Adolescence: The age of Proteus

This article focuses on adolescents as a group, who are exposed to major changes in their near future, with the key transformation being the epidemiological transition from the age of infectious and nutritional problems to that of the non-communicable  disorders (NCDs). The major NCDs are: obesity, diabetes, maternal, newborn and child, hypertension and mental health disorders. We also discuss allergies, exposure to pollutants, indoor open stoves, and behavioural factors, such as lack of exercise,  unhealthy diet, substance abuse, injuries and violence, and sexually transmitted  diseases, which contribute to a risky environment. We particularly emphasise the continuum from birth to old age, during which early events may produce lifelong diseases, and which requires serious attention with regard to preventive measures during the earliest period of susceptibility. Some indicators of disease can serve as diagnostic markers and help healthcare workers to avoid complications and manage a disorder efficiently

Genomic profiling of circulating tumor DNA from cerebrospinal fluid to guide clinical decision making for patients with primary and metastatic brain tumors

Despite advances in systemic therapies for solid tumors, the development of brain metastases remains a significant contributor to overall cancer mortality and requires improved methods for diagnosing and treating these lesions. Similarly, the prognosis for malignant primary brain tumors remains poor with little improvement in overall survival over the last several decades. In both primary and metastatic central nervous system (CNS) tumors, the challenge from a clinical perspective centers on detecting CNS dissemination early and understanding how CNS lesions differ from the primary tumor, in order to determine potential treatment strategies. Acquiring tissue from CNS tumors has historically been accomplished through invasive neurosurgical procedures, which restricts the number of patients to those who can safely undergo a surgical procedure, and for which such interventions will add meaningful value to the care of the patient. In this review we discuss the potential of analyzing cell free DNA shed from tumor cells that is contained within the cerebrospinal fluid (CSF) as a sensitive and minimally invasive method to detect and characterize primary and metastatic tumors in the CNS

A new combined DTP-HBV HiB vaccine- strategy for incorporation of HIB vaccination into childhood immunisation programmes

Objectives. To evaluate the immunogenicity and reactogenicity of a pentavalent vaccine prepared by extemporaneously mixing diphtheria-tetanus pertussis-hepatitis B vaccine (DTPHBV) and lyophilised Haemophilus influenzae type B (Hib)tetanus conjugate vaccines in the same syringe, compared with the same vaccines given as separate, concomitant administrations.Design. Open, randornised comparative study.Setting. Durban, South Africa.Subjects. A total of 120 healthy male and female infants were enrolled in the trial and randomised into two groups; group 1 received the combined administration (DTP-HBV-Hib), and group 2 received separate administrations of DTP-HBV and Hib vaccines. Vaccines were given as a three-dose primary vaccination course at 6,10 and 14 weeks of age.Outcome measures. Antibody levels were measured using standard techniques and local and general solicited symptoms were recorded using diary cards.Results. All subjects had seroprotective titres against diphtheria and tetanus; and antipolyribose-ribitol phosphate (PRP) titres ≥ 0.15 )μg/ ml 1 month after the final dose. A vaccine response (defined as post-vaccination titres ≥ 15 ELISA (EL).U/ ml in initially seronegative subjects; and as post- vaccination titres ≥ pre-vaccination titres in ini tially seropositive subjects) against the pertussis component was seen in 83% and 85% of subjects in the groups receiving combined and separate administration. No differences were  seen in any of the geometric mean titres (GMTs) between the two administrations either 2 months after the second dose or 1 month after the final dose. There was no observed increase in reactogenicity in the group receiving the mixed administration.Conclusions. The results demonstrate that combined DTPHBV- Hib vaccine is well tolerated and immunogeni

Immunogenicity and safety of a live attenuated varicella vaccine in healthy Indian children aged 9 - 24 months

Objectives. To investigate the safety of live attenuated varicella vaccine (aka strain) and the optimal virus titre/ dose required for immunogenicity in healthy South African children.Design. Double-blind randomised clinical study using two different lots of varicella vaccine, each at two different titres. Subjects were randomly allocated to groups 1, 2, 3 and 4 to receive vaccine containing a mean virus titre of 104,5, 103,1, 103,9 and 102,7 PFUs per dose respectively. Clinical signs and symptoms were followed up for 42 days post-vaccination. Specific varicella antibodies were measured by an indirect immunofluorescence method in sera obtained on day 0 and day 42.Setting. City Health Clinic, Chatsworth, Durban.Participants. A total of 200 healthy 9 - 24-month-old children were vaccinated, of whom 189 (44,5%) completed the study.Main outcome measures. Pre- and post-vaccination varicella antibody levels. Adverse events following varicella vaccination..Results. The vaccine was safe and well tolerated. No local symptoms were reported. Skin reactions were specifically solicited in this study: 21 reactions were reported in 8,5% (17/200) of children. Vesicles were reported in 2 vaccines (,,;: 10 vesicles in both cases). One serious adverse event was reported: hospitalisation for bronchopneumonia on day 16 post-vaccination which resolved without sequelae. Around day 42 postvaccination (range 35 - 63 days) all the 176 initially seronegative subjects had seroconverted for varicella antibodies. Post-vaccination geometric mean titres (GMTs) were 104,1, 66,2, 69,5 and 77,0 for groups 1 - 4 respectively. Six subjects who were initially seropositive maintained or increased their titres post-vaccination; 3 of the 6 showed a booster response (a ;:;, 4-fold increase from the pre-vaccination titre).Conclusions. Varicella vaccine was found to be safe, immunogenic and well tolerated. No difference in seroconversion rates or GMTs, either between groups receiving the two vaccine lots or between groups receiving the different titres of each lot, was shown

Delivery of Functional Anti-miR-9 by Mesenchymal Stem Cell–derived Exosomes to Glioblastoma Multiforme Cells Conferred Chemosensitivity

Glioblastoma multiforme (GBM), the most common and lethal tumor of the adult brain, generally shows chemo- and radioresistance. MicroRNAs (miRs) regulate physiological processes, such as resistance of GBM cells to temozolomide (TMZ). Although miRs are attractive targets for cancer therapeutics, the effectiveness of this approach requires targeted delivery. Mesenchymal stem cells (MSCs) can migrate to the sites of cancers, including GBM. We report on an increase in miR-9 in TMZ-resistant GBM cells. miR-9 was involved in the expression of the drug efflux transporter, P-glycoprotein. To block miR-9, methods were developed with Cy5-tagged anti-miR-9. Dye-transfer studies indicated intracellular communication between GBM cells and MSCs. This occurred by gap junctional intercellular communication and the release of microvesicles. In both cases, anti-miR-9 was transferred from MSCs to GBM cells. However, the major form of transfer occurred with the microvesicles. The delivery of anti-miR-9 to the resistant GBM cells reversed the expression of the multidrug transporter and sensitized the GBM cells to TMZ, as shown by increased cell death and caspase activity. The data showed a potential role for MSCs in the functional delivery of synthetic anti-miR-9 to reverse the chemoresistance of GBM cells

Clinical multiplexed exome sequencing distinguishes adult oligodendroglial neoplasms from astrocytic and mixed lineage gliomas

Classifying adult gliomas remains largely a histologic diagnosis based on morphology; however astrocytic, oligodendroglial and mixed lineage tumors can display overlapping histologic features. We used multiplexed exome sequencing (OncoPanel) on 108 primary or recurrent adult gliomas, comprising 65 oligodendrogliomas, 28 astrocytomas and 15 mixed oligoastrocytomas to identify lesions that could enhance lineage classification. Mutations in TP53 (20/28, 71%) and ATRX (15/28, 54%) were enriched in astrocytic tumors compared to oligodendroglial tumors of which 4/65 (6%) had mutations in TP53 and 2/65 (3%) had ATRX mutations. We found that oligoastrocytomas harbored mutations in TP53 (80%, 12/15) and ATRX (60%, 9/15) at frequencies similar to pure astrocytic tumors, suggesting that oligoastrocytomas and astrocytomas may represent a single genetic or biological entity. p53 protein expression correlated with mutation status and showed significant increases in astrocytomas and oligoastrocytomas compared to oligodendrogliomas, a finding that also may facilitate accurate classification. Furthermore our OncoPanel analysis revealed that 15% of IDH1/2 mutant gliomas would not be detected by traditional IDH1 (p.R132H) antibody testing, supporting the use of genomic technologies in providing clinically relevant data. In all, our results demonstrate that multiplexed exome sequencing can support evaluation and classification of adult low-grade gliomas with a single clinical test

CYLD mutation characterizes a subset of HPV-positive head and neck squamous cell carcinomas with distinctive genomics and frequent cylindroma-like histologic features

Mutations in the tumor suppressor CYLD, known to be causative of cylindromas, were recently described in a subset of high-risk (hr) HPV-positive head and neck squamous cell carcinomas (HNSCC). Pathologic and genetic characterization of these CYLD-mutant carcinomas, however, remains limited. Here, we investigated whether CYLD mutations characterize a histopathologically and genomically distinct subset of hrHPV-positive HNSCC. Comprehensive genomic profiling via hybrid capture-based DNA sequencing was performed on 703 consecutive head and neck carcinomas with hrHPV sequences, identifying 148 unique cases (21%) harboring CYLD mutations. Clinical data, pathology reports, and histopathology were reviewed. CYLD mutations included homozygous deletions (n = 61/148; 41%), truncations (n = 52; 35%), missense (n = 26; 18%) and splice-site (n = 9; 6%) mutations, and in-frame deletion (n = 1; 1%). Among hrHPV-positive HNSCC, the CYLD-mutant cohort showed substantially lower tumor mutational burden than CYLD-wildtype cases (n = 555) (median 2.6 vs. 4.4 mut/Mb, p \u3c 0.00001) and less frequent alterations in PIK3CA (11% vs. 34%, p \u3c 0.0001), KMT2D (1% vs. 16%, p \u3c 0.0001), and FBXW7 (3% vs. 11%, p = 0.0018). Male predominance (94% vs. 87%), median age (58 vs. 60 years), and detection of HPV16 (95% vs. 89%) were similar. On available histopathology, 70% of CYLD-mutant HNSCC (98/141 cases) contained hyalinized material, consistent with basement membrane inclusions, within crowded aggregates of tumor cells. Only 7% of CYLD-wildtype cases demonstrated this distinctive pattern (p \u3c 0.0001). Histopathologic patterns of CYLD-mutant HNSCC lacking basement membrane inclusions included nonkeratinizing (n = 22, 16%), predominantly nonkeratinizing (nonkeratinizing SCC with focal maturation; n = 10, 7%), and keratinizing (n = 11, 8%) patterns. The latter two groups showed significantly higher frequency of PTEN alterations compared with other CYLD-mutant cases (38% [8/21] vs. 7% [8/120], p = 0.0004). Within our cohort of hrHPV-positive HNSCCs, CYLD mutations were frequent (21%) and demonstrated distinctive clinical, histopathologic, and genomic features that may inform future study of prognosis and treatment

A Retrospective Genomic Landscape of 661 Young Adult Glioblastomas Diagnosed Using 2016 WHO Guidelines for Central Nervous System Tumors

The authors present a cohort of 661 young adult glioblastomas diagnosed using 2016 WHO World Health Organization Classification of Tumors of the Central Nervous System, utilizing comprehensive genomic profiling (CGP) to explore their genomic landscape and assess their relationship to currently defined disease entities. This analysis explored variants with evidence of pathogenic function, common copy number variants (CNVs), and several novel fusion events not described in literature. Tumor mutational burden (TMB) mutational signatures, anatomic location, and tumor recurrence are further explored. Using data collected from CGP, unsupervised machine-learning techniques were leveraged to identify 10 genomic classes in previously assigned young adult glioblastomas. The authors relate these molecular classes to current World Health Organization guidelines and reference current literature to give therapeutic and prognostic descriptions where possible

Clinical Laboratory Testing Practices in Diffuse Gliomas Prior to Publication of 2021 World Health Organization Classification of Central Nervous System Tumors

CONTEXT.—: Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear. OBJECTIVE.—: To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors. DESIGN.—: College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers in gliomas. RESULTS.—: The data provide perspective into the testing practices for diffuse gliomas from a broad group of clinical laboratories in 2020. More than 98% of participating laboratories perform testing for glioma biomarkers recognized as diagnostic for specific subtypes, including IDH. More than 60% of laboratories also use molecular markers to differentiate between astrocytic and oligodendroglial lineage tumors, with some laboratories providing more comprehensive analyses, including prognostic biomarkers, such as CDKN2A/B homozygous deletions. Almost all laboratories test for MGMT promoter methylation to identify patients with an increased likelihood of responding to temozolomide. CONCLUSIONS.—: These findings highlight the state of molecular testing in 2020 for the diagnosis and classification of diffuse gliomas at large academic medical centers. The findings show that comprehensive molecular testing is not universal across clinical laboratories and highlight the gaps between laboratory practices in 2020 and the recommendations in the 2021 World Health Organization Classification of Central Nervous System Tumors