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Open Access Publications from the University of California

Scholarly Works (12 results)

  • Article
  • Peer Reviewed
UCLA Previously Published Works (2017)

BACKGROUND:

Childhood germ cell tumors (GCTs) are a rare assortment of neoplasms, with mostly unknown etiology, that are believed to originate very early in life. Few studies have examined risk factors by histologic subtype, despite evidence of different risk profiles.

MATERIALS AND METHODS:

In this population-based case-control study, 451 childhood malignant GCT cases ages 0-5 years were identified from the California Cancer Registry. Differentiating between common histologic subtypes, we identified 181 yolk sac tumors, 216 teratomas, and 54 rarer subtypes. Cases were linked to their birth certificates and 271,381 controls, frequency matched by birth year, were randomly selected from California birthrolls to investigate the contributions of demographic, gestational, and pregnancy factors using unconditional logistic regression analysis.

RESULTS:

Compared to non-Hispanic whites, Asian/Pacific Islander children were at an increased risk for developing GCTs (odds ratio [OR]=1.94; 95% confidence interval [CI]=1.47, 2.56). Among pregnancy complications and procedures, yolk sac tumors were positively associated with the presence of fetopelvic disproportion (OR=2.97; 95% CI=1.55, 5.68), while teratomas were strongly associated with polyhydramnios or oligohydramnios (OR=14.76; 95% CI=7.21, 30.19) and the presence of an ear, face, or neck anomaly at birth (OR=93.70; 95% CI=42.14, 208.82).

CONCLUSIONS:

Malignant yolk sac tumors and malignant teratomas exhibited distinct demographic and gestational characteristics; additionally, complications in pregnancy and labor may be brought on by specific histologic subtypes.

    Cover page: Risk of malignant childhood germ cell tumors in relation to demographic, gestational, and perinatal characteristics
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2016)
    Smoking during pregnancy is a plausible risk factor for childhood cancer, yet previous studies have yielded conflicting results, and few prospective studies have been published. Data on maternal smoking were obtained from California birth certificates. We linked California birth certificates (births 2007-2011) with California Cancer Registry records for childhood cancer cases (diagnosed January 2007-September 2013) that were ages 5 or younger at diagnosis (N cases = 2,021). Controls (N = 40,356) were frequency-matched by birth year and randomly selected from birth certificate records. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI) to assess the association between smoking during pregnancy and childhood cancer. We observed positive associations for gliomas (OR = 1.8, 95% CI: 1.0-3.4) and retinoblastoma (OR = 3.0, 95% CI: 1.4-6.6), particularly bilateral retinoblastoma (OR = 9.4, 95% CI 3.6-24.7) with maternal smoking in pregnancy. Maternal smoking during pregnancy may be a risk factor for retinoblastoma and certain types of childhood brain tumors.
      • Article
      • Peer Reviewed
      Tobacco-Related Disease Research Program Funded Publications (2016)

      Smoking during pregnancy is a plausible risk factor for childhood cancer, yet previous studies have yielded conflicting results, and few prospective studies have been published. Data on maternal smoking were obtained from California birth certificates. We linked California birth certificates (births 2007-2011) with California Cancer Registry records for childhood cancer cases (diagnosed January 2007- September 2013) that were ages 5 or younger at diagnosis (N cases=2,021). Controls (N=40,356) were frequency-matched by birth year and randomly selected from birth certificate records. We used unconditional logistic regression to obtain odds ratios (OR) and 95% confidence intervals (CI) to assess the association between smoking during pregnancy and childhood cancer. We observed positive associations for gliomas (OR=1.8, 95% CI: 1.0-3.4) and retinoblastoma (OR=3.0, 95% CI: 1.4-6.6), particularly bilateral retinoblastoma (OR=9.4, 95% CI 3.6-24.7) with maternal smoking in pregnancy. Maternal smoking during pregnancy may be a risk factor for retinoblastoma and certain types of childhood brain tumors. This article is protected by copyright. All rights reserved.

        Cover page: Smoking in pregnancy and risk of cancer among young children: A population-based study.
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2016)

        Importance

        The Hispanic epidemiologic paradox is the phenomenon that non-US-born Hispanic mothers who immigrate to the United States have better pregnancy outcomes than their US-born counterparts. It is unknown whether this advantage extends to childhood cancer risk.

        Objective

        To determine whether the risk for childhood cancers among Hispanic children varies by maternal birthplace.

        Design, setting, and participants

        In this population-based case-control study conducted in June 2015, cohort members were identified through California birth records of children born in California from January 1, 1983, to December 31, 2011. Information on cancer diagnoses was obtained from California Cancer Registry records from 1988 to 2012. Cases (n = 13 666) were identified from among children younger than 6 years in the California Cancer Registry and matched to California birth certificates. Control children (n = 15 513 718) included all other children born in California during the same period. Maternal birthplace and ethnic ancestry were identified from the birth certificate.

        Main exposures

        Maternal race/ethnicity and birthplace.

        Main outcomes and measures

        We used Cox proportional hazards modeling to estimate hazard ratios (HRs) of childhood cancer.

        Results

        Included in the study were 4 246 295 children of non-Hispanic white mothers (51.3% male), 2 548 822 children of US-born Hispanic mothers (51.0% male), and 4 397 703 children of non-US-born Hispanic mothers (51.0% male). Compared with children of non-Hispanic white mothers, the children of non-US-born Hispanic mothers had a reduced risk for glioma (HR, 0.50; 95% CI, 0.44-0.58), astrocytoma (HR, 0.43; 95% CI, 0.36-0.51), neuroblastoma (HR, 0.47; 95% CI, 0.40-0.54), and Wilms tumor (HR, 0.70; 95% CI, 0.59-0.82). For these cancer types, the risk estimates for children of US-born Hispanic mothers fell between those of the children of US-born white and non-US-born Hispanic mothers. Children of Mexican-born mothers had a higher risk of yolk sac tumors (HR, 1.46; 95% CI, 0.99-2.17), while children of US-born Hispanic mothers with ancestry from countries other than Mexico had a higher risk for unilateral retinoblastoma (HR, 2.03; 95% CI, 1.33-3.11).

        Conclusions and relevance

        For several cancers, we observed differential risk by maternal place of birth. Examining the differences in health behaviors and environment between Hispanic groups may shed light on childhood cancer etiology.
          • Article
          • Peer Reviewed
          UC Irvine Previously Published Works (2020)
            Cover page: A case report of a novel germline GNAS mutation in sonic hedgehog activated medulloblastomaCreative Commons 'BY' version 4.0 license
            • Article
            • Peer Reviewed
            UCLA Previously Published Works (2012)
            Abstract Background Pierre-Robin sequence (PRS) is defined by micro- and/or retrognathia, glossoptosis and cleft soft palate, either caused by deformational defect or part of a malformation syndrome. Neurofibromatosis type 2 (NF2) is an autosomal dominant syndrome caused by mutations in the NF2 gene on chromosome 22q12.2. NF2 is characterized by bilateral vestibular schwannomas, spinal cord schwannomas, meningiomas and ependymomas, and juvenile cataracts. To date, NF2 and PRS have not been described together in the same patient. Case presentation We report a female with PRS (micrognathia, cleft palate), microcephaly, ocular hypertelorism, mental retardation and bilateral hearing loss, who at age 15 was also diagnosed with severe NF2 (bilateral cerebellopontine schwannomas and multiple extramedullary/intradural spine tumors). This is the first published report of an individual with both diagnosed PRS and NF2. High resolution karyotype revealed 46, XX, del(22)(q12.1q12.3), FISH confirmed a deletion encompassing NF2, and chromosomal microarray identified a 3,693 kb deletion encompassing multiple genes including NF2 and MN1 (meningioma 1). Five additional patients with craniofacial dysmorphism and deletion in chromosome 22-adjacent-to or containing NF2 were identified in PubMed and the DECIPHER clinical chromosomal database. Their shared chromosomal deletion encompassed MN1, PITPNB and TTC28. MN1, initially cloned from a patient with meningioma, is an oncogene in murine hematopoiesis and participates as a fusion gene (TEL/MN1) in human myeloid leukemias. Interestingly, Mn1-haploinsufficient mice have abnormal skull development and secondary cleft palate. Additionally, Mn1 regulates maturation and function of calvarial osteoblasts and is an upstream regulator of Tbx22, a gene associated with murine and human cleft palate. This suggests that deletion of MN1 in the six patients we describe may be causally linked to their cleft palates and/or craniofacial abnormalities. Conclusions Thus, our report describes a NF2-adjacent chromosome 22q12.2 deletion syndrome and is the first to report association of MN1 deletion with abnormal craniofacial development and/or cleft palate in humans.
              Cover page: Microdeletion del(22)(q12.2) encompassing the facial development-associated gene, MN1 (meningioma 1) in a child with Pierre-Robin sequence (including cleft palate) and neurofibromatosis 2 (NF2): a case report and review of the literature
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2016)
              Although immunotherapeutic strategies are emerging as adjunctive treatments for cancer, sensitive methods of monitoring the immune response after treatment remain to be established. We used a novel next-generation sequencing approach to determine whether quantitative assessments of tumor-infiltrating lymphocyte (TIL) content and the degree of overlap of T-cell receptor (TCR) sequences in brain tumors and peripheral blood were predictors of immune response and overall survival in glioblastoma patients treated with autologous tumor lysate-pulsed dendritic cell immunotherapy. A statistically significant correlation was found between a higher estimated TIL content and increased time to progression and overall survival. In addition, we were able to assess the proportion of shared TCR sequences between tumor and peripheral blood at time points before and after therapy, and found the level of TCR overlap to correlate with survival outcomes. Higher degrees of overlap, or the development of an increased overlap following immunotherapy, was correlated with improved clinical outcome, and may provide insights into the successful, antigen-specific immune response. Cancer Immunol Res; 4(5); 412-8. ©2016 AACR.
                Cover page: TCR Sequencing Can Identify and Track Glioma-Infiltrating T Cells after DC Vaccination
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2019)

                Purpose

                Glioblastoma (GBM) is the most common primary malignant tumor in the central nervous system. Our recent preclinical work has suggested that PD-1/PD-L1 plays an important immunoregulatory role to limit effective antitumor T-cell responses induced by active immunotherapy. However, little is known about the functional role that PD-1 plays on human T lymphocytes in patients with malignant glioma.Experimental Design: In this study, we examined the immune landscape and function of PD-1 expression by T cells from tumor and peripheral blood in patients with malignant glioma.

                Results

                We found several differences between PD-1+ tumor-infiltrating lymphocytes (TIL) and patient-matched PD-1+ peripheral blood T lymphocytes. Phenotypically, PD-1+ TILs exhibited higher expression of markers of activation and exhaustion than peripheral blood PD-1+ T cells, which instead had increased markers of memory. A comparison of the T-cell receptor variable chain populations revealed decreased diversity in T cells that expressed PD-1, regardless of the location obtained. Functionally, peripheral blood PD-1+ T cells had a significantly increased proliferative capacity upon activation compared with PD-1- T cells.

                Conclusions

                Our evidence suggests that PD-1 expression in patients with glioma reflects chronically activated effector T cells that display hallmarks of memory and exhaustion depending on its anatomic location. The decreased diversity in PD-1+ T cells suggests that the PD-1-expressing population has a narrower range of cognate antigen targets compared with the PD-1 nonexpression population. This information can be used to inform how we interpret immune responses to PD-1-blocking therapies or other immunotherapies.
                  Cover page: Expression of PD-1 by T Cells in Malignant Glioma Patients Reflects Exhaustion and Activation
                  • Article
                  • Peer Reviewed
                  UC San Francisco Previously Published Works (2018)
                  Abstract Glioblastoma is the most common malignant brain tumor in adults and is associated with poor survival. It is often resistant to standard-of-care chemotherapy and radiation, necessitating the development of more effective treatments. The Ivy Foundation Early Phase Clinical Trials’ Consortium conducted a randomized, multi-institution clinical trial to evaluate the immune response and survival following neoadjuvant and adjuvant therapy with pembrolizumab, a PD-1 monoclonal antibody, in thirty patients with recurrent, surgically resectable glioblastoma. Patients who received neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that received adjuvant, post-surgical PD-1 blockade alone (HR=0.33, p<0.008, log-rank test). Survival was directly associated with an elevated IFN-g gene expression signature in the tumor, but only in patients who received neoadjuvant PD-1 blockade (HR=0.15, p<0.02, Wald test). Focal induction of PD-L1 in the tumor microenvironment was observed in the neoadjuvant group and linked with the IFN-g gene expression signature and extended survival. Similarly, neoadjuvant pembrolizumab was associated with expanded T cell receptor clones, increased markers of activation in CD8+ T cells that expressed PD-1, and a decreasing monocytic population in the peripheral blood (p<0.03, two-sided t-test). These findings suggest that the neoadjuvant timing of PD-1 blockade enhances the local and systemic immune response, and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
                    Cover page: ATIM-12. NEOADJUVANT ANTI-PD-1 IMMUNOTHERAPY PROMOTES INTRATUMORAL AND SYSTEMIC IMMUNE RESPONSES IN RECURRENT GLIOBLASTOMA: AN IVY CONSORTIUM TRIAL
                    • Article
                    • Peer Reviewed
                    UCLA Previously Published Works (2019)
                    Glioblastoma is the most common primary malignant brain tumor in adults and is associated with poor survival. The Ivy Foundation Early Phase Clinical Trials Consortium conducted a randomized, multi-institution clinical trial to evaluate immune responses and survival following neoadjuvant and/or adjuvant therapy with pembrolizumab in 35 patients with recurrent, surgically resectable glioblastoma. Patients who were randomized to receive neoadjuvant pembrolizumab, with continued adjuvant therapy following surgery, had significantly extended overall survival compared to patients that were randomized to receive adjuvant, post-surgical programmed cell death protein 1 (PD-1) blockade alone. Neoadjuvant PD-1 blockade was associated with upregulation of T cell- and interferon-γ-related gene expression, but downregulation of cell-cycle-related gene expression within the tumor, which was not seen in patients that received adjuvant therapy alone. Focal induction of programmed death-ligand 1 in the tumor microenvironment, enhanced clonal expansion of T cells, decreased PD-1 expression on peripheral blood T cells and a decreasing monocytic population was observed more frequently in the neoadjuvant group than in patients treated only in the adjuvant setting. These findings suggest that the neoadjuvant administration of PD-1 blockade enhances both the local and systemic antitumor immune response and may represent a more efficacious approach to the treatment of this uniformly lethal brain tumor.
                      Cover page: Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma
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