Browsing by Subject "tumors"

Now showing 1 - 5 of 5
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    Effect of Midtreatment PET/CT-Adapted Radiation Therapy With Concurrent Chemotherapy in Patients With Locally Advanced Non–Small-Cell Lung Cancer
    (American Medical Association, 2017-10-01) Kong, Feng-Ming; Ten Haken, Randall K.; Schipper, Matthew; Frey, Kirk A.; Hayman, James; Gross, Milton; Ramnath, Nithya; Hassan, Khaled A.; Matuszak, Martha; Ritter, Timothy; Bi, Nan; Wang, Weili; Orringer, Mark; Cease, Kemp B.; Lawrence, Theodore S.; Kalemkerian, Gregory P.; Radiation Oncology, School of Medicine
    IMPORTANCE Our previous studies demonstrated that tumors significantly decrease in size and metabolic activity after delivery of 45 Gy of fractionated radiatiotherapy (RT), and that metabolic shrinkage is greater than anatomic shrinkage. This study aimed to determine whether 18F-fludeoxyglucose–positron emission tomography/computed tomography (FDG-PET/CT) acquired during the course of treatment provides an opportunity to deliver higher-dose radiation to the more aggressive areas of the tumor to improve local tumor control without increasing RT-induced lung toxicity (RILT), and possibly improve survival. OBJECTIVE To determine whether adaptive RT can target high-dose radiation to the FDG-avid tumor on midtreatment FDG-PET to improve local tumor control of locally advanced non–small-cell lung cancer (NSCLC). DESIGN, SETTING, AND PARTICIPANTS A phase 2 clinical trial conducted at 2 academic medical centers with 42 patients who had inoperable or unresectable stage II to stage III NSCLC enrolled from November 2008, to May 2012. Patients with poor performance, more than 10% weight loss, poor lung function, and/or oxygen dependence were included, providing that the patients could tolerate the procedures of PET scanning and RT. INTERVENTION Conformal RT was individualized to a fixed risk of RILT (grade >2) and adaptively escalated to the residual tumor defined on midtreatment FDG-PET up to a total dose of 86 Gy in 30 daily fractions. Medically fit patients received concurrent weekly carboplatin plus paclitaxel followed by 3 cycles of consolidation. MAIN OUTCOMES AND MEASURES The primary end point was local tumor control. The trial was designed to achieve a 20% improvement in 2-year control from 34% of our prior clinical trial experience with 63 to 69 Gy in a similar patient population. RESULTS The trial reached its accrual goal of 42 patients: median age, 63 years (range, 45–83 years); male, 28 (67%); smoker or former smoker, 39 (93%); stage III, 38 (90%). Median tumor dose delivered was 83 Gy (range, 63–86 Gy) in 30 daily fractions. Median follow-up for surviving patients was 47 months. The 2-year rates of infield and overall local regional tumor controls (ie, including isolated nodal failure) were 82% (95% CI, 62%–92%) and 62% (95% CI, 43%–77%), respectively. Median overall survival was 25 months (95% CI, 12–32 months). The 2-year and 5-year overall survival rates were 52% (95% CI, 36%–66%) and 30% (95% CI, 16%–45%), respectively. CONCLUSIONS AND RELEVANCE Adapting RT-escalated radiation dose to the FDG-avid tumor detected by midtreatment PET provided a favorable local-regional tumor control. The RTOG 1106 trial is an ongoing clinical trial to validate this finding in a randomized fashion. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01190527
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    ENHANCING THE TUMOR FIGHTING CAPACITY OF NK CELLS THROUGH THE USE OF SOYPEPTIDE
    (Office of the Vice Chancellor for Research, 2012-04-13) Lewis, David; Chang, Hua-Chen; Han, Ling; Voiles, Larry; Henriquez, Sarah M.P.
    Natural killer or (NK) cells are important components of the innate immune system, which play a major role in the rejection of tumors, and virally in-fected cells. By producing pro-inflammatory cytokines such as IFN-gamma, NK cells are able to exert immunoregulatory functions that influence the adaptive immunity of other immune cells. Due to its critical role in tumor inhibition, researchers, utilizing various cytokines, including IL-12 and IL-2, have fervently pursued the manipulation of NK activity. NK cells respond to cytokines in a dose-dependent manner; however, the toxicity of certain cy-tokines (like IL-2) in high doses prohibits their widespread clinical use. Therefore, efforts to activate NK cells without requiring high doses of cyto-kines is warranted. We recently exploited a soy derived dietary peptide called lunasin to improve the immune functions. The hypothesis was that the lunasin peptide has stimulatory effects on immune cells. To test this hy-pothesis, human peripheral blood mononuclear cells (PBMCs) of healthy do-nors were stimulated with and without lunasin in combination with cytokines IL-12 or IL-2. Our results showed that the lunasin peptide exerts a robust synergistic effect when combined with the selected cytokines. This effect ap-pears to regulate the expression of a number of genes that are important for NK activity. Our findings support the potential clinical use of lunasin in com-bination with cytokine to enhance the tumor fighting capacity of NK cells.
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    Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2
    (Rockefeller University Press, 2017-05-01) Moffitt, Andrea B.; Ondrejka, Sarah L.; McKinney, Matthew; Rempel, Rachel E.; Goodlad, John R.; Teh, Chun Huat; Leppa, Sirpa; Mannisto, Susanna; Kovanen, Panu E.; Tse, Eric; Au-Yeung, Rex K.H.; Kwong, Yok-Lam; Srivastava, Gopesh; Iqbal, Javeed; Yu, Jiayu; Naresh, Kikkeri; Villa, Diego; Gascoyne, Randy D.; Said, Jonathan; Czader, Magdalena B.; Chadburn, Amy; Richards, Kristy L.; Rajagopalan, Deepthi; Davis, Nicholas S.; Smith, Eileen C.; Palus, Brooke C.; Tzeng, Tiffany J.; Healy, Jane A.; Lugar, Patricia L.; Datta, Jyotishka; Love, Cassandra; Levy, Shawn; Dunson, David B.; Zhuang, Yuan; Hsi, Eric D.; Dave, Sandeep S.; Pathology and Laboratory Medicine, School of Medicine
    Enteropathy-associated T cell lymphoma (EATL) is the most common oncologic complication of celiac disease. Moffitt and colleagues identify novel EATL-defining mutations in SETD2, as well as clinically relevant mutations in the JAK-STAT pathway., Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1. We also identified mutations in KRAS, TP53, and TERT. Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.
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    HOXB13 Mediates Tamoxifen Resistance and Invasiveness in Human Breast Cancer by Suppressing ERα and Inducing IL-6 Expression
    (American Association for Cancer Research, 2013-09-01) Shah, Nilay; Jin, Kideok; Cruz, Leigh-Ann; Park, Sunju; Sadik, Helen; Cho, Soonweng; Goswami, Chirayu Pankaj; Nakshatri, Harikrishna; Gupta, Rajnish; Chang, Howard Y.; Zhang, Zhe; Cimino-Mathews, Ashley; Cope, Leslie; Umbricht, Christopher; Sukumar, Saraswati
    Most breast cancers expressing the estrogen receptor α (ERα) are treated successfully with the receptor antagonist tamoxifen (TAM), but many of these tumors recur. Elevated expression of the homeodomain transcription factor HOXB13 correlates with TAM-resistance in ERα-positive (ER+) breast cancer, but little is known regarding the underlying mechanism. Our comprehensive evaluation of HOX gene expression using tiling microarrays, with validation, showed that distant metastases from TAM-resistant patients also displayed high HOXB13 expression, suggesting a role for HOXB13 in tumor dissemination and survival. Here we show that HOXB13 confers TAM resistance by directly downregulating ERα transcription and protein expression. HOXB13 elevation promoted cell proliferation in vitro and growth of tumor xenografts in vivo. Mechanistic investigations showed that HOXB13 transcriptionally upregulated interleukin (IL)-6, activating the mTOR pathway via STAT3 phosphorylation to promote cell proliferation and fibroblast recruitment. Accordingly, mTOR inhibition suppressed fibroblast recruitment and proliferation of HOXB13-expressing ER+ breast cancer cells and tumor xenografts, alone or in combination with TAM. Taken together, our results establish a function for HOXB13 in TAM resistance through direct suppression of ERα and they identify the IL-6 pathways as mediator of disease progression and recurrence.
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    STAT3 activation impairs the stability of Th9 cells
    (American Association of Immunologists, 2017-03-15) Ulrich, Benjamin J.; Verdan, Felipe Fortino; McKenzie, Andrew N.J.; Kaplan, Mark H.; Olson, Matthew R.; Microbiology and Immunology, School of Medicine
    Th9 cells regulate multiple immune responses including immunity to pathogens and tumors, allergic inflammation, and autoimmunity. Despite ongoing research into Th9 development and function, little is known about the stability of the Th9 phenotype. In this report we demonstrate that IL-9 production is progressively lost in Th9 cultures over several rounds of differentiation. The loss of IL-9 is not due to an outgrowth of cells that do not secrete IL-9, as purified IL-9 secretors demonstrate the same loss of IL-9 in subsequent rounds of differentiation. The loss of IL-9 production correlates with increases in phospho-STAT3 levels within the cell, and the production of IL-10. STAT3-deficient Th9 cells have increased IL-9 production that is maintained for longer in culture than IL-9 in control cultures. IL-10 is responsible for STAT3 activation during the first round of differentiation, and contributes to instability in subsequent rounds of culture. Together, our results indicate that environmental cues dictate the instability of the Th9 phenotype, and suggest approaches to enhance Th9 activity in beneficial immune responses.