Association of Neighborhood Disadvantage with Short- and Long-Term Outcomes After Pancreatectomy for Pancreatic Ductal Adenocarcinoma.

BACKGROUND: While lower socioeconomic status has been shown to correlate with worse outcomes in cancer care, data correlating neighborhood-level metrics with outcomes are scarce. We aim to explore the association between neighborhood disadvantage and both short- and long-term postoperative outcomes in patients undergoing pancreatectomy for pancreatic ductal adenocarcinoma (PDAC). PATIENTS AND METHODS: We retrospectively analyzed 243 patients who underwent resection for PDAC at a single institution between 1 January 2010 and 15 September 2021. To measure neighborhood disadvantage, the cohort was divided into tertiles by Area Deprivation Index (ADI). Short-term outcomes of interest were minor complications, major complications, unplanned readmission within 30 days, prolonged hospitalization, and delayed gastric emptying (DGE). The long-term outcome of interest was overall survival. Logistic regression was used to test short-term outcomes; Cox proportional hazards models and Kaplan-Meier method were used for long-term outcomes. RESULTS: The median ADI of the cohort was 49 (IQR 32-64.5). On adjusted analysis, the high-ADI group demonstrated greater odds of suffering a major complication (odds ratio [OR], 2.78; 95% confidence interval [CI], 1.26-6.40; p = 0.01) and of an unplanned readmission (OR, 3.09; 95% CI, 1.16-9.28; p = 0.03) compared with the low-ADI group. There were no significant differences between groups in the odds of minor complications, prolonged hospitalization, or DGE (all p > 0.05). High ADI did not confer an increased hazard of death (p = 0.63). CONCLUSIONS: We found that worse neighborhood disadvantage is associated with a higher risk of major complication and unplanned readmission after pancreatectomy for PDAC.

A nationwide analysis of disparities in guideline-concordant care in American Indians and Alaska Natives with stage I non-small cell lung cancer.

Background: Several studies have shown racial disparities in lung cancer care in the United States in the Black and Hispanic populations but not many have included American Indian/Alaska Native (AI/AN) patients. We retrospectively evaluated the factors associated with receipt of guideline-concordant care in AI/AN and non-Hispanic White (NHW) patients with stage I non-small cell lung cancer (NSCLC) and describe the relationship between guideline-concordant care and survival outcomes in these populations. Methods: Using the National Cancer Database, we identified NHW and AI/AN patients diagnosed with stage I NSCLC between 2004 and 2017. We evaluated the utilization of anatomic resection among both NHW and AI/AN and described the variables associated with anatomic resection. We also evaluated 5-year overall survival (OS) by treatment and race. We used the chi-square test, multivariable analysis, and the Kaplan-Meier method for statistical analysis. Results: We identified 196,349 patients. Of these, 195,736 (99.69%) were NHW and 613 (0.31%) were AI/AN. Relative to NHW, AI/AN were more frequently diagnosed at a younger age (40% vs. 28% diagnosed at 18-64 years of age; P<0.001) and more commonly resided in rural areas (14% vs. 5%; P<0.001). In our multivariable analysis adjusting for all patient factors [age at diagnosis, sex, race, residence location, Charlson Comorbidity Index (CCI), tumor stage, lymph node status, and treatment facility], AI/AN patients were less likely to undergo anatomic resection than NHW patients [odds ratio (OR), 0.74; 95% confidence interval (CI): 0.62-0.89]. In our unadjusted survival analysis, AI/AN patients had lower 5-year OS than NHW (58% vs. 56%; P=0.04). When adjusted for surgery this difference was no longer significant. Conclusions: AI/AN patients with stage I NSCLC undergo anatomic resection less frequently than do NHW, with lower 5-year OS than NHW. However, this survival difference is mitigated when AI/AN undergo anatomic resection.

Laypeople's (Mis)Understanding of Common Medical Acronyms.

OBJECTIVES: Abbreviations are often used in medicine yet may be a source of confusion for patients and their families. We aimed to determine the general public's understanding of commonly used medical acronyms. METHODS: For this cross-sectional study, we surveyed state fair visitors regarding their understanding of 5 common medical acronyms. An electronic survey was administered to a volunteer sample of adults who spoke and read English and who had never trained to work in medicine or nursing. Free-text responses were coded as correct, partially correct, or incorrect by 2 independent researchers, adding a third researcher if consensus was not reached. Analysis methods included descriptive statistics, Fisher exact tests, and multivariable logistic regression models. RESULTS: We recruited 204 volunteers (55% female; mean age 43 years; 67% had a bachelor's degree or higher). ED (emergency department) was correctly defined by 32%, PCP (primary care provider/physician) by 18%, CBC (complete blood count) by 14%, and PRN (as needed) and NPO (nothing by mouth) by 13% each. Female gender was associated with higher odds of correctly understanding NPO (odds ratio, 3.11; 95% confidence interval, 1.18-8.21; P = .02); older age was associated with higher odds of understanding PRN (odds ratio, 1.03; 95% confidence interval, 1.00-1.05; P = .04). Education level was not found to correlate significantly with successful explanation of any tested acronym. CONCLUSIONS: Medical acronyms are a predictable source of miscommunication. In this large cross-sectional study, none of the acronyms evaluated was understood correctly by more than one-third of adults. Clinicians should avoid using acronyms with patients and families to minimize confusion.

Disparities in post-mastectomy reconstruction use among American Indian and Alaska Native women.

BACKGROUND: American Indian/Alaska Native (AI/AN) breast cancer patients undergo post-mastectomy reconstruction (PMR) infrequently relative to Non-Hispanic White (NHW) patients. Factors associated with low PMR rates among AI/AN are poorly understood. We sought to describe factors associated with this disparity in surgical care. METHODS: A retrospective cohort study of the National Cancer Database (2004 - 2017) identified AI/AN and NHW women, ages 18 - 64, who underwent mastectomy for stage 0 - III breast cancer. Patient characteristics, annual PMR rates, and factors associated with PMR were described with univariable analysis, the Cochran-Armitage test, and multivariable logistical regression. RESULTS: 414,036 NHW and 1,980 AI/AN met inclusion criteria. Relative to NHW, AI/AN had more comorbidities (20% vs 12% Charlson Comorbidity Index ≥ 1, p < 0.001), had non-private insurance (49% vs 20%, p < 0.001), and underwent unilateral mastectomy more frequently (69% vs 61%, p < 0.001). PMR rates increased over the study period, from 13% to 47% for AI/AN and from 29% to 62% for NHW (p <0.001). AI/AN race was independently associated with decreased likelihood of PMR (OR 0.62, 95% CI 0.56-0.69). Among AI/AN, decreased likelihood of PMR was significantly associated with older age at diagnosis, more remote year of diagnosis, advanced disease (tumor size > 5 cm, positive lymph nodes), unilateral mastectomy, non-private insurance, and lower educational attainment in patient's area of residence. CONCLUSION: PMR rates among AI/AN with stage 0 - III breast cancer have increased, yet remain significantly lower than among NHW. Further research should elicit AI/AN perspectives on PMR, and guide early breast cancer detection and treatment.

Jargon Be Gone - Patient Preference in Doctor Communication.

While it has been shown that healthcare providers often use medical jargon, less is known about how patients prefer their clinicians communicate. This mixed-methods study aimed to better understand the general public's preference in healthcare communication. A volunteer cohort of 205 adult attendees at the 2021 Minnesota State Fair was presented a survey with two scenarios at a doctor's office sharing the same information: one using medical terminology and one using simpler, jargon-free language. Survey participants were asked which doctor they preferred, to describe each doctor, and to explain why they believe that doctors may use medical terminology. Common descriptive themes for the jargon-using doctor included that this doctor caused confusion, was too technical, and was uncaring, while the doctor who spoke without jargon was perceived as a good communicator, caring/empathetic, and approachable. Respondents perceived a range of reasons why doctors use jargon, from not recognizing they are using words that are not understood to trying to make themselves feel more important. Overall, 91% of survey respondents preferred the doctor who communicated without medical jargon.

Chemotherapy refusal and subsequent survival in healthy older women with high genomic risk estrogen receptor-positive breast cancer.

BACKGROUND: Patients with estrogen receptor (ER)-positive, HER2-negative breast cancer (BC), and high-risk 21-gene recurrence score (RS) results benefit from chemotherapy. We evaluated chemotherapy refusal and survival in healthy older women with high-RS, ER-positive BC. METHODS: Retrospective review of the National Cancer Database (2010-2017) identified women ≥ 65 years of age, with ER-positive, HER2-negative, high-RS (≥ 26) BC. Patients with Charlson Comorbidity Index ≥ 1, stage III/IV disease, or incomplete data were excluded. Women were compared by chemotherapy receipt or refusal using the Cochrane-Armitage test, multivariable logistical regression modeling, the Kaplan-Meier method, and Cox's proportional hazards modeling. RESULTS: 6827 women met study criteria: 5449 (80%) received chemotherapy and 1378 (20%) refused. Compared to women who received chemotherapy, women who refused were older (71 vs 69 years), were diagnosed more recently (2014-2017, 67% vs 61%), and received radiation less frequently (67% vs 71%) (p ≤ 0.05). Refusal was associated with decreased 5-year OS for women 65-74 (92% vs 95%) and 75-79 (85% vs 92%) (p ≤ 0.05), but not for women ≥ 80 years old (84% vs 91%; p = 0.07). On multivariable analysis, hazard of death increased with refusal overall (HR 1.12, 95% CI 1.04-1.2); but, when stratified by age, was not increased for women ≥ 80 years (HR 1.10, 95% CI 0.80-1.51). CONCLUSIONS: Among healthy women with high-RS, ER-positive BC, chemotherapy refusal was associated with decreased OS for women ages 65-79, but did not impact the OS of women ≥ 80 years old. Genomic testing may have limited utility in this population, warranting prudent shared decision-making and further study.

Innate immune modulation in transplantation: mechanisms, challenges, and opportunities.

Organ transplantation is characterized by a sequence of steps that involve operative trauma, organ preservation, and ischemia-reperfusion injury in the transplant recipient. During this process, the release of damage-associated molecular patterns (DAMPs) promotes the activation of innate immune cells via engagement of the toll-like receptor (TLR) system, the complement system, and coagulation cascade. Different classes of effector responses are then carried out by specialized populations of macrophages, dendritic cells, and T and B lymphocytes; these play a central role in the orchestration and regulation of the inflammatory response and modulation of the ensuing adaptive immune response to transplant allografts. Organ function and rejection of human allografts have traditionally been studied through the lens of adaptive immunity; however, an increasing body of work has provided a more comprehensive picture of the pivotal role of innate regulation of adaptive immune responses in transplant and the potential therapeutic implications. Herein we review literature that examines the repercussions of inflammatory injury to transplantable organs. We highlight novel concepts in the pathophysiology and mechanisms involved in innate control of adaptive immunity and rejection. Furthermore, we discuss existing evidence on novel therapies aimed at innate immunomodulation and how this could be harnessed in the transplant setting.

Accuracy in Patient Understanding of Common Medical Phrases.

Importance: Despite acknowledging that medical jargon should be avoided, health care practitioners frequently use it when communicating with patients. Objective: To characterize the understanding of common medical jargon terms by surveying a cross section of the general public and studying phrases that have established meanings in regular usage but different meanings in a medical context (eg, negative and positive test results). Design, Setting, and Participants: In this cross-sectional study, participants indicated their understanding of phrases that may have different meanings in medicine than in colloquial English via a mix of short answer and multiple choice questions. Several questions included paired phrases to assess for differences in understanding with or without jargon. Volunteers were recruited at the 2021 Minnesota State Fair near St Paul, Minnesota. An electronic survey was given to a volunteer sample of 215 adults (>18 years) who did not work or train to work in the medical field and spoke and read English. Exposures: Completing a written or verbal survey. Main Outcomes and Measures: The main outcome was an accurate understanding of the medical terminology. Free-text responses were coded by 2 researchers for comprehension. Secondary outcomes looked for associations between volunteer demographics and understanding. Results: The 215 respondents (135 [63%] female; mean [SD] age, 42 [17] years) demonstrated a varied ability to interpret medical jargon phrases. For example, most participants (207 [96%]) knew that negative cancer screening results meant they did not have cancer, but fewer participants (143 [79%]) knew that the phrase "your tumor is progressing" was bad news, or that positive lymph nodes meant the cancer had spread (170 [67%]). While most (171 [80%]) recognized that an unremarkable chest radiography was good news, only 44 participants (21%) correctly understood that a clinician saying their radiography was impressive was generally bad news. In each of the paired phrases comparing jargon vs nonjargon approaches, the nonjargon phrase was understood significantly better (P < .001). Conclusions and Relevance: These findings suggest that several common phrases are misunderstood when used in a medical setting, with the interpreted meaning frequently the exact opposite of what is intended.

What's in a name? Laypeople's understanding of medical roles and titles.

BACKGROUND: Physicians regularly use jargon in patient communication, which can lead to confusion and misunderstanding. OBJECTIVE: To assess the general public's understanding of names and roles of medical specialties and job seniority titles. DESIGNS: Volunteer participants completed an electronic survey, filling-in-the-blanks for 14 medical specialties (e.g., "pediatricians are doctors who take care of _____"), and ranked physician titles in order of experience (medical student, intern, senior resident, fellow, attending). SETTING: The 2021 Minnesota State Fair. PARTICIPANTS: Volunteers >18 years old without medical or nursing training. MAIN OUTCOME AND MEASURES: We summarized responses with descriptive statistics. Two researchers coded open-ended answers as correct, partially correct, or incorrect, with a third researcher for coding discrepancies. RESULTS: Two hundred and four participants completed the survey (55% female; mean age 43; 67% of respondents with a bachelor's degree or higher). Of 14 medical specialties listed on the survey, respondents most accurately identified dermatologists (94%) and cardiologists (93%). Six specialties were understood by less than half of the respondents: neonatologists (48%), pulmonologists (43%), hospitalists (31%), intensivists (29%), internists (21%), and nephrologists (20%). Twelve percent of participants correctly identified medical roles in rank order. Most participants (74%) correctly identified medical students as the least experienced. Senior residents were most often identified as the most experienced (44%), with just 27% of respondents correctly placing the attending there. We conclude that medical professionals should recognize that titles are a common source of misunderstanding among the general public and should describe their role when introducing themselves to minimize confusion.

Say What? Quantifying and Classifying Jargon Use During Inpatient Rounds.

BACKGROUND: Although plain language is recognized as essential for effective communication, research reveals that medical providers regularly use jargon terminology that may be misunderstood by patients. Little is known, however, about the types and frequency of jargon used in the pediatric inpatient setting. We aimed to quantify jargon use by medical team members during inpatient family-centered rounds (FCRs) and to identify the most common categories of jargon used. METHODS: One of 3 trained medical students audited FCRs on a general pediatric service once weekly for 12 weeks, recording and categorizing jargon used with a published classification framework. Jargon usage was classified by category and quantified by using descriptive statistics. Rates were calculated by patient encounter and per minute. Feedback was provided to rounding teams after each observation. RESULTS: During 70 observed FCR patient encounters, there were a total of 443 jargon words or phrases spoken, of which 309 (70%) were not explicitly defined to the patient or family by the health care provider team. The mean number of undefined jargon words or phrases used per patient was 4.3 (±1.7), with a mean of 0.4 (±0.1) uses of undefined jargon per minute. The most common categories of undefined jargon used include technical terminology (eg, bronchiolitis), medical vernacular (eg, cultures), and abbreviations and acronyms (eg, NPO for "nothing by mouth") at 34%, 30%, and 17%, respectively. CONCLUSIONS: Undefined medical jargon was used frequently by health care providers during pediatric FCRs. We found it was feasible to measure provider jargon use and to use a jargon classification scheme to provide real-time, concrete feedback.

Frequency of false-positive FISH 1p/19q codeletion in adult diffuse astrocytic gliomas.

BACKGROUND: Oligodendroglioma is genetically defined by concomitant IDH (IDH1/IDH2) mutation and whole-arm 1p/19q codeletion. Codeletion of 1p/19q traditionally evaluated by fluorescence in situ hybridization (FISH) cannot distinguish partial from whole-arm 1p/19q codeletion. Partial 1p/19q codeletion called positive by FISH is diagnostically a "false-positive" result. Chromosomal microarray (CMA) discriminates partial from whole-arm 1p/19q codeletion. Herein, we aimed to estimate the frequency of partial 1p/19q codeletion that would lead to a false-positive FISH result. METHODS: FISH 1p/19q codeletion test probe coordinates were mapped onto Oncoscan CMA data to determine the rate of partial 1p/19q codeletion predicted to be positive by FISH. Diffuse astrocytic gliomas with available CMA data (2015-2018) were evaluated and classified based on IDH1-R132H/ATRX/p53 immunohistochemistry, IDH/TERT promoter targeted sequencing, and/or CMA according to classification updates. Predicted false-positive cases were verified by FISH whenever possible. RESULTS: The overall estimated false-positive FISH 1p/19q codeletion rate was 3.6% (8/223). Predicted false positives were verified by FISH in 6 (of 8) cases. False-positive rates did not differ significantly (P = .49) between IDH-mutant (4.6%; 4/86) and IDH-wildtype (2.9%; 4/137) tumors. IDH-wildtype false positives were all WHO grade IV, whereas IDH-mutant false positives spanned WHO grades II-IV. Testing for 1p/19q codeletion would not have been indicated for most false positives based on current classification recommendations. CONCLUSION: Selective 1p/19q codeletion testing and cautious interpretation for conflicting FISH and histopathological findings are recommended to avoid potential misdiagnosis.

Adult diffuse glioma GWAS by molecular subtype identifies variants in D2HGDH and FAM20C.

BACKGROUND: Twenty-five germline variants are associated with adult diffuse glioma, and some of these variants have been shown to be associated with particular subtypes of glioma. We hypothesized that additional germline variants could be identified if a genome-wide association study (GWAS) were performed by molecular subtype. METHODS: A total of 1320 glioma cases and 1889 controls were used in the discovery set and 799 glioma cases and 808 controls in the validation set. Glioma cases were classified into molecular subtypes based on combinations of isocitrate dehydrogenase (IDH) mutation, telomerase reverse transcriptase (TERT) promoter mutation, and 1p/19q codeletion. Logistic regression was applied to the discovery and validation sets to test for associations of variants with each of the subtypes. A meta-analysis was subsequently performed using a genome-wide P-value threshold of 5 × 10-8. RESULTS: Nine variants in or near D-2-hydroxyglutarate dehydrogenase (D2HGDH) on chromosome 2 were genome-wide significant in IDH-mutated glioma (most significant was rs5839764, meta P = 2.82 × 10-10). Further stratifying by 1p/19q codeletion status, one variant in D2HGDH was genome-wide significant in IDH-mutated non-codeleted glioma (rs1106639, meta P = 4.96 × 10-8). Further stratifying by TERT mutation, one variant near FAM20C (family with sequence similarity 20, member C) on chromosome 7 was genome-wide significant in gliomas that have IDH mutation, TERT mutation, and 1p/19q codeletion (rs111976262, meta P = 9.56 × 10-9). Thirty-six variants in or near GMEB2 on chromosome 20 near regulator of telomere elongation helicase 1 (RTEL1) were genome-wide significant in IDH wild-type glioma (most significant was rs4809313, meta P = 2.60 × 10-10). CONCLUSIONS: Performing a GWAS by molecular subtype identified 2 new regions and a candidate independent region near RTEL1, which were associated with specific glioma molecular subtypes.

Vitamin D3-mediated resistance to a multiple sclerosis model disease depends on myeloid cell 1,25-dihydroxyvitamin D3 synthesis and correlates with increased CD4+ T cell CTLA-4 expression.

Microglial cell activation is the earliest biomarker of the inflammatory processes that cause central nervous system (CNS) lesions in multiple sclerosis. We hypothesized that 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3) production by activated microglia and macrophages in the CNS inhibits these inflammatory processes. To test this hypothesis, we targeted the Cyp27b1 gene specifically in myeloid cells, then analyzed the influence of disrupted myeloid cell 1,25-(OH)2D3 synthesis on vitamin D3-mediated resistance to experimental autoimmune encephalomyelitis (EAE). Myeloid cell 1,25-(OH)2D3 synthesis was essential for vitamin D3-mediated EAE resistance. Increased CTLA-4 expression in the CNS-infiltrating CD4+ Tconv and Treg cells and decreased splenic B cell CD86 expression correlated with resistance. These new data provide solid support for the view that vitamin D3 reduces MS risk in part through a mechanism involving myeloid cell 1,25-(OH)2D3 production and CTLA-4 upregulation in CNS-infiltrating CD4+ T cells. We suggest that CTLA-4 serves as a vitamin D3-regulated immunological checkpoint in multiple sclerosis prevention.

Using germline variants to estimate glioma and subtype risks.

BACKGROUND: Twenty-five single nucleotide polymorphisms (SNPs) are associated with adult diffuse glioma risk. We hypothesized that the inclusion of these 25 SNPs with age at diagnosis and sex could estimate risk of glioma as well as identify glioma subtypes. METHODS: Case-control design and multinomial logistic regression were used to develop models to estimate the risk of glioma development while accounting for histologic and molecular subtypes. Case-case design and logistic regression were used to develop models to predict isocitrate dehydrogenase (IDH) mutation status. A total of 1273 glioma cases and 443 controls from Mayo Clinic were used in the discovery set, and 852 glioma cases and 231 controls from UCSF were used in the validation set. All samples were genotyped using a custom Illumina OncoArray. RESULTS: Patients in the highest 5% of the risk score had more than a 14-fold increase in relative risk of developing an IDH mutant glioma. Large differences in lifetime absolute risk were observed at the extremes of the risk score percentile. For both IDH mutant 1p/19q non-codeleted glioma and IDH mutant 1p/19q codeleted glioma, the lifetime risk increased from almost null to 2.3% and almost null to 1.7%, respectively. The SNP-based model that predicted IDH mutation status had a validation concordance index of 0.85. CONCLUSIONS: These results suggest that germline genotyping can provide new tools for the initial management of newly discovered brain lesions. Given the low lifetime risk of glioma, risk scores will not be useful for population screening; however, they may be useful in certain clinically defined high-risk groups.

Molecular subtyping of tumors from patients with familial glioma.

Background: Single-gene mutation syndromes account for some familial glioma (FG); however, they make up only a small fraction of glioma families. Gliomas can be classified into 3 major molecular subtypes based on isocitrate dehydrogenase (IDH) mutation and 1p/19q codeletion. We hypothesized that the prevalence of molecular subtypes might differ in familial versus sporadic gliomas and that tumors in the same family should have the same molecular subtype. Methods: Participants in the FG study (Gliogene) provided samples for germline DNA analysis. Formalin-fixed, paraffin-embedded tumors were obtained from a subset of FG cases, and DNA was extracted. We analyzed tissue from 75 families, including 10 families containing a second affected family member. Copy number variation data were obtained using a first-generation Affymetrix molecular inversion probe (MIP) array. Results: Samples from 62 of 75 (83%) FG cases could be classified into the 3 subtypes. The prevalence of the molecular subtypes was: 30 (48%) IDH-wildtype, 21 (34%) IDH-mutant non-codeleted, and 11 (19%) IDH-mutant and 1p/19q codeleted. This distribution of molecular subtypes was not statistically different from that of sporadic gliomas (P = 0.54). Of 10 paired FG samples, molecular subtypes were concordant for 7 (κ = 0.59): 3 IDH-mutant non-codeleted, 2 IDH-wildtype, and 2 IDH-mutant and 1p/19q codeleted gliomas. Conclusions: Our data suggest that within individual families, patients develop gliomas of the same molecular subtype. However, we did not observe differences in the prevalence of the molecular subtypes in FG compared with sporadic gliomas. These observations provide further insight into the distribution of molecular subtypes in FG.

Glioma Groups Based on 1p/19q, IDH, and TERT Promoter Mutations in Tumors.

BACKGROUND: The prediction of clinical behavior, response to therapy, and outcome of infiltrative glioma is challenging. On the basis of previous studies of tumor biology, we defined five glioma molecular groups with the use of three alterations: mutations in the TERT promoter, mutations in IDH, and codeletion of chromosome arms 1p and 19q (1p/19q codeletion). We tested the hypothesis that within groups based on these features, tumors would have similar clinical variables, acquired somatic alterations, and germline variants. METHODS: We scored tumors as negative or positive for each of these markers in 1087 gliomas and compared acquired alterations and patient characteristics among the five primary molecular groups. Using 11,590 controls, we assessed associations between these groups and known glioma germline variants. RESULTS: Among 615 grade II or III gliomas, 29% had all three alterations (i.e., were triple-positive), 5% had TERT and IDH mutations, 45% had only IDH mutations, 7% were triple-negative, and 10% had only TERT mutations; 5% had other combinations. Among 472 grade IV gliomas, less than 1% were triple-positive, 2% had TERT and IDH mutations, 7% had only IDH mutations, 17% were triple-negative, and 74% had only TERT mutations. The mean age at diagnosis was lowest (37 years) among patients who had gliomas with only IDH mutations and was highest (59 years) among patients who had gliomas with only TERT mutations. The molecular groups were independently associated with overall survival among patients with grade II or III gliomas but not among patients with grade IV gliomas. The molecular groups were associated with specific germline variants. CONCLUSIONS: Gliomas were classified into five principal groups on the basis of three tumor markers. The groups had different ages at onset, overall survival, and associations with germline variants, which implies that they are characterized by distinct mechanisms of pathogenesis. (Funded by the National Institutes of Health and others.).

Vitamin D Actions on CD4(+) T Cells in Autoimmune Disease.

This review summarizes and integrates research on vitamin D and CD4(+) T-lymphocyte biology to develop new mechanistic insights into the molecular etiology of autoimmune disease. A deep understanding of molecular mechanisms relevant to gene-environment interactions is needed to deliver etiology-based autoimmune disease prevention and treatment strategies. Evidence linking sunlight, vitamin D, and the risk of multiple sclerosis and type 1 diabetes is summarized to develop the thesis that vitamin D is the environmental factor that most strongly influences autoimmune disease development. Evidence for CD4(+) T-cell involvement in autoimmune disease pathogenesis and for paracrine calcitriol signaling to CD4(+) T lymphocytes is summarized to support the thesis that calcitriol is sunlight's main protective signal transducer in autoimmune disease risk. Animal modeling and human mechanistic data are summarized to support the view that vitamin D probably influences thymic negative selection, effector Th1 and Th17 pathogenesis and responsiveness to extrinsic cell death signals, FoxP3(+)CD4(+) T-regulatory cell and CD4(+) T-regulatory cell type 1 (Tr1) cell functions, and a Th1-Tr1 switch. The proposed Th1-Tr1 switch appears to bridge two stable, self-reinforcing immune states, pro- and anti-inflammatory, each with a characteristic gene regulatory network. The bi-stable switch would enable T cells to integrate signals from pathogens, hormones, cell-cell interactions, and soluble mediators and respond in a biologically appropriate manner. Finally, unanswered questions and potentially informative future research directions are highlighted to speed delivery of etiology-based strategies to reduce autoimmune disease.