Mortality: What Are the Roles of Risk Factor Prevalence,Screening, and Use of Recommended Treatment?

CONTEXT: Despite advances in early detection and prevention of cervical cancer, women living in rural areas, and particularly in Appalachia, the rural South, the Texas/Mexico border, and the central valley of California, have had consistently higher rates of cervical cancer mortality than their counterparts in other areas during the past several decades. METHODS: This paper reviews the published literature from 1966 to July 2002 to assess three potential pathways underlying this excess mortality--high human papilloma virus (HPV) prevalence, lack of or infrequent screening and advanced disease at diagnosis, and under-use of recommended treatment and shorter survival. FINDINGS: Living in rural areas may impose barriers to cervical cancer control, including lack of transportation and medical care infrastructures. Population characteristics that place women at greater risk for developing and dying from cervical cancer, such as low income, lack of health insurance, and physician availability, are concentrated in rural areas. Published data, however, are insufficient to identify the key reasons for the observed mortality patterns. CONCLUSIONS: At this time, given the lack of definitive evidence in the published literature, decisions about priorities in areas with high rates of cervical cancer mortality will depend on knowledge of current levels of screening, incidence, and stage distribution; and service delivery infrastructures, resources, and acceptability of interventions to the target population.     

Recent advances in non-surgical treatment for advanced hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is one of the most common cancers and is the leading cause of cancer death in Taiwan. Curative surgery is feasible for only about 30% of patients. Transarterial embolization or chemoembolization (TAE/TACE) has been demonstrated to provide a survival benefit compared with supportive care for HCC patients with adequate liver reserves, tumors confined to the liver, and no evidence of portal vein thrombosis. Percutaneous ethanol injection (PEI) may provide long-term disease control if the extent of liver tumors is limited (3 or less in number and less than 3 cm in diameter). The relative efficacy of TAE/TACE, PEI, and other locoregional treatment modalities, such as radiofrequency ablation or cryosurgery, remains unclear. Radiotherapy has been used mostly as a salvage therapy in combination with other locoregional modalities. Despite the incorporation of 3-dimensional conformal technology, radiation-induced liver injury remains an important problem, especially for patients with hepatitis B-related cirrhosis. Systemic therapy is difficult for HCC because of the underlying cirrhosis and accompanying hypersplenism and peripheral cytopenia. HCC is typically resistant to most cytotoxic agents. Biochemical modulation with high-dose tamoxifen may sensitize HCC cells to doxorubicin-induced apoptosis and improve the clinical response to doxorubicin in patients with advanced HCC. Thalidomide, which inhibits angiogenesis induced by vascular endothelial growth factor and basic fibroblast growth factor, can produce a response in some HCC patients. Future research on drug therapy for HCC will focus on identification of tumor-specific targets.     

Teaching on the run: teaching skills for surgical trainees

BACKGROUND: Increasing recognition of the need for training in teaching skills for clinical teachers has coincided with data that registrars and residents conduct much 'on the job' teaching as part of their routine work. While attention has been devoted to training consultants, support for the teaching role of the junior staff has been relatively neglected. The aim of the present report is to describe the teaching experiences of surgical registrars and the impact of a registrar teaching workshop. METHOD: A half-day programme combining presentation and discussion of surgical teaching with practical skills sessions was designed for surgical registrars at Prince of Wales Hospital. The programme included observation and feedback of brief teaching simulations at the bedside of volunteer patients to newly commenced clinical students, and small group sessions on clinic and operating theatre teaching. A pre-workshop questionnaire sought information about the registrars' own teaching, and a survey 3 months after the workshop determined if any changes to teaching practice had occurred. RESULTS: The registrars were generally moderately to very confident with their teaching ability but more than 75% felt that they were more confident after the workshop. Only three of 39 registrars had received any instruction aimed at improving their teaching skills, yet 34/39 had taught either on the ward, in the clinics or in the operating room. Follow-up after 3 months revealed that most registrars were enjoying their teaching tasks more, and half had increased their teaching since the workshop and began discussing teaching with their surgical colleagues. CONCLUSIONS: The present project demonstrates that relatively brief interventions focused on skill development may enhance the confidence and enjoyment of junior clinical teachers and increase the frequency of 'teaching on the run'.     

Mutations in the tyrosine kinase domain of the epidermal growth factor receptor in non-small cell lung cancer.

We evaluated somatic genetic alterations in the kinase domain of the EGFR gene in the tumors of 219 non-small cell lung cancer patients of primarily Caucasian and African American origins. We identified 26 patients (12%) whose tumors had a mutation in the EGFR gene, and 11 (5%) patients carried novel genomic variations consistent with germ-line polymorphisms. All but one mutation were identified in Caucasian patients affected with adenocarcinoma. EGFR mutations were more frequent in women and in nonsmokers, but a significant portion of the affected patients were men (12 of 26) and current or past smokers accounted for half of the patients affected (13 of 26). Screening subjects with EGFR mutations may identify patients whose tumors could respond to targeted therapy using tyrosine kinase inhibitors.     

Identification of HLA-DRB1*1501-restricted T-cell epitopes from prostate-specific antigen.

The development of immunotherapy for prostate cancer based on the induction of autoimmunity to prostate tissue is very attractive because prostate is not a vital organ beyond the reproductive years. CD4 T cells play an important role in the development of antitumor immune responses, yet the identification of naturally processed MHC Class II-restricted epitopes derived from prostate differentiation antigens has not been described. To facilitate the search for prostate-specific antigen (PSA)-derived MHC class II-restricted peptides, we immunized mice transgenic for HLA-DRB1*1501 with human PSA and showed a robust dose-dependent immune response to the antigen. Screening a library of overlapping 20-mer peptides that span the entire PSA sequence identified two 20-mer peptides, PSA(171-190) and PSA(221-240), which were responsible for this reactivity. Immunization of DR2b transgenic mice with these peptides induced specific responses to the peptide and whole PSA. Identified peptides were used to stimulate CD4 T cells from HLA-DRB1*1501+ patients with a rare condition, granulomatous prostatitis, and who seem to have a preexisting immune response directed against the prostate gland. We previously showed a linkage of granulomatous prostatitis to HLA-DRB1*1501, suggesting that this disease may have an autoimmune etiology. Peptide-specific CD4 T-cell lines were generated from the peripheral blood of these patients as well as one patient with prostate cancer. These lines also recognized whole, processed PSA in the context of HLA-DRB1*1501. This study will be instrumental in understanding the interaction between circulating self-reactive T cells, organ-specific autoimmunity, and antitumor immune response. The use of these peptides for the immunotherapy of prostate cancer is under investigation.     

Clinicopathologic and genetic profile of intracranial marginal zone lymphoma: a primary low-grade CNS lymphoma that mimics meningioma.

PURPOSE: Although rare overall, marginal zone B-cell lymphoma (MZBCL) is the most common primary low-grade CNS lymphoma reported in the literature. The aim of this study is to elucidate the biology and genetic features of this unusual tumor. PATIENTS AND METHODS: Fifteen CNS MZBCLs were studied clinically, pathologically, and genetically, including fluorescent in situ hybridization analyses with commercially available MALT1 and IgH break-apart and centromere 3, 7, 12, and 18 probes. RESULTS: CNS MZBCLs preferentially affect middle-aged women (female-to-male ratio, 4:1), with 93% presenting as dural-based masses mimicking meningioma. Ten patients with 1 to 7.6 years of follow-up after diagnosis showed no evidence of disease after radiation and/or chemotherapy. Like MZBCLs outside of the CNS, they consisted of CD20+, CD3- small B lymphocytes with varying degrees of plasmacytic differentiation and predominantly kappa light-chain restriction (78%). Lymphoid follicles with follicular colonization were seen in three patients and deposition of amyloid was noted in samples from two patients, one of which was tumefactive. Neither Bcl-6 protein nor Epstein-Barr virus-encoded RNA was expressed. Trisomy 3 was detected in six of 12 patients, with no rearrangements of MALT1 or IgH and no trisomies of 7, 12, or 18 detected. CONCLUSION: Our data suggest that intracranial MZBCL is an indolent primary CNS lymphoma that typically presents as a meningioma-like dural-based mass. Trisomy 3, but not MALT1 or IgH translocation, is a common genetic abnormality that may contribute to the pathogenesis of this CNS lymphoma.     

An antibody targeting the N-terminal domain of SARS-CoV-2 disrupts the spike trimer

The protective human antibody response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) focuses on the spike (S) protein, which decorates the virion surface and mediates cell binding and entry. Most SARS-CoV-2 protective antibodies target the receptor-binding domain or a single dominant epitope (“supersite”) on the N-terminal domain (NTD). Using the single B cell technology called linking B cell receptor to antigen specificity through sequencing (LIBRA-Seq), we isolated a large panel of NTD-reactive and SARS-CoV-2–neutralizing antibodies from an individual who had recovered from COVID-19. We found that neutralizing antibodies against the NTD supersite were commonly encoded by the IGHV1-24 gene, forming a genetic cluster representing a public B cell clonotype. However, we also discovered a rare human antibody, COV2-3434, that recognizes a site of vulnerability on the SARS-CoV-2 S protein in the trimer interface (TI) and possesses a distinct class of functional activity. COV2-3434 disrupted the integrity of S protein trimers, inhibited the cell-to-cell spread of the virus in culture, and conferred protection in human angiotensin-converting enzyme 2–transgenic (ACE2-transgenic) mice against the SARS-CoV-2 challenge. This study provides insight into antibody targeting of the S protein TI region, suggesting this region may be a site of virus vulnerability.     

Factors associated with early uptake of COVID‐19 vaccination among healthcare workers in Azerbaijan, 2021

IntroductionWe evaluated uptake and factors associated with COVID‐19 vaccination among health workers (HWs) in Azerbaijan.ResultsAmong 1575 HWs, 73% had received at least one dose, and 67% received two doses; all received CoronaVac. Factors associated with vaccination uptake included no previous COVID‐19 infection, older age, belief in the vaccine''s safety, previous vaccination for influenza, having patient‐facing roles and good or excellent health by self‐assessment.ConclusionThese findings could inform strategies to increase vaccination uptake as the campaign continues.     

Predicting the depressive status using empirical dietary inflammatory index in patients with antineutrophil cytoplasmic antibody‐associated vasculitis

BackgroundThis study investigated whether the empirical dietary inflammatory index (eDII) score is associated with the inflammatory burden as well as the depressive status in patients with antineutrophil cytoplasmic antibody‐associated vasculitis (AAV).MethodsEighty‐four patients with AAV participated in this study. Birmingham vasculitis activity score (BVAS) and short‐form 36‐item Health Survey mental component summary (SF‐36 MCS) were considered as indices assessing the inflammatory burden and depressive status, respectively. The eDII includes 16 food components and consists of three groups: −9 to −2, the low eDII group; −1 to +1, the moderate eDII group; and +2 to +10, the high eDII group. Furthermore, the lower eDII group includes both the low and moderate eDII groups.ResultsThe median age was 64.5 years (36 men). The eDII scores inversely correlated with SF‐36 MCS (r = −0.298, p = 0.006) but not with BVAS. SF‐36 MCS significantly differ between the lower and higher eDII groups (69.7 vs. 56.7, p = 0.016), but not among the low, moderate and high eDII groups. Additionally, when patients with AAV were divided into two groups according to the upper limit of the lowest tertile of SF‐36 MCS of 55.31, patients in the higher eDII group exhibited a significantly higher risk for the lowest tertile of SF‐36 MCS than those in the lower eDII group (RR 3.000).ConclusionWe demonstrated for the first time that the eDII could predict the depressive status by estimating SF‐36 MCS without utilising K‐CESD‐R ≥ 16 in patients with AAV.     

Effects of DDT on Amyloid Precursor Protein Levels and Amyloid Beta Pathology: Mechanistic Links to Alzheimer’s Disease Risk

Background: The interaction of aging-related, genetic, and environmental factors is thought to contribute to the etiology of late-onset, sporadic Alzheimer’s disease (AD). We previously reported that serum levels of p,p′-dichlorodiphenyldichloroethylene (DDE), a long-lasting metabolite of the organochlorine pesticide dichlorodiphenyltrichloroethane (DDT), were significantly elevated in patients with AD and associated with the risk of AD diagnosis. However, the mechanism by which DDT may contribute to AD pathogenesis is unknown.Objectives: This study sought to assess effects of DDT exposure on the amyloid pathway in multiple in vitro and in vivo models.Methods: Cultured cells (SH-SY5Y and primary neurons), transgenic flies overexpressing amyloid beta (Aβ), and C57BL/6J and 3xTG-AD mice were treated with DDT to assess impacts on the amyloid pathway. Real time quantitative polymerase chain reaction, multiplex assay, western immunoblotting and immunohistochemical methods were used to assess the effects of DDT on amyloid precursor protein (APP) and other contributors to amyloid processing and deposition.Results: Exposure to DDT revealed significantly higher APP mRNA and protein levels in immortalized and primary neurons, as well as in wild-type and AD-models. This was accompanied by higher levels of secreted Aβ in SH-SY5Y cells, an effect abolished by the sodium channel antagonist tetrodotoxin. Transgenic flies and 3xTG-AD mice had more Aβ pathology following DDT exposure. Furthermore, loss of the synaptic markers synaptophysin and PSD95 were observed in the cortex of the brains of 3xTG-AD mice.Discussion: Sporadic Alzheimer’s disease risk involves contributions from genetic and environmental factors. Here, we used multiple model systems, including primary neurons, transgenic flies, and mice to demonstrate the effects of DDT on APP and its pathological product Aβ. These data, combined with our previous epidemiological findings, provide a mechanistic framework by which DDT exposure may contribute to increased risk of AD by impacting the amyloid pathway. https://doi.org/10.1289/{"type":"entrez-protein","attrs":{"text":"EHP10576","term_id":"372009961","term_text":"EHP10576"}}EHP10576