Assessment of Therapeutic Outcome and Role of Reirradiation in Patients With Radiation-induced Glioma

Abstract Background: We retrospectively reviewed the clinical characteristics and treatment outcomes to clarify the optimal therapeutic strategy, especially the role of reirradiation in patients with radiation-induced glioma (RIG). Methods: We identified patients with high-grade glioma who satisfied Cahan’s criteria for RIG in our database during 2001–2021 and analyzed the outcomes.Results: We identified 11 patients with RIG. The primary diseases included germinomas (n=2), acute lymphoblastic lymphomas (n=2), medulloblastomas (n=3), diffuse astrocytoma with isocitrate dehydrogenase (IDH) 2 mutant (n=1), pilocytic astrocytoma (n=1), pituitary adenoma (n=1), and a metastatic tumor from lung cancer (n=1). The median latency period was 17 years (range: 9–30 years). The RIGs included glioblastoma with IDH 1/2 wild-type (n=7), glioblastoma not otherwise specified (n=2), anaplastic astrocytoma with IDH1/2 wild-type (n=1), and anaplastic astrocytoma not otherwise specified (n=1). All patients underwent tumor removal or biopsy, 5 patients postoperatively received reirradiation combined with chemotherapy, and 6 patients were treated with chemotherapy alone. The median progression-free and overall survival times were 11.3 and 28.3 months, respectively. The median progression-free survival time of patients treated with reirradiation and chemotherapy (n=5) tended to be longer than that of patients that received chemotherapy alone (n=6) (17.0 vs 8.1 months; p=0.45); the median survival time was similar (29.6 vs 27.4 months; p=0.28). Local recurrences were observed less frequently in patients who received reirradiation combined with chemotherapy (50%) than in those who received chemotherapy alone (100%; p=0.046). None of the patients developed radiation necrosis. In one case, the different IDH2 mutational states between the primary and secondary tumors were useful for diagnosing the secondary tumor as RIG. Conclusions: RIG can occur more than 20 years after successful treatment of the primary disease using radiotherapy; thus, follow-up times should be extended to 30 years. Reirradiation combined with chemotherapy appears to be feasible and have favorable outcomes. Identifying the IDH1/2 mutational status can have a diagnostic effect on establishing RIG in recurrent gliomas.

Download Full-text

The Arabidopsis HOP2 Gene Has a Role in Preventing illegitimate Exchanges between Nonhomologous Chromosomes

10.1101/2021.08.04.455073 ◽

2021 ◽

Author(s):

YIsell Farahani-Tafreshi ◽

Chun Wei ◽

Peilu Gan ◽

Jenya Daradur ◽

C. Daniel Riggs ◽

...

Keyword(s):

Active Role ◽

Crossing Over ◽

Wild Type ◽

Positive Role ◽

Homologous Chromosomes ◽

Chromosome Synapsis ◽

Radiation Induced ◽

Nonhomologous Chromosome ◽

Chromosome Exchanges

Meiotic homologous chromosomes pair up and undergo crossing over. In many eukaryotes both intimate pairing and crossing over require the induction of double stranded breaks (DSBs) and subsequent repair via Homologous Recombination (HR). In these organisms, two key proteins are the recombinases RAD51 and DMC1. Recombinase-modulators HOP2 and MND1 have been identified as proteins that assist RAD51 and DMC1 and are needed to promote stabilized pairing. We have probed the nature of the genetic lesions seen in hop2 mutants and looked at the role of HOP2 in the fidelity of genetic exchanges. Using γH2AX as a marker for unrepaired DSBs we found that hop2-1 and mnd1 mutants have different appearance/disappearance for DSBs than wild type, but all DSBs are repaired by mid-late pachytene. Therefore, the bridges and fragments seen from metaphase I onward are due to mis-repaired DSBs, not unrepaired ones. Studying Arabidopsis haploid meiocytes we found that wild type haploids produced the expected five univalents, but hop2-1 haploids suffered many illegitimate exchanges that were stable enough to produce bridged chromosomes during segregation. Our results suggest that HOP2 has a significant active role in preventing nonhomologous associations. We also found evidence that HOP2 plays a role in preventing illegitimate exchanges during repair of radiation-induced DSBs in rapidly dividing petal cells. Thus, HOP2 plays both a positive role in promoting homologous chromosome synapsis and a separable role in preventing nonhomologous chromosome exchanges. Possible mechanisms for this second important role are discussed.

Download Full-text

The AIM2 and NLRP3 inflammasomes trigger IL-1–mediated antitumor effects during radiation

Science Immunology ◽

10.1126/sciimmunol.abc6998 ◽

2021 ◽

Vol 6 (59) ◽

pp. eabc6998

Author(s):

Chuanhui Han ◽

Victoria Godfrey ◽

Zhida Liu ◽

Yanfei Han ◽

Longchao Liu ◽

...

Keyword(s):

Antitumor Immunity ◽

Radiation Treatment ◽

Wild Type ◽

Antitumor Effects ◽

Radiation Induced ◽

Effects Of Radiation ◽

Nlrp3 Inflammasomes ◽

Priming Activity ◽

Deficient Mice

The inflammasome promotes inflammation-associated diseases, including cancer, and contributes to the radiation-induced tissue damage. However, the role of inflammasome in radiation-induced antitumor effects is unclear. We observed that tumors transplanted in Casp1−/− mice were resistant to radiation treatment compared with tumors in wild-type (WT) mice. To map out which molecule in the inflammasome pathway contributed to this resistant, we investigated the antitumor effect of radiation in several inflammasome-deficient mice. Tumors grown in either Aim2−/− or Nlrp3−/− mice remained sensitive to radiation, like WT mice, whereas Aim2−/−Nlrp3−/− mice showed radioresistance. Mechanistically, extracellular vesicles (EVs) and EV-free supernatant derived from irradiated tumors activated both Aim2 and Nlrp3 inflammasomes in macrophages, leading to the production of interleukin-1β (IL-1β). IL-1β treatment helped overcome the radioresistance of tumors growing in Casp1−/− and Aim2−/−Nlrp3−/− mice. IL-1 signaling in dendritic cells (DCs) promoted radiation-induced antitumor immunity by enhancing the cross-priming activity of DCs. Overall, we demonstrated that radiation-induced activation of the AIM2 and NLRP3 inflammasomes coordinate to induce some of the antitumor effects of radiation by triggering IL-1 signaling in DCs, leading to their activation and cross-priming.

Download Full-text

Amphiregulin (AR) expression in the prediction of benefit from cetuximab plus irinotecan in KRAS wild-type metastatic colorectal cancer (mCRC) patients

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.4021 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 4021-4021

Author(s):

F. Loupakis ◽

C. Cremolini ◽

G. Perrone ◽

I. Stasi ◽

L. Salvatore ◽

...

Keyword(s):

Growth Factor Receptor ◽

Median Number ◽

Prognostic Impact ◽

Wild Type ◽

Primary Tumors ◽

Tissue Sections ◽

Mutational Status ◽

Epidermal Growth ◽

Score Range

4021 Background: AR is an endogenous ligand of Epidermal Growth Factor Receptor (EGFR), whose binding is prevented in the presence of cetuximab. Methods: We retrospectively assessed KRAS mutational status and AR expression at immunohistochemistry (IHC) in 86 irinotecan-refractory EGFR-positive mCRC patients treated with cetuximab plus irinotecan. AR-IHC was performed on tissue sections from paraffin-embedded primary tumors. Specimens were defined AR-low or AR-high according to a score (range 0–300) obtained multiplying intensity (0 to 3+) by percentage of stained cells (0–100%). According to the results of a ROC analysis, we identified a cut-off value of 18. The association between AR-IHC and treatment outcome in terms of response rate (RR), PFS, and OS was investigated in the subgroup of KRAS wild-type patients. Results: Eighty-six consecutive patients were included. M/F = 44/42, median age = 67 (41–78), median number of previous lines of chemotherapy = 2 (1–5). Among 51 (59%) KRAS wild-type patients, 12 PRs and 1 CR were observed, for an overall RR of 25% (13/51). AR-IHC was high, low or unconclusive in 27, 22 and 2 cases respectively. AR-low patients reported a significantly worse RR (2/22, 9%) compared with AR-high (10/27, 37%) (p = 0.024) and a trend toward shorter PFS (3.5 vs 5.3 months, HR 0.88 [95%CI: 0.46–1.60], p = 0.628) and OS (8.8 vs 15.1 months, HR 0.60 [95%CI: 0.30–1.10], p = 0.106). Conclusions: These results underline the potential role of endogenous ligands in influencing the activity of anti-EGFR monoclonal antibodies. Absent or low AR expression at IHC may be related to resistance to cetuximab plus irinotecan. Further data regarding the prognostic impact of AR expression are needed. No significant financial relationships to disclose.

Download Full-text

The Contribution of PspC to Pneumococcal Virulence Varies between Strains and Is Accomplished by Both Complement Evasion and Complement-Independent Mechanisms

Infection and Immunity ◽

10.1128/iai.00543-06 ◽

2006 ◽

Vol 74 (9) ◽

pp. 5319-5324 ◽

Cited By ~ 36

Author(s):

Alison R. Kerr ◽

Gavin K. Paterson ◽

Jackie McCluskey ◽

Francesco Iannelli ◽

Marco R. Oggioni ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Protein C ◽

Pneumococcal Pneumonia ◽

Surface Protein ◽

Murine Models ◽

Wild Type ◽

Survival Times ◽

Pneumococcal Strain ◽

Wild Type Parent

ABSTRACTPneumococcal surface protein C (PspC) is a virulence factor ofStreptococcus pneumoniaepreviously shown to play a role in bacterial adherence, invasion, and evasion of complement. We investigated the role of this protein in our murine models of pneumococcal pneumonia with different pneumococcal strains. The deletion ofpspCin strains of serotypes 2, 3, and 19F did not significantly alter host survival times in the pneumonia model. In contrast,pspCdeletion significantly reduced the virulence of the serotype 4 strain, TIGR4, in both the pneumonia and bacteremia models. Therefore,pspCis a systemic and pulmonary virulence determinant forS. pneumoniae, but its effects are influenced by the pneumococcal strain. Finally, pneumonia infection of complement-deficient (C3−/−) mice enhancedpspCvirulence, illustrating that PspC-mediated complement evasion contributes to virulence. However, other functions of PspC also contribute to virulence, as demonstrated by the finding that thepspC-deficient TIGR4 mutant was still attenuated relative to the wild-type parent, even in the absence of C3.

Download Full-text

The Haemostatic Mechanism and Menstruation: The Role of Intra-Uterine Contraceptive Devices

Thrombosis and Haemostasis ◽

10.1055/s-0038-1657057 ◽

1979 ◽

Vol 42 (05) ◽

pp. 1548-1556 ◽

Cited By ~ 2

Author(s):

S M Rajah ◽

M E Foley ◽

J K Clayton ◽

S R Aparicio ◽

C C Bird ◽

...

Keyword(s):

Survival Time ◽

Survival Times ◽

Platelet Function Tests ◽

Control Groups ◽

Contraceptive Devices ◽

Platelet Survival ◽

Before And After ◽

And Control ◽

Platelet Functions

SummaryThe haemostatic mechanism of 40 female patients undergoing menstruation, 20 with intra-uterine devices (IUCD) and 20 without (Control), were studied. The patients’ coagulation profiles, fibrinolytic system and platelet functions were studied before and after hysterectomy. Platelet survival times and platelet consumption was determined using 51Cr. labelled autologous platelets. Patients who menstruated during the study had their pads collected and radioactivity measured. Histology, autoradiography and scintillation counting was performed on uteri obtained from a hysterectomy performed towards the end of the platelet survival study period. There were no significant differences in the coagulation, fibrinolytic and platelet function tests in these 2 groups, though in each group there were the expected changes after operation.Platelet survival time, consumption and radioactivity in the tampons showed no significant differences between the IUCD and control groups, although there were 6 patients with low platelet survival times in the IUCD group. Resected uteri showed surprising lack of concentration of platelets which may have been due in part to loss of blood at operation and handling of the uterus. Surprisingly, in the control patients, platelet survival time in response to the severe haemosatic challenge of menstruation were normal. However in the IUCD group, 6 patients showed shortening of platelet survival. Also surprisingly and equally in both control and IUCD groups, was the small amount of platelet related radioactivity in the menstruating fluid.

Download Full-text

The Role of Wild-Type p53 in Cisplatin-Induced Chk2 Phosphorylation and the Inhibition of Platinum Resistance with a Chk2 Inhibitor

Chemotherapy Research and Practice ◽

10.1155/2011/715469 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 3

Author(s):

Xiaobing Liang ◽

Yi Guo ◽

William Douglas Figg ◽

Antonio Tito Fojo ◽

Michael D. Mueller ◽

...

Keyword(s):

Alternative Pathway ◽

Functional Differentiation ◽

Platinum Resistance ◽

Wild Type ◽

Mutational Status ◽

Molecule Inhibitor ◽

Research Goal ◽

Wild Type P53 ◽

Platinum Chemotherapy

The major obstacle in platinum chemotherapy is the repair of platinum-damaged DNA that results in increased resistance, reduced apoptosis, and finally treatment failure. Our research goal is to determine and block the mechanisms of platinum resistance. Our recent studies demonstrate that several kinases in the DNA-repair pathway are activated after cells are exposed to cisplatin. These include ATM, p53, and Chk2. The increased Chk2 phosphorylation is modulated by p53 in a wild-type p53 model. Overexpression of p53 by cDNA transfection in wt-p53 (but not p53 deficient) cells doubled the amount of Chk2 phosphorylation 48 hours after cisplatin treatment. p53 knockdown by specific siRNA greatly reduced Chk2 phosphorylation. We conclude that wild-type p53, in response to cisplatin stimulation, plays a role in the upstream regulation of Chk2 phosphorylation at Thr-68. Cells without normal p53 function survive via an alternative pathway in response to the exogenous influence of cisplatin. We strongly suggest that it is very important to include the p53 mutational status in any p53 involved studies due to the functional differentiation of wt p53 and p53 mutant. Inhibition of Chk2 pathway with a Chk2 inhibitor (C3742) increased cisplatin efficacy, especially those with defective p53. Our findings suggest that inhibition of platinum resistance can be achieved with a small-molecule inhibitor of Chk2, thus improving the therapeutic indices for platinum chemotherapy.

Download Full-text

IRTKS is correlated with progression and survival time of patients with gastric cancer

Gut ◽

10.1136/gutjnl-2016-313478 ◽

2017 ◽

Vol 67 (8) ◽

pp. 1400-1409 ◽

Cited By ~ 10

Author(s):

Li-Yu Huang ◽

Xuefei Wang ◽

Xiao-Fang Cui ◽

He Li ◽

Junjie Zhao ◽

...

Keyword(s):

Gastric Cancer ◽

Survival Time ◽

Target Genes ◽

Human Gastric Cancer ◽

Wild Type ◽

Gastric Cancer Cells ◽

Ubiquitin Proteasome ◽

Proteasome Pathway

Background and objectivesIRTKS functions as a novel regulator of tumour suppressor p53; however, the role of IRTKS in pathogenesis of gastric cancer is unclear.DesignWe used immunohistochemistry to detect IRTKS levels in 527 human gastric cancer specimens. We generated both IRTKS-deficient and p53-deficient mice to observe survival time of these mice and to isolate mouse embryonic fibroblasts (MEFs) for evaluating in vivo tumorigenicity. Co-immunoprecipitation was used to study the interaction among p53, MDM2 and IRTKS, as well as the ubiquitination of p53.ResultsIRTKS was significantly overexpressed in human gastric cancer, which was conversely associated with wild-type p53 expression. Among patients with wild-type p53 (n=206), those with high IRTKS expression (n=141) had a shorter survival time than those with low IRTKS (n=65) (p=0.0153). Heterozygous p53+/− mice with IRTKS deficiency exhibited significantly delayed tumorigenesis and an extended tumour-free survival time. p53+/− MEFs without IRTKS exhibited attenuated in vivo tumorigenicity. IRTKS depletion upregulated p53 and its target genes, such as BAX and p21. Intriguingly, IRTKS overexpression promoted p53 ubiquitination and degradation in MEFs and gastric cancer cells. Under DNA damage conditions, IRTKS was phosphorylated at Ser331 by the activated Chk2 kinase and then dissociated from p53, along with the p53-specific E3 ubiquitin ligase MDM2, resulting in attenuated p53 ubiquitination and degradation.ConclusionIRTKS overexpression is negatively correlated with progression and overall survival time of patients with gastric cancer with wild-type p53 through promotion of p53 degradation via the ubiquitin/proteasome pathway.

Download Full-text

Activation of Notch1 drives the development of radiation-induced thymic lymphoma in p53 wild-type mice

10.1101/2020.08.21.261487 ◽

2020 ◽

Author(s):

Chang-Lung Lee ◽

Kennedy Davis Brock ◽

Stephanie Hasapis ◽

Dadong Zhang ◽

Alexander B. Sibley ◽

...

Keyword(s):

Lymphoblastic Leukemia ◽

Critical Role ◽

Wild Type ◽

Thymic Lymphoma ◽

Normal Tissues ◽

Notch1 Signaling ◽

Mutational Status ◽

Recurrent Mutations ◽

Radiation Induced

ABSTRACTMouse models of radiation-induced thymic lymphoma are widely used to study the development of radiation-induced blood cancers and to gain insights into the biology of human T-lymphoblastic leukemia/lymphoma. Here, we aimed to determine key oncogenic drivers for the development of radiation-induced thymic lymphoma by performing whole-exome sequencing using tumors and paired normal tissues from mice with and without irradiation. Thymic lymphomas from irradiated wild-type (WT), p53+/- and KrasLA1 mice were not observed to harbor significantly higher numbers of non-synonymous somatic mutations compared to thymic lymphomas from unirradiated p53-/- mice. However, we observed distinct patterns of recurrent mutations in genes that control the Notch1 signaling pathway based on the mutational status of p53. Preferential activation of Notch1 signaling in p53 WT lymphomas was also observed at the RNA and protein level. Using reporter mice for activation of the Notch1 signaling we observed that TBI enriched Notch1hi CD44+ thymocytes, which are capable of self-renewal in vivo. Mechanistically, genetic inhibition of Notch1 signaling in thymocytes prevented the formation of radiation-induced thymic lymphoma in p53 WT mice. Taken together, our results demonstrate a critical role of activated Notch1 signaling in driving multi-step carcinogenesis of thymic lymphoma following total-body irradiation in p53 WT mice.

Download Full-text

The Ami-AliA/AliB Permease of Streptococcus pneumoniae Is Involved in Nasopharyngeal Colonization but Not in Invasive Disease

Infection and Immunity ◽

10.1128/iai.72.7.3902-3906.2004 ◽

2004 ◽

Vol 72 (7) ◽

pp. 3902-3906 ◽

Cited By ~ 54

Author(s):

A. R. Kerr ◽

P. V. Adrian ◽

S. Estevão ◽

R. de Groot ◽

G. Alloing ◽

...

Keyword(s):

Streptococcus Pneumoniae ◽

Invasive Disease ◽

Wild Type ◽

Survival Times ◽

Triple Mutant ◽

Nasopharyngeal Colonization ◽

Atp Binding Cassette Transporter ◽

Pneumococcal Colonization ◽

Oligopeptide Permease

ABSTRACT The Ami-AliA/AliB oligopeptide permease is an ATP-binding cassette transporter which is found in Streptococcus pneumoniae and which is involved in nutrient uptake. We investigated the role of the three paralogous oligopeptide-binding lipoproteins AmiA, AliA, and AliB by using murine models of pneumococcal colonization and invasive disease. A series of mutants lacking aliA, aliB, and amiA either alone or in combination as double or triple mutations were used. Inoculation of the nasopharynx with a mixture of the obl (oligopeptide-binding lipoprotein-negative) triple-mutant and wild-type (D39) bacteria resulted in significantly smaller numbers of obl bacteria colonizing the nasopharynx. The use of a mixture of individual mutants and wild-type pneumococci revealed that AmiA, AliA, and AliB were all required for successful colonization of the nasopharynx. The obl mutant was more attenuated than the aliB mutant but not the aliA or amiA mutant. Therefore, there is some redundancy in the Ami-AliA/AliB complex in terms of nasopharyngeal colonization, with AliA and AmiA being able to compensate for the removal of AliB. Animals with invasive disease caused by these mutants had survival times, bacterial loads, and inflammatory cytokine production levels similar to those of animals infected with wild-type pneumococci. Our results show that although the Ami-AliA/AliB complex is not required for virulence during pneumococcal pneumonia, it does play a role in colonization of the nasopharynx.

Download Full-text

NOTCH1 Activation Negatively Impacts on Chronic Lymphocytic Leukemia Outcome and Is Not Correlated to the NOTCH1 and IGHV Mutational Status

Frontiers in Oncology ◽

10.3389/fonc.2021.668573 ◽

2021 ◽

Vol 11 ◽

Author(s):

Stefano Baldoni ◽

Beatrice Del Papa ◽

Filomena De Falco ◽

Erica Dorillo ◽

Carlo Sorrentino ◽

...

Keyword(s):

Chronic Lymphocytic Leukemia ◽

Clinical Course ◽

Lymphocytic Leukemia ◽

Wild Type ◽

New Approach ◽

Mutational Status ◽

Time To First Treatment ◽

The Impact ◽

First Time

NOTCH1 mutations and deregulated signal have been commonly found in chronic lymphocytic leukemia (CLL) patients. Whereas the impact of NOTCH1 mutations on clinical course of CLL has been widely studied, the prognostic role of NOTCH1 activation in CLL remains to be defined. Here, we analyzed the activation of NOTCH1/NOTCH2 (ICN1/ICN2) and the expression of JAGGED1 (JAG1) in 163 CLL patients and evaluated their impact on TTFT (Time To First Treatment) and OS (Overall Survival). NOTCH1 activation (ICN1+) was found in 120/163 (73.6%) patients. Among them, 63 (52.5%) were NOTCH1 mutated (ICN1+/mutated) and 57 (47.5%) were NOTCH1 wild type (ICN1+/WT). ICN1+ patients had a significant reduction of TTFT compared to ICN1-negative (ICN1−). In the absence of NOTCH1 mutations, we found that the ICN1+/WT group had a significantly reduced TTFT compared to ICN1− patients. The analysis of IGHV mutational status showed that the distribution of the mutated/unmutated IGHV pattern was similar in ICN1+/WT and ICN1− patients. Additionally, TTFT was significantly reduced in ICN1+/ICN2+ and ICN1+/JAG1+ patients compared to ICN1−/ICN2− and ICN1−/JAG1− groups. Our data revealed for the first time that NOTCH1 activation is a negative prognosticator in CLL and is not correlated to NOTCH1 and IGHV mutational status. Activation of NOTCH2 and JAGGED1 expression might also influence clinical outcomes in this group, indicating the need for further dedicated studies. The evaluation of different NOTCH network components might represent a new approach to refine CLL risk stratification.

Download Full-text