70 patients were recruited in the RCT comparing surgery and endovascular treatment. After informed discussion at time of consent, 141 of 159 patients (89%) agreed with the randomly allocated management plan, while 11% crossed over to the alternative management option., Conclusions: CAM was successfully integrated into routine practice. Meaningful conclusions can be obtained if multiple centers actively participate in the trial., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: The evolution of COVID-19 is a controversial topic in cancer patients. They have been designated by international organizations as a vulnerable population at greater risk for contracting SARS-CoV-2 and having a more severe clinical outcome., Patients and Methods: Active screening at our institution became routine early in the pandemic. We have examined the clinical data of 341 cancer patients, with a positive RT-PCR SARS-CoV-2 test between April 2020 and February 2021, in the prevaccination era., Results: During the infection, 40.5% remained asymptomatic, 27.6% developed a mild form, 20.5% had a moderate form, and 11.4% a severe/critical form of COVID-19 that led to death in 7.6% of cases. Treatment was adapted to disease severity according to national guidelines. In our series, the incidence of COVID-19 infection was lower in cancer patients compared with the general population (P < 0.001), however, the mortality rate was higher in cancer patients in comparison with the general population (7.6% versus 2.9%, P < 0.001). The prognostic factors were assessed by three distinct univariate and multivariate analyses: (i) evolution to a moderate or severe/critical clinical manifestation, (ii) clinical worsening (severe/critical form or death), and (iii) overall survival. In the multivariate analysis, the prognostic factors associated with the evolution to a moderate or severe/critical clinical manifestation were: performance status (PS) (P < 0.0001) and no active treatment in the previous 3 months (P = 0.031). Factors associated with clinical worsening were: PS (P < 0.0001), peripheral arterial disease (P = 0.03), and chronic liver disease (P = 0.04). Factors associated with impaired overall survival were PS (P < 0.0001), ischemic cardiac disease (P = 0.0126), chronic liver disease (P = 0.001), and radiotherapy (P = 0.0027)., Conclusion: Our series confirms a more severe evolution for COVID-19 infection in cancer patients, with PS as the most prominent prognostic factor in all three multivariate analyses. By active screening, efforts should be in place to keep cancer units as coronavirus-free sanctuaries., Competing Interests: Disclosure ACP reports personal fees from Roche, Merck Serono, Sandoz, support for attending meetings and/or travel from Accord, Pfizer, grants from University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, outside the submitted work. TC reports personal fees from Astellas Pharma, Janssen, Merck Sharp & Dohme, Merck Serono, Amgen, Roche, Pfizer, Sanofi Genzyme, Servier, Ipsen, AstraZeneca, Lilly, Novartis, Boehringer Ingelheim, Bristol Myers Squibb, grants from University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, outside the submitted work. PK reports personal fees from Roche, Sandoz, Bristol Myers Squibb, AstraZeneca, Merck Serono, Pproevents, Astellas Pharma, support for attending meetings and/or travel from Sandoz, Elli Lilly, Roche, Boehringer Ingelheim, grants from University of Medicine and Pharmacy Iuliu Hatieganu Cluj-Napoca, Romanian National Authority for Scientific Research, COST Association, outside the submitted work. CM reports support for attending meetings and/or travel from Roche, Pfizer, Accord, outside the submitted work. MBV reports support for attending meetings and/or travel from Roche, Pfizer, Accord, Servier, outside the submitted work. CV reports grants from the Romanian National Authority for Scientific Research, COST Association, outside the submitted work. All other authors have declared no conflicts of interest., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Whether the best management of middle cerebral artery (MCA) aneurysm patients is surgical or endovascular remains uncertain, with little evidence to guide decision-making. A randomized care trial offering MCA aneurysm patients a 50% chance of surgical and a 50% chance of endovascular management may optimize outcomes in the presence of uncertainty., Methods: The Middle Cerebral Artery Aneurysm Trial (MCAAT) is an investigator-initiated, multicenter, parallel group, prospective, 1:1 randomized controlled clinical trial. All adult patients with MCA aneurysms, ruptured or unruptured, amenable to surgical and endovascular treatment can be included. The composite primary outcome is "Treatment Success": (i) occlusion or exclusion of the aneurysm using the allocated treatment modality; (ii) no intracranial hemorrhage during follow-up; (iii) no retreatment of the target aneurysm during follow-up, (iv) no residual aneurysm on angiographic follow-up; and (v) independence (mRS <3) at 1 year. The trial tests 2 versions of the same hypothesis (one for ruptured and one for unruptured MCA aneurysm patients): Surgical management will lead to a 15% absolute increase in the proportion of patients reaching Treatment Success from 55% to 70% (ruptured) or from 75% to 90% (unruptured aneurysm patients) compared with endovascular treatment (any method). In this pragmatic trial, outcome evaluations are by treating physicians, except for 1-year angiographic results which will be core lab assessed. The trial will be monitored by an independent data safety monitoring committee to assure safety of participants. MCAAT is registered at clinicaltrials.gov: NCT05161377., Conclusions: Patients with MCA aneurysms can be optimally managed within a care trial protocol., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objective: There are few randomized data comparing clipping and coiling for middle cerebral artery (MCA) aneurysms. We analyzed results from patients with MCA aneurysms enrolled in the CURES (Collaborative UnRuptured Endovascular vs. Surgery) and ISAT-2 (International Subarachnoid Aneurysm Trial II) randomized trials., Methods: Both trials are investigator-led parallel-group 1:1 randomized studies. CURES includes patients with 3-mm to 25-mm unruptured intracranial aneurysms (UIAs), and ISAT-2 includes patients with ruptured aneurysms (RA) for whom uncertainty remains after ISAT. The primary outcome measure of CURES is treatment failure: 1) failure to treat the aneurysm, 2) intracranial hemorrhage during follow-up, or 3) residual aneurysm at 1 year. The primary outcome of ISAT-2 is death or dependency (modified Rankin Scale score >2) at 1 year. One-year angiographic outcomes are systematically recorded., Results: There were 100 unruptured and 71 ruptured MCA aneurysms. In CURES, 90 patients with UIA have been treated and 10 await treatment. Surgical and endovascular management of unruptured MCA aneurysms led to treatment failure in 3/42 (7%; 95% confidence interval [CI], 0.02-0.19) for clipping and 13/48 (27%; 95% CI, 0.17-0.41) for coiling (P = 0.025). All 71 patients with RA have been treated. In ISAT-2, patients with ruptured MCA aneurysms managed surgically had died or were dependent (modified Rankin Scale score >2) in 7/38 (18%; 95% CI, 0.09-0.33) cases, and 8/33 (24%; 95% CI, 0.13-0.41) for endovascular. One-year imaging results were available in 80 patients with UIA and 62 with RA. Complete aneurysm occlusion was found in 30/40 (75%; 95% CI, 0.60-0.86) patients with UIA allocated clipping, and 14/40 (35%; 95% CI, 0.22-0.50) patients with UIA allocated coiling. Complete aneurysm occlusion was found in 24/34 (71%; 95% CI, 0.54-0.83) patients with RA allocated clipping, and 15/28 (54%; 95% CI, 0.36-0.70) patients with RA allocated coiling., Conclusions: Randomized data from 2 trials show that better efficacy may be obtained with surgical management of patients with MCA aneurysms., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Background: In the absence of randomized evidence, the optimal management of patients with unruptured intracranial aneurysms (UIA) remains uncertain., Methods: Comprehensive Aneurysm Management (CAM) is an all-inclusive care trial combined with a registry. Any patient with a UIA (no history of intracranial hemorrhage within the previous 30 days) can be recruited, and treatment allocation will follow an algorithm combining clinical judgment and randomization. Patients eligible for at least 2 management options will be randomly allocated 1:1 to conservative or curative treatment. Minimization will be used to balance risk factors, using aneurysm size (≥7 mm), location (anterior or posterior circulation), and age <60 years., Results: The CAM primary outcome is survival without neurologic dependency (modified Rankin Scale [mRS] score <3) at 10 years. Secondary outcome measures include the incidence of subarachnoid hemorrhage during follow-up and related morbidity and mortality; morbidity and mortality related to endovascular treatment or surgical treatment of the UIA at 1 year; overall morbidity and mortality at 1, 5, and 10 years; when relevant, duration of hospitalization; and, when relevant, discharge to a location other than home. The primary hypothesis for patients randomly allocated to at least 2 options, 1 of which is conservative management, is that active UIA treatment will reduce the 10-year combined neurologic morbidity and mortality (mRS score >2) from 24% to 16%. At least 961 patients recruited from at least 20 centers over 4 years will be needed for the randomized portion of the study., Conclusions: Patients with unruptured intracranial aneurysms can be comprehensively managed within the context of an all-inclusive care trial., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Background: Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke., Methods: For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018., Findings: Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups., Interpretation: Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo., Funding: Canadian Institutes for Health Research, Alberta Innovates, and NoNO., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Hereditary tubulopathies are rare diseases with unknown prevalence in adults. Often diagnosed in childhood, hereditary tubulopathies can nevertheless be evoked in adults. Precise diagnosis can be difficult or delayed due to insidious development of symptoms, comorbidities and polypharmacy. Here we evaluated the diagnostic value of a specific panel of known genes implicated in tubulopathies in adult patients and compared to our data obtained in children. To do this we analyzed 1033 non-related adult patients of which 744 had a clinical diagnosis of tubulopathy and 289 had a diagnosis of familial hypercalcemia with hypocalciuria recruited by three European reference centers. Three-quarters of our tubulopathies cohort included individuals with clinical suspicion of Gitelman syndrome, kidney hypophosphatemia and kidney tubular acidosis. We detected pathogenic variants in 26 different genes confirming a genetic diagnosis of tubulopathy in 29% of cases. In 16 cases (2.1%) the genetic testing changed the clinical diagnosis. The diagnosis of familial hypercalcemia with hypocalciuria was confirmed in 12% of cases. Thus, our work demonstrates the genetic origin of tubulopathies in one out of three adult patients, half of the rate observed in children. Hence, establishing a precise diagnosis is crucial for patients, in order to guide care, to survey and prevent chronic complications, and for genetic counselling. At the same time, this work enhances our understanding of complex phenotypes and enriches the database with the causal variants described., (Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.)

Enamel renal syndrome (ERS) is a rare autosomal recessive disorder not fully characterized. Here we investigated ERS characteristics in 11 patients from 5 Brazilian families through clinical examination, imaging, renal ultrasonography, laboratory tests and DNA sequencing. The patients' age ranged from 6 to 25 years-old, and the presence of hypoplastic amelogenesis imperfecta, microdontia, intra-pulpal calcification, impacted posterior teeth with hyperplastic pericoronal follicles, gingival fibromatosis, ectopic calcifications on gingival and pericoronal tissues, and nephrocalcinosis were common findings to all patients. Only 4 patients showed abnormal laboratory tests (vitamin D, parathyroid hormone, phosphate, calcium). Intellectual disability and renal cysts were present in 2 patients each. Biallelic loss of function mutation in FAM20A gene, characterized by one base pair deletion in exon 11, resulting in a frameshift replacing a glutamine at codon 483 for a lysine and terminating at position 24 [NG&#95;029809.1: c.1447delG; p.(Glu483Lysfs*24)], was detected in all patients, strongly suggesting a founder effect. Our results reinforce the distinct orofacial features of ERS, which are the clue for kidney examination and genetic testing. Early diagnosis is essential to minimize the deleterious effects related to ERS. Here we report the largest series of patients with ERS in a same population, and describe, for the first time, a founder mutation for FAM20A., (Copyright © 2018 Elsevier Masson SAS. All rights reserved.)

The clinical diagnosis of inherited renal tubulopathies can be challenging as they are rare and characterized by significant phenotypic variability. Advances in sequencing technologies facilitate the establishment of a molecular diagnosis. Therefore, we determined the diagnostic yield of a next generation sequencing panel assessing relevant disease genes in children followed through three national networks with a clinical diagnosis of a renal tubulopathy. DNA was amplified with a kit provided by the European Consortium for High-Throughput Research in Rare Kidney Diseases with nine multiplex PCR reactions. This kit produced 571 amplicons covering 37 genes associated with tubulopathies followed by massive parallel sequencing and bioinformatic interpretation. Identified mutations were confirmed by Sanger sequencing. Overall, 384 index patients and 16 siblings were assessed. Most common clinical diagnoses were 174 patients with Bartter/Gitelman syndrome and 76 with distal renal tubular acidosis. A total of 269 different variants were identified in 27 genes, of which 95 variants were considered likely, 136 definitely pathogenic and 100 had not been described at annotation. These mutations established a genetic diagnosis in 245 of the index patients. Genetic testing changed the clinical diagnosis in 16 cases and provided insights into the phenotypic spectrum of the respective disorders. Our results demonstrate a high diagnostic yield of genetic testing in children with a clinical diagnosis of a renal tubulopathy, consistent with a predominantly genetic etiology in known disease genes. Thus, genetic testing helped establish a definitive diagnosis in almost two-thirds of patients thereby informing prognosis, management and genetic counseling., (Copyright © 2017 International Society of Nephrology. Published by Elsevier Inc. All rights reserved.)

Enamel-renal syndrome (OMIM #204690) is an uncommon disorder characterized by amelogenesis imperfecta and nephrocalcinosis and is caused by mutations in FAM20 A. We report 2 patients with enamel-renal syndrome who exhibited the typical features of this syndrome and a homozygous nonsense mutation in the FAM20 A gene (c.406 C>T), genetically confirming the diagnosis. They also exhibited 2 undescribed clinical features, hypertrichosis and hearing loss. Alterations in genes frequently associated with nonsyndromic hearing loss in the Brazilian population, including connexin 26 (GJB2), connexin 30 (GJB6) and mitochondrial 12 S rRNA (m.A1555 G mutation), were not found. These results suggest a putative function of FAM20 A in the development of the inner ear and in the formation of hair. The presence of nephrocalcinosis is a risk factor for renal impairment, and it is important to perform regular renal monitoring in order to avoid renal failure., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Mutations in the methyl-CpG-binding protein 2 (MECP2) gene are associated with Rett syndrome (RTT). The MECP2 gene has some unique characteristics: (1) it is mainly affected by de novo mutations, due to recurrent independent mutational events in a defined "hot spot" regions or positions; (2) complex mutational events along a single allele are frequently found in this gene; (3) most mutations arise on paternal X chromosome. The recurrent point mutations involve mainly CpG dinucleotides, where C>T transitions are explained by methylation-mediated deamination. The complex mutational events might be explained by the genomic architecture of the region involving the MECP2 gene. The finding that most spontaneous mutations arise on paternal X-chromosome supports the higher contribution of replication-mediated mechanism of mutagenesis. We present 9 types of mutations in the MECP2 gene, detected in a group of 22 Bulgarian and 6 Romanian classical RTT patients. Thirteen patients were clarified on molecular level (46.4%). The point mutations in our sample account for 61.5%. One intraexonic deletion was detected in the present study (7.7%). One novel insertion c.321&#95;322insGAAG, p.(Lys107&#95;Leu108insGluAlafs2*) was found (7.7%). Large deletions and complex mutations account for 23%. A novel complex mutational event c.[584&#95;624del41insTT; 638delTinsCA] was detected in a Romanian patient. We discuss different types of the MECP2 mutations detected in our sample in the light of the possible mechanisms of mutagenesis. Complex gene rearrangements involving a combination of deletions and insertions have always been most difficult to detect, to specify precisely and hence to explain in terms of their underlying mutational mechanisms., (Copyright © 2012 Elsevier B.V. All rights reserved.)

We present a traveling-wave analysis of a reduced mathematical model describing the growth of a solid tumor in the presence of an immune system response in the framework of Scale Relativity theory. Attention is focused upon the attack of tumor cells by tumor-infiltrating cytotoxic lymphocytes (TICLs), in a small multicellular tumor, without necrosis and at some stage prior to (tumor-induced) angiogenesis. For a particular choice of parameters, the underlying system of partial differential equations is able to simulate the well-documented phenomenon of cancer dormancy and propagation of a perturbation in the tumor cell concentration by cnoidal modes, by depicting spatially heterogeneous tumor cell distributions that are characterized by a relatively small total number of tumor cells. This behavior is consistent with several immunomorphological investigations. Moreover, the alteration of certain parameters of the model is enough to induce soliton like modes and soliton packets into the system, which in turn result in tumor invasion in the form of a standard traveling wave. In the same framework of Scale Relativity theory, a very important feature of malignant tumors also results, that even in avascular stages they might propagate and invade healthy tissues, by means of a diffusion on a Newtonian fluid., (Copyright © 2011 Elsevier Ltd. All rights reserved.)