Immunomodulatory effect of vitamin D after allo-SCT

Purpose: we describe the results of a prospective multicenter phase I/II trial evaluating the impact of the use of vitamin D (VitD) from day -5 to +100 on the outcome of patients undergoing allogeneic transplantation (EudraCT: 2010-023279-25; ClinicalTrials.gov: NCT02600988). Patients and methods:150 patients were included in three consecutive cohorts of 50 patients each group: control group (CG, not receive VitD); low dose group (LdD, received 1,000 UI VitD daily; and high dose group (HdD, 5,000 UI VitD daily). We measured levels of VitD, cytokines and immune subpopulations after transplantation. Results: No significant differences were observed in terms of cumulative incidence of overall and grades II-IV acute graft-versus-host disease (aGVHD), in terms of relapse, non-relapse mortality and overall survival. However a significantly lower cumulative incidence of both overall and moderate plus severe chronic GVHD at 1 year was observed in LdD (37.5% and 19.5%, respectively) and HdD (42.4% and 27%, respectively) as compared to CG (67.5% and 44.7%, respectively) (p<0.05). In multivariable analysis, treatment with VitD significantly decreased the risk of both overall: for LdD (HR=0.31, p=0.002) and for HdD (HR=0.36, p=0.006) and moderate plus severe cGVHD: for LdD (HR=0.22, p=0.001) and for HdD (HR=0.33, p=0.01). VitD modified the immune response, decreasing number of B-cells, naïve CD8 T-cells and with a lower expression of CD40L. Conclusions: This is the first prospective trial which analyzes the effect of VitD postransplant. We observed a significantly lower incidence of cGVHD among patients receiving VitD. Interestingly, VitD modified the immune response after alloSCT.

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DNA methylation biomarkers and prostate cancer prognosis

Purpose: Aside from Gleason sum few factors accurately identify the subset of prostate cancer (PCa) patients at high risk for metastatic progression. We hypothesized that epigenetic alterations could distinguish prostate tumors with life-threatening potential. Experimental Design: Epigenome-wide DNA methylation profiling was performed in surgically resected primary tumor tissues from a population-based (n = 430) and a replication (n = 80) cohort of PCa patients followed prospectively for at least five years. Metastasis was confirmed by positive bone scan, MRI, CT or biopsy, and death certificates confirmed cause of death. AUC, partial AUC (pAUC, 95% specificity), and P-value criteria were used to select differentially methylated CpG sites that robustly stratify patients with metastatic-lethal from non-recurrent tumors, and which were complementary to Gleason sum. Results: Forty-two biomarkers stratified patients with metastatic-lethal versus non-recurrent PCa in the discovery cohort, and eight of these CpGs replicated in the validation cohort based on a significant (P <0.05) AUC (range: 0.66-0.75) or pAUC (range: 0.007-0.009). The biomarkers that improved discrimination of patients with metastatic-lethal PCa include CpGs in five genes (ALKBH5, ATP11A, FHAD1, KLHL8, and PI15) and three intergenic regions. In the validation dataset the AUC for Gleason sum alone (0.82) significantly increased with the addition of four individual CpGs (range: 0.86-0.89; all P <0.05). Conclusions: Eight differentially methylated CpGs that distinguish patients with metastatic-lethal from non-recurrent tumors were validated. These novel epigenetic biomarkers warrant further investigation as they may improve prognostic classification of patients with clinically localized PCa and provide new insights on tumor aggressiveness.

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A novel molecular subtype of stage I lung adenocarcinoma

Purpose: The National Lung Cancer Screening Trial has confirmed that lung cancer mortality can be reduced if tumors are diagnosed early, i.e. at stage I. However, a substantial fraction of stage I lung cancer patients still develop metastatic disease within 5 years from surgery. Prognostic biomarkers are therefore needed to identify patients at risk of an adverse outcome, who might benefit from multimodality treatment. Experimental Design: We extensively validated a 10-gene prognostic signature in a cohort of 507 lung adenocarcinoma patients using formalin-fixed paraffin-embedded samples. Furthermore, we performed an integrated analysis of gene expression, methylation, somatic mutations, copy number variations, and proteomic profiles on an independent cohort of 468 patients from The Cancer Genome Atlas (TCGA). Results: Stage I lung cancer patients (N=351) identified as high-risk by the 10-gene signature displayed a 4-fold increased risk of death (HR=3.98; 95% CI: 1.73-9.14), with a 3-year overall survival of 84.2% (95% CI: 78.7-89.7) compared to 95.6% (92.4-98.8) in low-risk patients. The analysis of TCGA cohort revealed that the 10-gene signature identifies a subgroup of stage I lung adenocarcinomas displaying distinct molecular characteristics and associated with aggressive behavior and poor outcome. Conclusions: We validated a 10-gene prognostic signature capable of identifying a molecular subtype of stage I lung adenocarcinoma with characteristics remarkably similar to those of advanced lung cancer. We propose that our signature might aid the identification of stage I patients who would benefit from multimodality treatment.

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XPO1 inhibition synergizes with chemotherapy in AML

Purpose: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore we asked whether adding already established effective drugs such as Topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML. Experimental Design: The efficacy of combinatorial drug treatment using Topo II inhibitors (Idarubicin, Daunorubicin, Mitoxantrone, Etoposide) and selinexor was evaluated in established cellular and animal models of AML. Results: Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared to each single therapy. Conclusions: Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of AML patients that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression, and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML.

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HER3 targeting sensitizes HNSCC to cetuximab cell PDX models

Purpose:Our previous work suggested that HER3 inhibition sensitizes HNSCC to EGFR inhibition with cetuximab. This study aimed to define the role of HER3 in cetuximab resistance and the anti-tumor mechanisms of EGFR/HER3 dual targeting in HNSCC. Experimental Design:We treated cetuximab-resistant HNSCC UMSCC1-C and parental UMSCC1-P cell lines with anti-EGFR antibody cetuximab, anti-HER3 antibody MM-121, and their combination. We assessed activities of HER2, HER3 and downstream signaling pathways by Western blotting, and cell growth by sulforhodamine B (SRB) and colony formation assays. HER3-specific shRNA was used to confirm the role of HER3 in cetuximab response. The combined efficacy and alterations in biomarkers were evaluated in UMSCC1-C xenograft and patient-derived xenograft (PDX) models. Results:Cetuximab treatment induced HER3 activation and HER2/HER3 dimerization in HNSCC cell lines. Combined treatment with cetuximab and MM-121 blocked EGFR and HER3 activities and inhibited PI3K/AKT and ERK signaling pathways and HNSCC cell growth more effectively than each antibody alone. HER3 knockdown reduced HER2 activation and re-sensitized cells to cetuximab. Cetuximab-resistant xenografts and PDX models revealed greater efficacy of dual EGFR and HER3 inhibition compared to single antibodies. In PDX tissue samples, cetuximab induced HER3 expression and MM-121 reduced AKT activity. Conclusions:Clinically relevant PDX models demonstrate that dual targeting of EGFR and HER3 is superior to EGFR targeting alone in HNSCC. Our study illustrates the upregulation of HER3 by cetuximab as one mechanism underlying resistance to EGFR inhibition in HNSCC, supporting further clinical investigations using multiple targeting strategies in patients who have failed cetuximab-based therapy.

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Myc modulation by HDACi in cancer

Purpose: Histone deacetylase inhibitors (HDACi) are promising anticancer drugs. Although some HDACi have entered the clinic, the mechanism(s) underlying their tumor selectivity are poorly understood. Experimental Design/Results: Using gene expression analysis, we define a core set of 6 genes commonly regulated in acute myeloid leukemia (AML) blasts and cell lines. c-Myc, the most prominently modulated, is preferentially altered in leukemia. Upon HDACi treatment, c-Myc is acetylated at lysine 323 and its expression decreases, leading to TRAIL activation and apoptosis. c-Myc binds to the TRAIL promoter on the proximal GC box through Sp1 or Miz1, impairing TRAIL activation. HDACi exposure triggers TRAIL expression, altering c-Myc-TRAIL binding. These events do not occur in normal cells. Excitingly, this inverse correlation between TRAIL and c-Myc is supported by HDACi treatment ex vivo of AML blasts and primary human breast cancer cells. The predictive value of c-Myc to HDACi responsiveness is confirmed in vivo in AML patients undergoing HDACi-based clinical trials. Conclusions: Collectively, our findings identify a key role for c-Myc in TRAIL deregulation and as a biomarker of the anticancer action of HDACi in AML. The potential improved patient stratification could pave the way towards personalized therapies.

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Anti-PD-1, anti-TIM-3, and radiation in glioma model

Introduction: Checkpoint molecules like programmed death-1 (PD-1) and T cell immunoglobulin mucin-3 (TIM-3) are negative immune regulators that may be upregulated in the setting of glioblastoma multiforme (GBM). Combined PD-1 blockade and stereotactic radiosurgery (SRS) have been shown to improve antitumor immunity and produce long-term survivors in a murine glioma model (1) . However, tumor-infiltrating lymphocytes (TILs) can express multiple checkpoints, and expression of {greater than or equal to}2 checkpoints corresponds to a more exhausted T cell phenotype (2) . We investigate TIM-3 expression in a glioma model and the antitumor efficacy of TIM-3 blockade alone and in combination with anti-PD-1 and SRS. Methods: C57BL/6 mice were implanted with murine glioma cell line GL261-luc2 and randomized into 8 treatment arms: (1) control, (2) SRS, (3) anti-PD-1 antibody, (4) anti-TIM-3 antibody, (5) anti-PD-1+SRS, (6) anti-TIM-3+SRS, (7) anti-PD-1+anti-TIM-3, and (8) anti-PD-1+anti-TIM-3+SRS. Survival and immune activation were assessed. Results: Dual therapy with anti-TIM-3 antibody+SRS or anti-TIM-3+anti-PD-1 improved survival compared to anti-TIM-3 antibody alone. Triple therapy resulted in 100% OS (p<0.05), a significant improvement compared to other arms. Long-term survivors demonstrated increased immune cell infiltration and activity, and immune memory. Lastly, positive staining for TIM-3 was detected in 7/8 human GBM samples. Conclusions: This is the first preclinical investigation on the effects of dual PD-1 and TIM-3 blockade with radiation. We also demonstrate the presence of TIM-3 in human GBM and provide preclinical evidence for a novel treatment combination that can potentially result in long-term glioma survival and constitutes a novel immunotherapeutic strategy for the treatment of GBM.

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Projections of cancer incidence and cancer-related deaths in Germany by 2020 and 2030

Abstract

Past patterns of cancer disease and future changes in the demographic structure have a major influence on the projected incidences of human malignancies. In Germany, nearly a quarter of men and 20% of women die of cancer, and it is estimated that in Germany around 51% men and 43% women will develop cancer during lifetime. Here, we project the cancer incidence case number as well as the number of deaths for the most common cancers in the German population for the years 2020 and 2030. By 2030, prostate cancer will be the most common malignancy, surpassing breast cancer. Lung cancer will rank third most frequent cancer and will remain the most common cause of cancer-related mortality. Additionally, our projections show a marked increase in liver cancer cases with a continuous rise in liver cancer-related deaths. Finally, we project a constant increase in the incidence of pancreatic cancer. Based on our projections, pancreatic cancer will surpass colorectal and breast cancer to rank as the second most common cause of cancer-related deaths in Germany by 2030.

In 2014, Rahib and colleagues have reported future cancer incidences and death rates for the United States. In our work, we have further developed the analytical approach and present projections for Germany, which represents a different Western population. While we find differences in incidence and death rates between Germany and the United States for several cancers, the alarming rise of incidence and death rates for pancreatic and liver cancer seem to hold true for both countries. Furthermore, we see a sharp rise in female lung cancers.

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Preoperative chemoradiotherapy with cisplatin and docetaxel for stage IIIB non-small cell lung cancer: 10-year follow-up of the SAKK 16/01 trial

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Ipilimumab related hypophysitis may precede severe CNS immune attack

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Outcome according to KRAS-, NRAS- and BRAF-mutation as well as KRAS mutation variants - pooled analysis of five randomized trials in metastatic colorectal cancer by the AIO colorectal cancer study group

In this pooled analysis of mCRC patients, mutations in KRAS, and BRAF were associated with inferior PFS and OS compared to patients with non-mutated tumors. KRAS exon 2 mutation variants were associated with heterogeneous outcome compared to unmutated tumors with KRAS G12C and G13D being associated with rather poor survival.

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Is CA125 useful in monitoring patients with platinum resistant ovarian cancer?

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A tribute to biologics in advanced colorectal cancer treatment

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PIK3CA mutations in HER2-positive breast cancer - an ongoing conundrum

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Prognostic pathways in early stage ovarian cancer - can gene expression transcend histological subtype?

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Inclusion Of Elderly Patients In Oncology Clinical Trials

Since the creation of the International Society of Geriatric Oncology, the proportion of phase III trials reporting at least one analysis dedicated to elderly patients has grown (46.7% between 2011 and 2014 versus 19.3% between 2001 and 2004). However, evidence based data is mostly extracted from subgroup analyses that can only be considered as preliminary evidence.

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LONG-TERM SIGNIFICANCE OF URINARY NEOPTERIN IN OVARIAN CANCER - A STUDY BY THE AUSTRIAN ASSOCIATION FOR GYNECOLOGIC ONCOLOGY (AGO)

Interaction between cancer cells and the immune system is becoming an increasingly important issue. Neopterin can serve as a marker of the host's immunological response. Elevated neopterin levels at time of diagnosis of ovarian cancer are associated with impaired prognosis and may indicate a detrimental effect of cancer-associated inflammatory reaction.

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Randomized, double-blind, phase III trial of palonosetron versus granisetron in the triplet regimen for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy: TRIPLE study

This paper reports the result of the first phase III study of comparing the efficacy of first- and second-generation 5-HT3 receptor antagonists, palonosetron and granisetron, in the triplet regimen with dexamethasone and aprepitant for preventing chemotherapy-induced nausea and vomiting after highly emetogenic chemotherapy.

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Safety of Everolimus Plus Exemestane In Patients With Hormone-Receptor-Positive, HER2-Negative Locally Advanced or Metastatic Breast Cancer Progressing on Prior Non-Steroidal Aromatase Inhibitors: Primary Results of a Phase 3b, Open-Label, Single-Arm, Expanded-Access Multicenter Trial (BALLET)

This is the largest ever reported safety dataset on a general patient population presenting ABC treated with EVE plus EXE and included a sizeable elderly subset. This is also the first trial reporting the impact of BMI on safety. These data reinforce observations from the BOLERO-2 trial that the safety profile of everolimus plus exemestane was manageable; there were no new safety signals.

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The Genomic Data Commons Expands with New Data Sharing Agreement

Today the National Cancer Institute signed an agreement with Foundation Medicine, Inc., that will greatly increase the size of the Genomic Data Commons (GDC). The addition of data from 18,000 patients in the FoundationOne database to the GDC will provide the research community with more statistical power in their studies and will work toward building a smarter knowledge base.

Foundation Medicine, Inc., is a molecular profiling company that developed FoundationOne, a commercially available cancer profiling test that identifies known genetic alterations in cancer and potential therapeutic opportunities. The data in the FoundationOne dataset that will be submitted to the GDC contains information on the key genetic alterations of a large number of cancer patients and all patient information has been de-identified to protect patient privacy.

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The pattern of prognostic and risk indicators among women with breast cancer undergoing modified radical mastectomy in Dar es Salaam, Tanzania

Abstract

Background

Breast cancer is the commonest female malignancy globally and the second (after uterine cervix) in sub-Saharan Africa including Tanzania. Prognostic indicators reportedly influence post-mastectomy adjuvant therapy by predicting risks on survival and recurrence although in Tanzania this data is lacking. Here, we evaluate the pattern of prognostic and risk indicators among women with breast cancer undergoing modified-radical-mastectomy (MRM) at Muhimbili National Hospital (MNH) and Tumaini Hospital (TH), Dar es Salaam, Tanzania.

Methods

This hospital-based prospective cross-sectional study included female patients undergoing MRM from April 2011 to January 2012. Clinical stage I-III patients were enrolled after being scheduled for mastectomy. Patients with evidence of distant metastasis (stage IV) were excluded. Mastectomy and axillary lymph nodes biopsies were submitted to the Histopathology laboratory for grade, type, nodal and margins status. Data was collected using a structured questionnaire and analyzed using SPSS.

Results

A total of 348 patients were admitted with breast cancer including 86 patients (with 16 from TH having similar demography and presentation) meeting inclusion criteria. Age-range at diagnosis was 28–79 years, mean 52.1 years. Most (89 %) attained menarche after 11 years. About 56 % were postmenopausal. The majority (78 %) were multiparous with positive family history in 14.1 and 37.6 % used hormonal contraceptives.

About 27.1 % were social alcohol drinkers. The majority (61 %) had T4b disease, 75.6 % had positive axillary nodes including 42.7 % with 4–9 involved nodes (N2). The commonest (91.9 %) histological type was invasive ductal carcinoma. Lobular, medullary and mucinous carcinomas were rare. Most (83.7 %) of our patients presented with stage III and the rest stage II. Intermediate- and high-grade tumors accounted for 73.5 %. Following MRM, 25 % of our patients had positive surgical margins and similarly for the base.

Conclusions

Most of our breast cancer patients present with frequent risks including younger age, multiparity, hormonal contraceptives use, alcohol use and family history. Unfavourable prognostic indicators including late stages, large primary tumor size, skin infiltration, positive surgical margins, positive axillary lymph nodes and a high histological grade were associated.

A sustainable screening program by self-examination to allow early diagnosis is needed to reduce morbidity and mortality from this cancer.

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Unfavorable neuroblastoma prognostic factor NLRR2 inhibits cell differentiation by transcriptional induction through JNK pathway

Summary

The novel human gene family encoding Neuronal Leucine Rich Repeat (NLRR) proteins were identified as prognostic markers from our previous screening of primary neuroblastoma (NB) cDNA libraries. Of the NLRR gene family members, NLRR1 and NLRR3 are associated with the regulation of cellular proliferation and differentiation, respectively. However, the functional regulation and clinical significance of NLRR2 in NB remain unclear. Here we evaluated the differential expression of NLRR2, where high expressions of NLRR2 were significantly associated with a poor prognosis of NB (P=0.0009), in 78 NBs. Enforced expression of NLRR2 in NB cells enhanced cellular proliferation and induced resistance to retinoic acid (RA)-mediated cell growth inhibition. On the other hand, knock-down of NLRR2 exhibited growth inhibition effects and enhanced RA-induced cell differentiation in NB cells. After RA treatment, NLRR2 expression was increased and correlated with the upregulation of c-Jun, a member of the activator protein-1 (AP-1) family in NB cells. Moreover, the expressions of NLRR2 and c-Jun were suppressed by treatment with a JNK inhibitor, which ameliorated the promoter activity of the NLRR2 gene while knock-down of c-Jun reduced NLRR2 expression. Then we searched AP-1 binding consensus in the NLRR2 promoter region and confirmed c-Jun recruitment at a consensus. Conclusively, NLRR2 must be an inducible gene regulated by the JNK pathway to enhance cell survival and inhibit NB cell differentiation. Therefore, NLRR2 should have an important role in NB aggressiveness and be a potential therapeutic target for the treatment of RA resistant and aggressive NBs.

This article is protected by copyright. All rights reserved.

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Palliative primary tumor resection provides survival benefits for the patients with metastatic colorectal cancer and low circulating levels of dehydrogenase and carcinoembryonic antigen

It remains controversial whether palliative primary tumor resection (PPTR) can provide survival benefits to the patients with metastatic colorectal cancer (mCRC) who have unresectable metastases. The aim of th...

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Low expression of centrosomal protein 78 (CEP78) is associated with poor prognosis of colorectal cancer patients

Centrosomal protein 78 (CEP78) has been characterized as a component of the centrosome required for the regulation of centrosome-related events during the cell cycle, but its role in human cancers remains uncl...

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Protein stability regulators screening assay (Pro-SRSA): protein degradation meets the CRISPR–Cas9 library

The regulation of protein stability is a fundamental issue for biophysical processes, but there has not previously been a convenient and unbiased method of identifying regulators of protein stability. However,...

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A model to predict the risk of lethal nasopharyngeal necrosis after re-irradiation with intensity-modulated radiotherapy in nasopharyngeal carcinoma patients

For patients with nasopharyngeal carcinoma (NPC) who undergo re-irradiation with intensity-modulated radiotherapy (IMRT), lethal nasopharyngeal necrosis (LNN) is a severe late adverse event. The purpose of thi...

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Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Validated preclinical studies have provided evidence that anti-vascular endothelial growth factor (VEGF) compounds enhance the activity of subsequent antitumor therapy, but the mechanism of this potentiation i...

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Childbirth after surgery for familial adenomatous polyposis in Japan

Abstract

Purpose

Familial adenomatous polyposis (FAP) is a genetic disorder. Some female patients with FAP can become pregnant. However, the current state of childbirth after surgery for FAP is unclear in Japan.

Methods

The study investigated 303 patients (147 female) who had undergone surgery for FAP at the 23 institutions between 2000 and 2012.

Results

Eighty female patients had information available on childbirth after surgery for FAP. Eight patients (10 %) gave birth after surgery. The mean age at surgery for FAP was 27 (range 20–41) years and 37 years in patients with and without childbirth after surgery, respectively (P = 0.044). The rate of childbirth after surgery was 17 % in women ≤30 years of age and 13 % in those ≤40 years of age. Although only one patient with invasive cancer (2.9 %) gave childbirth after surgery, seven patients without cancer (15.6 %) gave birth (P = 0.045).

Conclusions

This study clarified the current state of childbirth after surgery for FAP in Japan. It is important to use these data to determine the best therapeutic approach for female FAP patients.

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Ethyl-2-amino-pyrrole-3-carboxylates are novel potent anticancer agents that affect tubulin polymerization, induce G2/M cell-cycle arrest, and effectively inhibit soft tissue cancer cell growth in vitro

Microtubules are known to be one of the most attractive and validated targets in cancer therapy. However, the clinical use of drugs that affect the dynamic state of microtubules has been hindered by chemoresistance and toxicity issues. Accordingly, the development of novel agents that target microtubules is needed. Here, we report the identification of novel compounds with pirrole and carboxylate structures: ethyl-2-amino-pyrrole-3-carboxylates (EAPCs) that provide potent cytotoxic activities against multiple soft tissue cancer cell lines in vitro. Using the MTS cell proliferation assay, we assessed the activity of EAPCs on various cancer cell lines including leiomyosarcoma SK-LMS-1, rhabdomyosarcoma RD, gastrointestinal stromal tumor GIST-T1, A-673 Ewing's sarcoma, and U-2 OS osteosarcoma. We found that in the majority of cases, two EAPC compounds (EAPC-20 and EAPC-24) considerably inhibited cancer cell proliferation in vitro. The growth-inhibitory effects of EAPC-20 and EAPC-24 were time and dose dependent. The molecular mechanisms of action of these compounds were because of the inhibition of tubulin polymerization and induction of a robust G2/M cell-cycle arrest, leading to considerable accumulation of tumor cells in the M-phase. Finally, EAPCs induced tumor cell death by apoptotic pathways. The above-mentioned effects were also observed in most soft tissue tumor cell lines and the gastrointestinal stromal tumor cell line investigated. Taken together, our data identify potent antitumor activity of EAPCs in vitro, thus providing a novel scaffold with which to develop potent chemotherapeutic agents for cancer therapy.

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Dryofragin inhibits the migration and invasion of human osteosarcoma U2OS cells by suppressing MMP-2/9 and elevating TIMP-1/2 through PI3K/AKT and p38 MAPK signaling pathways

Dryofragin, a phloroglucinol derivative extracted from Dryopteris fragrans (L.) Schott, was found to inhibit proliferation and induce apoptosis of tumor cells. However, the mechanism involved in the suppression of cancer cell metastasis by dryofragin remains unclear. Our study investigated the mechanisms for the antitumor properties of dryofragin on the migration and invasion of human osteosarcoma U2OS cells. Dryofragin suppressed the migration and invasive ability of U2OS cells, and it decreased the expression of MMP-2 and MMP-9 and elevated the expression of TIMP-1 and TIMP-2. Western blotting assays indicated that dryofragin was effective in suppressing the phosphorylation of phosphatidylinositide-3 kinase (PI3K), Akt, and p38 MAPK. These results suggest that dryofragin inhibited U2OS cell migration and invasion by reducing the expression of MMP-2 and MMP-9 and elevating the expression of TIMP-1 and TIMP-2 through the PI3K/AKT and p38 MAPK signaling pathways. Above all, we conclude that dryofragin represents an anti-invasive agent and may potentially be applicable in osteosarcoma therapy.

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Small Cell Undifferentiated Hepatoblastomas (SCUD): All Malignant Rhabdoid Tumors?

Abstract

Small cell undifferentiated hepatoblastoma (SCUD) is a rare variant of hepatoblastoma with poor outcome and loss of INI1 expression, sharing this with malignant rhabdoid tumors (MRT). We studied all tumors from the files of the Kiel Pediatric Tumor Registry (KTR) with the initial diagnosis of SCUD and MRT. After re-review, we performed immunistochemistry, FISH and MLPA for loss of expression and deletion of INI1/SMARCB1 in 23 tumors. Morphologically, 12 of the tumors had a small cell morphology, nine showed the typical picture of MRT and two were composed of both small cells and rhabdoid cells. All but one of the 23 tumors showed loss of INI1 protein expression by immunohistochemistry. Nineteen of the INI1 negative tumors were analysed by FISH technique and all showed a deletion of the INI1/SMARCB1 gene (17 homozygous deletions, 2 heterozygous deletions). We investigated 14 of these cases by MLPA and verified the deletions in all cases. In conclusion, we postulate that small cell undifferentiated hepatoblastoma (HB) is not a hepatoblastoma but represents a malignant rhabdoid tumor of the liver. This article is protected by copyright. All rights reserved.

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PET Imaging of T-cell Receptor-Engineered T Cells

Sensitive in vivo imaging technologies applicable to the clinical setting are still lacking for adoptive T-cell–based immunotherapies, an important gap to fill if mechanisms of tumor rejection or escape are to be understood. Here, we propose a highly sensitive imaging technology to track human TCR-transgenic T cells in vivo by directly targeting the murinized constant TCR beta domain (TCRmu) with a zirconium-89 (89Zr)-labeled anti–TCRmu-F(ab')2 fragment. Binding of the labeled or unlabeled F(ab')2 fragment did not impair functionality of transgenic T cells in vitro and in vivo. Using a murine xenograft model of human myeloid sarcoma, we monitored by Immuno-PET imaging human central memory T cells (TCM), which were transgenic for a myeloid peroxidase (MPO)–specific TCR. Diverse T-cell distribution patterns were detected by PET/CT imaging, depending on the tumor size and rejection phase. Results were confirmed by IHC and semiquantitative evaluation of T-cell infiltration within the tumor corresponding to the PET/CT images. Overall, these findings offer a preclinical proof of concept for an imaging approach that is readily tractable for clinical translation. Cancer Res; 76(14); 1–11. ©2016 AACR.

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