Creutzfeldt astrocytes may be seen in IDH‐wildtype glioblastoma and retain expression of DNA repair and chromatin binding proteins

Astrocytes with multiple micronuclei (“Creutzfeldt cells”) in a brain biopsy are classically associated with demyelinating disease. However, glioblastoma may also have prominent Creutzfeldt astrocytes, along with granular mitoses. Therefore, Creutzfeldt cells may raise the diagnostic dilemma of high‐grade glioma vs tumefactive demyelination. While cases of glioblastoma (GBM) with Creutzfeldt astrocytes have been reported, their clinicopathologic spectrum and genetic features are not understood. Studies have proposed that micronuclei in Creutzfeldt cells are a consequence of DNA damage, or may be susceptible to DNA damage and chromothripsis, but their biology in the context of glioblastoma remains unclear. Based on a challenging index case of GBM with mild hypercellularity, Creutzfeldt astrocytes, and granular mitoses on biopsy, we searched our archives for additional cases with similar histopathologic features. We identified 13 cases, reviewed their clinico‐radiologic and pathologic features, and examined them for recurrent genetic alterations via NGS (9 cases) and for evidence of DNA damage by immunohistochemistry for DNA repair and chromatin remodeling proteins. We found that Creutzfeldt cell‐rich GBMs were IDH‐wildtype with no recurring genetic alterations. To test our hypothesis that micronuclei demonstrate loss of DNA repair or chromatin remodeling proteins, we examined the expression of various proteins (MDM2, p53, MLH1, MSH2, PMS2, MSH6, ATRX, INI1, SATB2, Ki67, pHH3) in Creutzfeldt cell rich‐GBM. There was intact expression of DNA repair and chromatin remodeling proteins, with accumulation of p53 and reduced MDM2 expression within micronuclei. In contrast, granular mitoses showed pHH3 expression, confirming these cells are undergoing mitotic division, with no accumulation of p53 and reduced expression of DNA repair proteins. Our results emphasize that Creutzfeldt cells are part of the morphologic spectrum of IDH‐wildtype glioblastoma. We did not find a role for DNA damage in the generation of Creutzfeldt cells, as both DNA repair and chromatin remodeling protein expression was retained in these cells.     

Good outcome of the single‐center pediatric kidney transplant program in Abu Dhabi

Renal transplantation is the treatment of choice for ESRD in children. It is associated with better quality of life, growth of children, and improved long‐term survival. The aim of the study was to evaluate the outcomes of pediatric renal transplantation at a tertiary care center in UAE. A retrospective chart review was undertaken for all the pediatric renal transplants performed at Sheikh Khalifa Medical City, Abu Dhabi, UAE, over the past 9 years. The study evaluated the demographic data, outcomes, and complications of pediatric renal transplantation. The post‐transplantation outcomes including surgical complications, documented infections, graft rejection, graft and patient survival, effect on growth, and eGFR were reviewed. Between 2010 and 2018, 30 pediatric patients underwent renal transplantation. The follow‐up period ranged from 1 to 9 years with a mean of 3.3 years. The mean age of the patients at the time of transplant was 9.8 years, and 56.7% were males. Prior to the transplantation, the majority of the recipients were on peritoneal dialysis (70.0%). Main source of renal donation at our center was from LRD, chiefly from parents. Patient survival at 1 and 5 years was 100% and 96.7%, respectively. Graft survival at 1 and 5 years was 96.7% and 83.3%, respectively. During the 9‐year follow‐up period, 5 (16.7%) recipients experienced rejection episode. This study demonstrates that during 5‐year period, pediatric kidney transplantation program has achieved optimal patient (96.7%) and graft (83.3%) survival rates and is comparable to well‐established centers.     

Potentially malignant disorders of the oral cavity: Current practice and future directions in the clinic and laboratory

Despite commendable progress in the prevention, detection, and treatment of a wide variety of solid tumor types, oral squamous cell carcinoma (OSCC) remains a significant health burden across the globe. OSCC carcinogenesis involves accumulation of genetic alterations that coincide with the multistep malignant transformation of normal oral epithelium. OSCC is often first diagnosed at late stages of the disease (advanced regional disease and/or metastasis). Delayed diagnosis precludes successful treatment and favorable outcomes. In clinical practice, opportunities exist to identify patients with oral potentially malignant disorders (OPMDs), which precede the development of cancer. This review addresses the current status of laboratory and clinical research on OPMDs, with emphasis on leukoplakia and erythroplakia. OSF is also presented, though there is a paucity of published studies on this disorder. We focus on findings that could translate into earlier diagnosis and more efficacious treatment of those lesions with significant malignant potential. We explore how markers of OPMD malignant transformation might be implemented into current diagnostic practice to help clinicians objectively stratify patients into treatment/follow‐up groups according to relative risk. We provide an overview of recently concluded and ongoing OPMD chemoprevention trials. We describe laboratory OPMD models that can be used to not only to reveal the genetic and molecular intricacies of oral cancer but also to develop novel screening methods and therapeutic approaches. Finally, we call for targeted screening programs of at‐risk populations in order to facilitate diagnosis and treatment of OPMD and early OSCC.     

Vaccination in pregnancy

Vaccination is one of the most effective strategies employed to prevent morbidity and mortality from infectious diseases. Pregnancy is considered to be a time when women have consistent contact with their healthcare providers and it presents an opportunity for providers to review their immunization status and to advocate for appropriate vaccination antepartum and in the immediate postpartum period. All forms of immunization, with the exception of live viral or live bacterial vaccines are generally considered to be safe for administration during pregnancy. It is important that healthcare providers counsel pregnant women about the benefits of receiving the vaccines that are recommended during pregnancy as well as the potential risks to the developing fetus. It is imperative that obstetricians and primary care providers are aware of and implement the vaccination guidelines for women, both during pregnancy and in the postpartum period.     

Oncogenic fingerprint of epidermal growth factor receptor pathway and emerging epidermal growth factor receptor blockade resistance in colorectal cancer

Epidermal growth factor receptor (EGFR) has been an attractive target for treatment of epithelial cancers, including colorectal cancer (CRC). Evidence from clinical trials indicates that cetuximab and panitumumab (anti-EGFR monoclonal antibodies) have clinical activity in patients with metastatic CRC. The discovery of intrinsic EGFR blockade resistance in Kirsten RAS (KRAS)-mutant patients led to the restriction of anti-EGFR antibodies to KRAS wild-type patients by Food and Drug Administration and European Medicine Agency. Studies have since focused on the evaluation of biomarkers to identify appropriate patient populations that may benefit from EGFR blockade. Accumulating evidence suggests that patients with mutations in EGFR downstream signaling pathways including KRAS, BRAF, PIK3CA and PTEN could be intrinsically resistant to EGFR blockade. Recent whole genome studies also suggest that dynamic alterations in signaling pathways downstream of EGFR leads to distinct oncogenic signatures and subclones which might have some impact on emerging resistance in KRAS wild-type patients. While anti-EGFR monoclonal antibodies have a clear potential in the management of a subset of patients with metastatic CRC, further studies are warranted to uncover exact mechanisms related to acquired resistance to EGFR blockade.     

MDM2 SNP309 does not confer an increased risk to oral squamous cell carcinoma but may modulate the age of disease onset

The MDM2 SNP309 has been associated with increased expression of the protein which could suppress p53 function, and has been shown to modulate risk to cancer. We have previously shown that overexpression of MDM2 is a common event in oral cancers. In the present study, we determined the association between the MDM2 SNP309 polymorphism and oral cancer in 207 oral cancer patients and 116 normal subjects. We genotyped the MDM2 SNP309 by PCR-RFLP. Logistic regression was adapted to calculate odds ratios for MDM2 SNP309 polymorphism from univariate and multivariable adjusted models. Our results suggest that MDM2 SNP309 does not confer increased risk to oral cancer (OR=1.55, 95% CI=0.77-3.11). However, the GG/TG genotype was associated with later disease onset in women above 55 years of age. Collectively, our data suggests that MDM2 SNP309 may modulate the risk to oral cancer and is a modifier of the age at oral cancer onset in women above the age of 55 years.     

Population Burden of Betel Quid Abuse and Its Relation to Oral Premalignant Disorders in South,Southeast, and East Asia: An Asian Betel-Quid Consortium Study

Objectives. We investigated the population burden of betel quid abuse and its related impact on oral premalignant disorders (OPDs) in South, Southeast, and East Asia.Methods. The Asian Betel-Quid Consortium conducted a multistage sampling of 8922 representative participants from Taiwan, Mainland China, Malaysia, Indonesia, Nepal, and Sri Lanka. Participants received an interviewer-administered survey and were examined for oral mucosal disorders.Results. The prevalence of betel quid abuse was 0.8% to 46.3% across 6 Asian populations. The abuse frequency was over 40.5% for current chewers, with the highest proportion in Nepalese and Southeast Asian chewers (76.9%−99.6%). Tobacco-added betel quid conferred higher abuse rates (74.4%−99.6%) among Malaysian, Indonesian, and Sri Lankan men than did tobacco-free betel quid (21.8%−89.1%). Gender, lower education level, younger age at chewing initiation, and clustering of familial betel quid use significantly contributed to higher abuse rates. Indonesian betel quid abusers showed the highest prevalence of OPDs and had a greater risk of OPDs than did nonabusers.Conclusions. Betel quid abuse is high in regions of Asia where it is customarily practiced, and such abuse correlates highly with OPDs. By recognizing abuse-associated factors, health policies and preventive frameworks can be effectively constructed to combat these oral preneoplasms.The chewing of betel quid, a combination of areca nut, betel leaf, slaked lime, and region-dependent flavoring ingredients, is a uniquely Asian, culturally derived lifestyle habit. Bred from ancient tradition, its use is socially accepted in all groups, including women and young children, although other substance use such as tobacco smoking is deemed objectionable.1,2 Chemical composition studies have showed that areca nut includes psychoactive alkaloids, of which arecoline contributes the most quantity.3 By raising epinephrine and norepinephrine plus modulation of cholinergic and monoamine transmission, areca nut exerts neurobiological effects on the sympathetic and parasympathetic nervous systems.3–5 In human studies, tolerance and withdrawal symptoms have been clearly detected in regular betel quid chewers.6–8 Such a pharmacological profile is comparable with nicotine, a well-known substance that leads to abuse and dependence. In recent decades, successful marketing of commercially manufactured betel quid has dramatically increased its accessibility and widespread use throughout Asia.9 An increased availability indicates that betel quid may be abused throughout different cultures, but the extent is unknown.Studies on the natural history of oral cancer suggest that several oral premalignant disorders (OPDs), including oral lichen planus (OLP), oral submucous fibrosis (OSF), oral leukoplakia (OL) and oral erythroplasia, precede the development of this neoplasm.10 In Asia, the prevalence of oral precancerous conditions and lesions was estimated to be 1.7% to 11.7% in western India,11 4.4% to 12.7% in southern Taiwan,12,13 0.1% to 4.7% in the Hunan province of Mainland China,14 1.4% in Malaysia,15 and 6.7% in the central Sri Lanka.16 Although there is evidence to support that chronic consumption of betel quid products, with or without added tobacco, is a central etiological agent for OPD and neoplasms of the oral cavity, pharynx, esophagus and larynx,10,17–23 no data are available concerning the oral precancerous consequences among betel quid abusers.To study the health effects of betel quid consumption in Asian populations and mobilize outreach activities in disease prevention, in 2008, the Center of Excellence for Environmental Medicine at Kaohsiung Medical University in Kaohsiung, Taiwan, in consultation with the World Health Organization (WHO) Collaborating Centre for Oral Cancer in the United Kingdom, launched an international collaborative project that constitutes the Asian Betel-quid Consortium (ABC) study. Six large research centers from East Asia (Kaohsiung Medical University, Taiwan, and Central South University, Changsha, Mainland China), Southeast Asia (Airlangga University, Surabaya, Indonesia and University of Malaya, Kuala Lumpur, Malaysia), and South Asia (University of Peradeniya, Peradeniya, Sri Lanka and Kathmandu University, Kavrepalanchwok, Nepal) participated in this investigation. Because of varying practices and particular marketing of betel quid products in those countries (detailed explanations shown in Table A, available as a supplement to the online version of this article at http://www/ajph.org), present study actions are promisingly warranted. The purposes of this report are twofold: (1) to present the current population burden of betel quid abuse and the factors associated with this behavior in the investigated Asian communities, and (2) to evaluate the impact of betel quid abuse on oral premalignant disorders.