Non-alcoholic fatty liver disease (NAFLD), characterized by fat accumulation in liver, is closely associated with central obesity, over-nutrition and other features of metabolic syndrome, which elevate the risk of developing hepatocellular carcinoma (HCC). The Wnt/β-catenin signaling pathway plays a significant role in the physiology and pathology of liver. Up to half of HCC patients have activation of Wnt/β-catenin signaling. However, the mutation frequencies of CTNNB1 (encoding β-catenin protein) or other antagonists targeting Wnt/β-catenin signaling are low in HCC patients, suggesting that genetic mutations are not the major factor driving abnormal β-catenin activities in HCC. Emerging evidence has demonstrated that obesity-induced metabolic pathways can deregulate chromatin modifiers such as histone deacetylase 8 to trigger undesired global epigenetic changes, thereby modifying gene expression program which contributes to oncogenic signaling. This review focuses on the aberrant epigenetic activation of Wnt/β-catenin in the development of NAFLD-associated HCC. A deeper understanding of the molecular mechanisms underlying such deregulation may shed light on the identification of novel druggable epigenetic targets for the prevention and/or treatment of HCC in obese and diabetic patients.
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Cancer Medicine by Alexandros G.Sfakianakis,Anapafseos 5 Agios Nikolaos,Crete 72100,Greece,tel :00302841026182 & 00306932607174
Παρασκευή 19 Αυγούστου 2016
Cancers, Vol. 8, Pages 76: Epigenetic Activation of Wnt/β-Catenin Signaling in NAFLD-Associated Hepatocarcinogenesis
RHAMM defects result in hypofertility and seminoma
Hypofertility is a risk factor for the development of testicular germ cell tumors (TGCTs), but the initiating event linking these pathologies is unknown. We hypothesized that excessive planar division of undifferentiated germ cells promotes their self-renewal and TGCT development. However, our results obtained from mouse models and seminoma patients demonstrated the opposite. Defective planar divisions of undifferentiated germ cells caused their premature exit from the seminiferous tubule niche, resulting in germ cell depletion, hypofertility, intratubular germ cell neoplasia and seminoma development. Oriented divisions of germ cells, which determine their fate, were regulated by spindle-associated RHAMM - a function we found to be abolished in 96% of human seminomas. Mechanistically, RHAMM expression is regulated by the testis-specific polyadenylation protein CFIm25, which is downregulated in the human seminomas. These results suggested that spindle misorientation is oncogenic, not by promoting self‐renewing GC divisions within the niche, but by prematurely displacing proliferating cells from their normal epithelial milieu. Further, they suggested RHAMM loss-of-function and spindle misorientation as an initiating event underlying both hypofertility and TGCT initiation. These findings identify spindle-associated RHAMM as an intrinsic regulator of male germ cell fate and as a gatekeeper preventing initiation of TGCTs.
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Nanotechnology-enabled theranostics of lung cancer
Early detection and efficient treatment modality of early-stage peripheral lung cancer is essential. Current non-surgical treatments for peripheral lung cancer show critical limitations associated with various complications, requiring alternative minimally invasive therapeutics. Porphysome nanoparticle-enabled fluorescence-guided transbronchial photothermal therapy (PTT) of peripheral lung cancer was developed and demonstrated in preclinical animal models. Systemically-administered porphysomes accumulated in lung tumors with significantly enhanced disease-to-normal tissue contrast, as confirmed in three subtypes of orthotopic human lung cancer xenografts (A549, H460 and H520) in mice and in an orthotopic VX2 tumor in rabbits. An in-house prototype fluorescence bronchoscope demonstrated the capability of porphysomes for in vivo imaging of lung tumors in the mucosal/submucosal layers, providing real-time fluorescence guidance for transbronchial PTT. Porphysomes also enhanced the efficacy of transbronchial PTT significantly and resulted in selective and efficient tumor tissue ablation in the rabbit model. A clinically used cylindrical diffuser fiber successfully achieved tumor-specific thermal ablation, showing promising evidence for the clinical translation of this novel platform to impact upon non-surgical treatment of early-stage peripheral lung cancer.
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FGFR2-targeting antibody-drug conjugate in cancer
The fibroblast growth factor receptor FGFR2 is overexpressed in a variety of solid tumors, including breast, gastric and ovarian tumors, where it offers a potential therapeutic target. In this study, we present evidence of the preclinical efficacy of BAY 1187982, a novel antibody-drug conjugate (ADC). It consists of a fully human FGFR2 monoclonal antibody (mAb BAY 1179470), which is specific for the FGFR2 isoforms FGFR2-IIIb and FGFR2-IIIc, conjugated through a non-cleavable linker to a novel derivative of the microtubule-disrupting cytotoxic drug auristatin (FGFR2-ADC). In FGFR2-expressing cancer cell lines, this FGFR2-ADC exhibited potency in the low nM to sub-nM range and was more than 100-fold selective against FGFR2-negative cell lines. High expression levels of FGFR2 in cells correlated with efficient internalization, efficacy and cytotoxic effects in vitro. Pharmacokinetic analyses in mice bearing FGFR2-positive NCI-H716 tumors indicated that the toxophore metabolite of FGFR2-ADC was enriched more than 30-fold in tumors compared to healthy tissues. Efficacy studies demonstrated that FGFR2-ADC treatment leads to a significant tumor growth inhibition or tumor regression of cell line-based or patient-derived xenograft models of human gastric or breast cancer. Further, FGFR2 amplification or mRNA overexpression predicted high efficacy in both of these types of in vivo model systems. Taken together, our results strongly support the clinical evaluation of BAY 1187982 in cancer patients, and a Phase I study (NCT02368951) has been initiated.
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CXCL12/CXCR4 signaling axis in NPC-derived GBM
Purpose: One likely cause of treatment failure in glioblastoma is the persistence of glioma stem-like cells (GSLCs), highly resistant to therapies currently employed. We found that CXCL12 has highest expression in glioma cells derived from neural progenitor cells (NPCs). The development and molecular signature of NPC-derived GBMs were analyzed and the therapeutic effect of blocking CXCL12 was tested. Experimental Design: Tumors were induced by injecting DNA into the lateral ventricle of neonatal mice, using the Sleeping Beauty transposase method. Histology and expression of GSLC markers were analyzed during disease progression. Survival upon treatment with pharmacologic (Plerixafor) or genetic inhibition of CXCR4 was analyzed. Primary neurospheres were generated and analyzed for proliferation, apoptosis and expression of proteins regulating survival and cell cycle progression. Results: Tumors induced from NPCs display histological features of human GBM and express markers of GSLC. In vivo, inhibiting the CXCL12/CXCR4 signaling axis results in increased survival of tumor-bearing animals. In vitro, CXCR4 blockade induces apoptosis and inhibits cell cycle progression, downregulates molecules regulating survival and proliferation and also blocks the hypoxic-induction of HIF-1α and CXCL12. Exogenous administration of CXCL12 rescues the drug-induced decrease in proliferation. Conclusions: This study demonstrates that the CXCL12/CXCR4 axis operates in GBM cells under hypoxic stress via an autocrine positive feedback mechanism, which promotes survival and cell cycle progression. Our study brings new mechanistic insight and encourages further exploration of the use of drugs blocking CXCL12 as adjuvant agents to target hypoxia-induced GBM progression, prevent resistance to treatment and recurrence of the disease.
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PDE4 inhibitors are safe and active in B cell malignancies
Purpose:In this study, we aimed to validate our extensive pre-clinical data on phosphodiesterase 4 (PDE4) as actionable target in B-cell malignancies. Our specific objectives were to determine the safety, pharmacokinetics and pharmacodynamics (PI3K/AKT activity), as well as to capture any potential anti-tumor activity of the FDA-approved PDE4 inhibitor roflumilast in combination with prednisone in patients with advanced B cell malignancies. Experimental Design: Single center, exploratory phase Ib open-label, non-randomized study. Roflumilast (500 mcg PO) was given daily for 21 days with prednisone on days 8-14. Additional 21-day cycles were started if patients tolerated cycle 1 and had at least stable disease. Results:Ten patients, median age 65 years with an average of three prior therapies were enrolled. The median number of cycles administered was 4 [range: 1-13]. Treatment was generally well tolerated; the most common {greater than or equal to}Grade 2 treatment-related adverse events ({greater than or equal to}25%) were fatigue, anorexia and transient {greater than or equal to} grade 2 neutropenia (30%). Treatment with roflumilast as a single agent significantly suppressed PI3K activity in the 77% of patients evaluated; on average, patients with PI3K/AKT suppression stayed in trial for 156 days (49 - 315) vs. 91 days (28 - 139 days) for those without this biomarker response. Six of the nine evaluable patients (66%) had partial response or stable disease. The median number of days in trial was 105 days [range: 28-315]. Conclusions:Repurposing the PDE4 inhibitor roflumilast for treatment of B-cell malignancies is a safe, suppresses the activity of the oncogenic PI3K/AKT kinases, and may have clinical activity in this setting
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Ribociclib (LEE011) in advanced solid tumors or lymphomas
Purpose: Ribociclib (an oral, highly-specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the maximum tolerated dose (MTD), recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas. Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle. Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during Cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses {greater than or equal to}600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months. Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I-III studies of ribociclib are underway in various indications.
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MAGE-A expression predicts survival in NSCLC
Purpose: Quantitative measurement of minimal residual disease (MRD) predicting recurrence in individual cancer patients is available only in very few indications such as acute lymphoblastic leukemia but is still missing in most solid tumors including non-small cell lung cancer (NSCLC). Experimental design: MAGE-A expression levels in blood and bone marrow determined as calibrator normalized relative ratios by quantitative multimarker real-time RT-PCR for transcript amplification of MAGE-A1, -A2, -A3/6, -A4, -A10 and -A12 in 94 patients with completely resected NSCLC were correlated with survival in a clinical study. Results: Patients with MAGE-A expression levels {greater than or equal to} 0.2 in at least one sample of bone marrow or blood at tumor surgery had a significantly reduced overall (p = 0.007), cancer-free (p = 0.002), and distant-metastasis-free survival (p < 0.001) versus patients below 0.2 in all samples without significant difference in locoregional-recurrence-free survival. The corresponding hazard ratios ({greater than or equal to} 0.2 vs. < 0.2) for death, cancer-related death and development of distant metastasis were 2.56 (95% CI, 1.42 - 4.63), 3.32 (95% CI, 1.66 - 6.61), and 4.03 (95% CI, 1.77 - 9.18), respectively. Five-year Kaplan-Meier estimates of distant-metastasis-free survival were 43% (MAGE-A {greater than or equal to} 0.2) versus 87% (MAGE-A < 0.2). Conclusions: MAGE-A expression in blood or bone marrow at tumor surgery is an independent predictor of survival in resected NSCLC. The reliable prediction of distant metastasis in individual patients with a statistically proven impact on overall survival may help to refine patient selection for adjuvant therapy urgently needed especially in the clinical management of elderly patients.
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Pancreatic cancer tissue banks: where are we heading?
Future Oncology Ahead of Print.
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Pharmacokinetics and pharmacogenetics of 13- cis retinoic acid in Indian high-risk neuroblastoma patients
Abstract
Purpose
To compare the pharmacokinetics of 13-cis retinoic acid (13-cisRA) between Indian and UK neuroblastoma patients receiving comparable treatment, alongside measures of toxicity and response.
Methods
13-cisRA (160 mg/m2/day) was administered to 36 patients ≤16 years in two divided doses. Plasma 13-cisRA concentrations were determined on days 1 and 14 of cycles 1 and 4 of treatment. Area under the plasma concentration–time curve (AUC0–6h) was estimated using non-compartment modelling. Patients were genotyped for UGT2B7, CYP3A5*3, CYP3A7*2 and *2, *3 and *4 variants of CYP2C8.
Results
Marked inter-patient variability in 13-cisRA pharmacokinetics was observed. There was a trend towards a higher AUC0–6h on day 1 versus day 14 for both treatment cycles studied. Children who swallowed 13-cisRA capsules (n = 18) achieved higher AUC0–6h values compared to those who could not (n = 16) (Mean AUC 21.53 vs. 9.35 µM h, P < 0.05). Patients who were event free at 1 year tended to have higher AUC0–6h on C1D1 compared to those patients who progressed, although this did not reach significance with the number of patients studied (P = 0.08). Similarly, patients who achieved a 13-cisRA C max of ≥2 µM on C1D1 tended to have higher median EFS compared to those who did not (17.0 vs. 8.1 months). UGT2B7, CYP2C8*2/*3/*4 or CYP3A5*3 genotype did not have any effect on 13-cisRA pharmacokinetics.
Conclusions
Method of administration markedly affects 13-cisRA pharmacokinetics in Indian neuroblastoma patients, supporting similar findings in UK patients. An appropriate oral liquid formulation of 13-cisRA that can be administered to all children with neuroblastoma is urgently needed on an international level.
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Liver metastatic disease: new concepts and biomarker panels to improve individual outcomes
Abstract
Liver cancer, one of the leading causes of all cancer related deaths, belongs to the most malignant cancer types. In fact, the secondary hepatic malignancies (liver metastases) are more common than the primary ones. Almost all solid malignancies can metastasise to the liver. It is well justified that the "treat and wait" approach in the overall management of the liver cancer is not up-to-date and so creation of complex individual patient profiles is needed. This review is specifically focused on the liver metastases originating from the colorectum, breast and prostate cancer. Innovative multilevel diagnostics may procure specific panels of validated biomarkers for predisposition, development and progression of metastatic disease. Creation of the patient specific "molecular portrait" is an essential part of the diagnostic strategy. Contextually, analysis of molecular and cellular patterns in blood samples as the minimally invasive diagnostic tool and construction of diagnostic windows based on individual patient profiling is highly recommended for patient cohorts predisposed to and affected by the liver metastatic disease. Summarised information on risk assessment, predictive and prognostic panels for diagnosis and treatments of the liver metastatic disease in colorectal, breast and prostate cancer is provided.
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Functional MRI for the prediction of treatment response in head and neck squamous cell carcinoma: potential and limitations
Abstract
Pre-treatment or early intra-treatment prediction of patients with head and neck squamous cell carcinomas (HNSCC) who are likely to have tumours that are resistant to chemoradiotherapy (CRT) would enable treatment regimens to be changed at an early time point, or allow patients at risk of residual disease to be targeted for more intensive post-treatment investigation. Research into the potential advantages of using functional-based magnetic resonance imaging (MRI) sequences before or during cancer treatments to predict treatment response has been ongoing for several years. In regard to HNSCC, the reported results from functional MRI research are promising but they have yet to be transferred to the clinical domain. This article will review the functional MRI literature in HNSCC to determine the current status of the research and try to identify areas that are close to application in clinical practice. This review will focus on diffusion-weighted imaging (DWI) and dynamic contrast-enhanced MRI (DCE–MRI) and briefly include proton magnetic resonance spectroscopy (1H-MRS)and blood oxygen level dependent (BOLD) MRI.
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Establishment and characterization of a clear cell carcinoma cell line, designated NOCC, derived from human ovary
Abstract
A cell line, designated NOCC, was established from the ascites of a patient with clear cell adenocarcinoma of the ovary. The cell line has been grown without interruption and continuously propagated by serial passaging (more than 76 times) over 7 years. The cells are spherical to polygonal-shaped, display neoplastic, and pleomorphic features, and grow in a jigsaw puzzle-like pattern while forming monolayers without contact inhibition. The cells proliferate rapidly, but are easily floated as a cell sheet. The population doubling time is about 29 h. The number of chromosomes ranges from 60 to 83. The modal number of chromosomes is 70–74 at the 30th passage. NOCC cells secreted 750.5 ng/ml of VEGF over 3 days of culture. Hypoxia inducible factor-1α (HIF-1α) is a primary regulator of VEGF under hypoxic conditions. NOCC cells were not sensitive to the anticancer drugs BEV, DOX, GEM, ETP, CDDP, or TXT. The graft of NOCC cells to a scid mouse displayed similar histological aspects to the original tumor. Both the NOCC cells and the graft of the NOCC cells gave a positive PAS reaction.
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Sentinel lymph node biopsy as a prognostic factor in non-metastatic colon cancer: a prospective study
Abstract
Purpose
Around a third of node-negative patients with colon cancer experience a recurrence after surgery, suggesting poor staging. Sentinel lymph node techniques combined with immunochemistry could improve colon cancer staging. We prospectively assessed the effect of Sentinel node mapping on staging and survival in patients with non-metastatic colon cancer.
Methods
An observational and prospective study was designed. 105 patients with colon cancer were selected. Patients were classified according to node involvement as: N1, with node invasion detected by the conventional techniques; up-staged, with node invasion detected only by sentinel node mapping; and N0, with negative lymph node involvement by both techniques. Five-year survival and disease-free survival rates were analysed. Multivariate regression analyses were performed to identify prognostic factors for disease-free and overall survival.
Results
Sentinel node mapping was successfully applied in 78 patients: 33 % were N1; 24.5 % were up-staged (18 patients with isolated tumour cells and 1 patient with micrometastases); and 42.5 % were N0. N1 patients had the poorest overall 5-year survival (65.4 %) and 5-year disease-free survival (69.2 %) rates compared with the other two groups. No significant 5-year survival differences were observed between N0 patients (87.9 %) and up-staged patients (84.2 %).
Conclusions
Patients up-staged after sentinel node mapping do not have a poorer prognosis than patients without node involvement. Detection of isolated cancer cells was not a poor prognosis factor in these patients.
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Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib
Abstract
Background
Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers.
Methods
Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively.
Results
Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8–5.2) and 6.5 (95 % CI 4.9–8.01) months, respectively. Child–Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5–12.4) compared with 4.1 (95 % CI 2.7–5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2–0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006).
Conclusion(s)
The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.
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Sentinel lymph node biopsy as a prognostic factor in non-metastatic colon cancer: a prospective study
Abstract
Purpose
Around a third of node-negative patients with colon cancer experience a recurrence after surgery, suggesting poor staging. Sentinel lymph node techniques combined with immunochemistry could improve colon cancer staging. We prospectively assessed the effect of Sentinel node mapping on staging and survival in patients with non-metastatic colon cancer.
Methods
An observational and prospective study was designed. 105 patients with colon cancer were selected. Patients were classified according to node involvement as: N1, with node invasion detected by the conventional techniques; up-staged, with node invasion detected only by sentinel node mapping; and N0, with negative lymph node involvement by both techniques. Five-year survival and disease-free survival rates were analysed. Multivariate regression analyses were performed to identify prognostic factors for disease-free and overall survival.
Results
Sentinel node mapping was successfully applied in 78 patients: 33 % were N1; 24.5 % were up-staged (18 patients with isolated tumour cells and 1 patient with micrometastases); and 42.5 % were N0. N1 patients had the poorest overall 5-year survival (65.4 %) and 5-year disease-free survival (69.2 %) rates compared with the other two groups. No significant 5-year survival differences were observed between N0 patients (87.9 %) and up-staged patients (84.2 %).
Conclusions
Patients up-staged after sentinel node mapping do not have a poorer prognosis than patients without node involvement. Detection of isolated cancer cells was not a poor prognosis factor in these patients.
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Identification of clinical biomarkers for patients with advanced hepatocellular carcinoma receiving sorafenib
Abstract
Background
Identification of patients with advanced HCC-deriving preferential benefit from sorafenib is desirable, and treatment-related adverse events are potential clinical biomarkers.
Methods
Survival and toxicity data for patients with HCC treated with sorafenib at the Christie NHS Foundation Trust from 11/09 to 02/15 were collected retrospectively.
Results
Eighty-five eligible patients were identified. The most common grade 3 or 4 treatment-related toxicities were hypertension (HTN, 45 %), fatigue (8 %), and hand-foot syndrome (HFS, 8 %). Any-grade HFS and/or worsening HTN (HFS/HTN) were experienced by 58 % of patients. Estimated median progression-free and overall survival (OS) were 4.6 (95 % CI 2.8–5.2) and 6.5 (95 % CI 4.9–8.01) months, respectively. Child–Pugh score (p value <0.001) and the development of HFS/HTN were independent prognostic factors impacting on OS on multivariable analysis. Patients who developed HFS/HTN had median OS of 8.2 months (95 % CI 6.5–12.4) compared with 4.1 (95 % CI 2.7–5.4) for those without this toxicity (Hazard Ratio (HR) 0.4, 95 % CI 0.2–0.7, p value 0.003). The prognostic impact of HFS/HTN was confirmed by landmark analyses limited to patients who lived a minimum of 2 months (p value 0.019) or who developed HFS/HTN in the first 3 months of treatment (p value 0.006).
Conclusion(s)
The development of toxicities specific to sorafenib is associated with prolonged survival in a UK-based HCC patient series; prospective assessment of their significance is required.
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Oligo-recurrence predicts favorable prognosis of brain-only oligometastases in patients with non-small cell lung cancer treated with stereotactic radiosurgery or stereotactic radiotherapy: a multi-institutional study of 61 subjects
Abstract
Background
To investigate the prognostic value of oligo-recurrence in patients with brain-only oligometastases of non-small cell lung cancer (NSCLC) treated with stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT).
Methods
Patients treated with SRS or SRT for brain-only NSCLC oligometastases in 6 high-volume institutions in Japan between 1996 and 2008 were reviewed. Eligible patients met 1), 2), and 4) or 1), 3), and 4) of the following: 1) NSCLC with 1 to 4 brain metastases on magnetic resonance imaging (MRI) treated with SRS or SRT; 2) control of the primary lesions (thorax) at the time of SRS or SRT for brain metastases (patients meeting this criterion formed the oligo-recurrence group); 3) with SRS or SRT for brain metastases, concomitant treatment for active primary lesions (thorax) with curative surgery or curative stereotactic body radiotherapy (SBRT), or curative chemoradiotherapy (sync-oligometastases group); and 4) Karnofsky performance status (KPS) ≥70.
Results
The median overall survival (OS) of all 61 patients was 26 months (95 % CI: 17.5–34.5 months). The 2-year and 5-year overall survival rates were 60.7 and 15.7 %, respectively. Stratified by oligostatus, the sync-oligometastases group achieved a median OS of 18 months (95 % CI: 14.8–21.1 months) and a 5-year OS of 0 %, while the oligo-recurrence group achieved a median OS of 41 months (95 % CI: 27.8–54.2 months) and a 5-year OS of 18.6 %. On multivariate analysis, oligo-recurrence was the only significant independent factor related to a favorable prognosis (hazard ratio: 0.253 (95 % CI: 0.082–0.043) (p = 0.025).
Conclusions
The presence of oligo-recurrence can predict a favorable prognosis of brain-only oligometastases in patients with NSCLC treated with SRS or SRT.
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Pembrolizumab-associated minimal change disease in a patient with malignant pleural mesothelioma
Abstract
Background
Pembrolizumab is an anti- Programmed Death 1 (PD-1) antibody approved in melanoma, non-small cell lung cancer and investigated in malignant pleural mesothelioma.
The most frequent immunotherapy related autoimmune reactions include dermatitis, pneumonitis, colitis, hypophysitis, uveitis, hypothyreodism, hepatitis and interstitial nephritis.
Case presentation
We describe a 62-year old patient diagnosed with malignant pleural mesothelioma who experienced ten days after the second dose of third line therapy with pembrolizumab sudden onset of generalized edema including legs and eyelids and weight gain of 15 kg resulting from nephrotic syndrome and acute renal failure. Pembrolizumab was discontinued and prednisone, diuretics and angiotensin II receptor blocker were initiated with full recovery of symptoms and renal function. Pembrolizumab-associated minimal change disease (MCD) was confirmed by electron microscopy in the renal biopsy.
Conclusion
We are the first to describe pembrolizumab-related minimal change disease (MCD).
Physicians should be aware of this side effect in patients presenting with edema and weight gain and initiate prompt renal function testing, serum albumin and urinalysis followed by steroid treatment if pembrolizumab-related MCD is suspected.
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Dactolisib (NVP-BEZ235) toxicity in murine brain tumour models
Abstract
Background
Glioblastomas (GBMs) are highly malignant brain tumours with a poor prognosis, and current cytotoxic regimens provide only a limited survival benefit. The PI3K/Akt/mTOR pathway has been an attractive target for therapy due to its high activation in GBMs as well as other cancers. The dual pan-PI3K/mTOR kinase inhibitor dactolisib (NVP-BEZ235) is an anti-neoplastic compound currently under investigation. However, little is known about its efficacy in human GBMs. We aimed at evaluating the efficacy of dactolisib in human glioblastoma cells, as well as in murine models carrying human GBM xenografts.
Methods
To assess the effect of dactolisib in vitro, MTS assay, manual cell count, BrdU incorporation and Annexin V staining experiments were used to observe growth and apoptosis. Furthermore, Akt phosphorylation (S473), a downstream target of PI3K, was explored by western blotting. Animal studies utilizing orthotopic xenograft models of glioblastoma were performed in nude rats and NOD/SCID mice to monitor survival benefit or inhibition of tumor growth.
Results
We found that dactolisib in vitro shows excellent dose dependent anti-growth properties and increase in apoptosis. Moreover, dose dependent inhibition of Akt phosphorylation (S473), a downstream effect of PI3K, was observed by western blotting. However, in two independent animal studies utilizing nude rats and NOD/SCID mice in orthotopic xenograft models of glioblastoma, we observed no survival benefit or inhibition of tumour growth. Severe side effects were observed, such as elevated levels of blood glucose and the liver enzyme alanine transaminase (ALT), in addition to diarrhoea, hair loss (alopecia), skin rash and accumulation of saliva in the oral cavity.
Conclusion
Taken together, our results suggest that despite the anti-neoplastic efficacy of dactolisib in glioma treatment in vitro, its utility in vivo is questionable due to toxicity.
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Dynamic changes of tumor gene expression during repeated pressurized intraperitoneal aerosol chemotherapy (PIPAC) in women with peritoneal cancer
Abstract
Background
Intraperitoneal chemotherapy is used to treat peritoneal cancer. The pattern of gene expression changes of peritoneal cancer during intraperitoneal chemotherapy has not been studied before. Pressurized intraperitoneal aerosol chemotherapy is a new form of intraperitoneal chemotherapy using repeated applications and allowing repeated tumor sampling during chemotherapy. Here, we present the analysis of gene expression changes during pressurized intraperitoneal aerosol chemotherapy with doxorubicin and cisplatin using a 22-gene panel.
Methods
Total RNA was extracted from 152 PC samples obtained from 63 patients in up to six cycles of intraperitoneal chemotherapy. Quantitative real-time PCR was used to determine the gene expression levels. For select genes, immunohistochemistry was used to verify gene expression changes observed on the transcript level on the protein level. Observed (changes in) expression levels were correlated with clinical outcomes.
Results
Gene expression profiles differed significantly between peritoneal cancer and non- peritoneal cancer samples and between ascites-producing and non ascites-producing peritoneal cancers. Changes of gene expression patterns during repeated intraperitoneal chemotherapy cycles were prognostic of overall survival, suggesting a molecular tumor response of peritoneal cancer. Specifically, downregulation of the whole gene panel during intraperitoneal chemotherapy was associated with better treatment response and survival.
Conclusions
In summary, molecular changes of peritoneal cancer during pressurized intraperitoneal aerosol chemotherapy can be documented and may be used to refine individual treatment and prognostic estimations.
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Increased long noncoding RNA SNHG20 predicts poor prognosis in colorectal cancer
Abstract
Background
Long noncoding RNAs (lncRNAs) have been suggested to be involved in the development and progression of malignancies. However, the investigation of small nucleolar RNA host gene 20 (SNHG20) on cancer progression remains unknown. The present study aims to explore the clinical significance of SNHG20 and its potential molecular mechanism in colorectal cancer (CRC).
Methods
Quantitative real-time PCR (qRT-PCR) was used to measure the SNHG20 expression in a total of 107 CRC tissues and CRC cell lines. Loss of function approach was employed to explore the biological roles of SNHG20 in vitro. Its potential molecular mechanism was further verified by western blotting and qRT-PCR.
Results
The results suggested that SNHG20 expression was significantly upregulated in CRC tissues compared to corresponding normal tissues from 107 CRC patients. High expression of SNHG20 was remarkably associated with advanced TNM stage in patients with CRC. Multivariate analyses unraveled that SNHG20 expression was an independent prognostic factor for overall survival in CRC patients. Further functional assays revealed that knockdown of SNHG20 suppressed cell proliferation, invasion and migration, and cell cycle progression in CRC cells. Moreover, SNHG20 regulated cell growth through modulation of a series of cell cycle-associated genes.
Conclusions
Our findings suggest that dysregulation of SNHG20 participates in CRC progression and may serve as a potential therapeutic target in CRC patients.
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A family-based study of gene variants and maternal folate and choline in neuroblastoma: a report from the Children’s Oncology Group
Abstract
Purpose
Neuroblastoma is a childhood cancer of the sympathetic nervous system with embryonic origins. Previous epidemiologic studies suggest maternal vitamin supplementation during pregnancy reduces the risk of neuroblastoma. We hypothesized offspring and maternal genetic variants in folate-related and choline-related genes are associated with neuroblastoma and modify the effects of maternal intake of folate, choline, and folic acid.
Methods
The Neuroblastoma Epidemiology in North America (NENA) study recruited 563 affected children and their parents through the Children's Oncology Group's Childhood Cancer Research Network. We used questionnaires to ascertain pre-pregnancy supplementation and estimate usual maternal dietary intake of folate, choline, and folic acid. We genotyped 955 genetic variants related to folate or choline using DNA extracted from saliva samples and used a log-linear model to estimate both child and maternal risk ratios and stratum-specific risk ratios for gene–environment interactions.
Results
Overall, no maternal or offspring genotypic results met criteria for a false discovery rate (FDR) Q-value <0.2. Associations were also null for gene–environment interaction with pre-pregnancy vitamin supplementation, dietary folic acid, and folate. FDR-significant gene–choline interactions were found for offspring SNPs rs10489810 and rs9966612 located in MTHFD1L and TYMS, respectively, with maternal choline dietary intake dichotomized at the first quartile.
Conclusion
These results suggest that variants related to one-carbon metabolism are not strongly associated with neuroblastoma. Choline-related variants may play a role; however, the functional consequences of the interacting variants are unknown and require independent replication.
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Variability of high risk HPV genotypes among HIV infected women in Mwanza, Tanzania- the need for evaluation of current vaccine effectiveness in developing countries
Abstract
Background
High risk (HR) human papilloma Virus (HPV) genotypes have been associated with cervical cancer. In Tanzania there is a limited data on the epidemiology of HPV and genotypes distribution among HIV infected women. Here we document varieties of HPV genotypes associated with cervical squamous intraepithelial lesions (SIL) among HIV- infected women at Bugando Medical Centre, Mwanza-Tanzania.
Methods
A cross sectional hospital based study involving HIV infected women was conducted between August and October, 2014. Exfoliated cells from ectocervix and endocervix were collected using cytobrush. HPV genotypes were detected using polymerase chain reaction (PCR) followed by sequencing using specific primers targeting broad range of HPV types. Cytology was done to establish squamous intraepithelial lesions. Log binomial regression analysis was done to establish risk ratios (RR) associated with HPV infection using STATA version 11.
Results
A total of 255 HIV infected women with mean age 39.2 ± 9.1 years were enrolled in the study. HPV DNA was detected in 138/255 (54.1 %, 95 % CI: 47-60) of HIV infected women. Twenty six genotypes were detected in various combinations; of these 17(65.3 %) were of HR genotypes. HR genotypes were detected in 124(48.6 %) of HIV infected women. Common HR genotypes detected were HPV-52(26), HPV-58(21), HPV-35(20) and HPV-16(14). The risk of being HPV positive was significantly higher among women with CD4 counts <100 (RR: 1.20, 95 % CI: 1.05-1.35, P = 0.006) and women with SIL (RR: 1.37, 95 % CI: 1.11-1.68, P = 0.005)
Conclusion
Significant proportion of HIV infected women with low CD4 counts have various grades of cervical SIL associated with varieties of uncommon HR genotypes. There is a need to evaluate the effectiveness of the current vaccine in preventing cervical cancer in developing countries where HIV is endemic.
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Clinical Implications of Sarcopenic Obesity in Cancer
Abstract
Sarcopenia has been associated with several negative clinical outcomes in cancer. However, the consequences of sarcopenic obesity, a condition of combined sarcopenia and obesity burden, have been less extensively investigated. The aim of this paper was to review the current evidence on the prevalence and clinical implications of sarcopenic obesity in cancer. A total of 14 studies linking sarcopenic obesity to a clinical outcome in cancer were included. There is considerable inconsistency in methods used to evaluate body composition as well as in the criteria used to define sarcopenic obesity, which limits comparison among studies. Therefore, the prevalence of sarcopenic obesity varied substantially: between 1 and 29 % in studies including individuals from all body mass index categories and between 15 and 36 % for those including obese individuals only. Negative clinical outcomes reported to be associated with sarcopenic obesity included higher risk of dose-limiting toxicity, surgical complications, physical disability, and shorter survival.
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Will cervical screening remain cost-effective in women offered the next generation nonavalent HPV vaccine? Results for four developed countries
Abstract
A next generation nonavalent human papillomavirus (HPV) vaccine ('HPV9 vaccine') is being introduced in several countries. The aims of this study were to evaluate whether cervical screening will remain cost-effective in cohorts offered nonavalent vaccines and if so, to characterize the optimal number of screening tests. We used a dynamic model of HPV vaccination and cervical screening to evaluate the cost-effectiveness of strategies involving varying numbers of primary HPV tests per lifetime for cohorts offered the nonavalent vaccine as 12 year-olds. For each of four countries – the USA, New Zealand (NZ), Australia and England - we considered local factors including vaccine uptake rates (USA/NZ uptake ∼50%; Australia/England uptake >70%); attributable fractions of HPV9-included types; demographic factors, costs and indicative willingness-to-pay (WTP) thresholds. Extensive sensitivity analysis was performed. We found that, in the USA, four screens per lifetime was the most likely scenario, with a 34% probability of being optimal at WTP US$50,000/LYS, increasing to 84% probability US$100,000/LYS. In New Zealand, five screens per lifetime was the most likely scenario, with 100% probability of being optimal at NZ$42,000/LYS. In Australia, two screens per lifetime was the most likely scenario, with 62% probability of being optimal at AU$50,000/LYS. In England, four screens per lifetime was the most likely scenario, with 32% probability of being optimal at WTP of GB£20,000/QALY, increasing to 92% probability at GB£30,000/QALY. We conclude that some cervical screening will remain cost-effective, even in countries with high vaccination coverage. However, the optimal number of screens may vary between countries. This article is protected by copyright. All rights reserved.
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Aluminium chloride promotes tumorigenesis and metastasis in normal murine mammary gland (NMuMG) epithelial cells
ABSTRACT
Aluminium salts, present in many industrial products of frequent use like antiperspirants, anti-acid drugs, food additives, and vaccines, have been incriminated in contributing to the rise in breast cancer incidence in Western societies. However, current experimental evidence supporting this hypothesis is limited. For example, no experimental evidence that aluminium promotes tumorigenesis in cultured mammary epithelial cells exists. We report here that long-term exposure to concentrations of aluminium - in the form of aluminium chloride (AlCl3) - in the range of those measured in the human breast transform normal murine mammary gland (NMuMG) epithelial cells in vitro as revealed by the soft agar assay. Subcutaneous injections into three different mouse strains with decreasing immunodeficiency, namely, NOD SCID gamma (NSG), NOD SCID or nude mice, revealed that untreated NMuMG cells form tumors and metastasize, to a limited extent, in the highly immunodeficient and natural killer (NK) cell deficient NSG strain, but not in the less permissive and NK cell competent NOD SCID or nude strains. In contrast, NMuMG cells transformed in vitro by AlCl3 form large tumors and metastasize in all three mouse models. These effects correlate with a mutagenic activity of AlCl3. Our findings demonstrate for the first time that concentrations of aluminium in the range of those measured in the human breast fully transform cultured mammary epithelial cells, thus enabling them to form tumors and metastasize in well-established mouse cancer models. Our observations provide experimental evidence that aluminium salts could be environmental breast carcinogens. This article is protected by copyright. All rights reserved.
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Prior human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccination prevents recurrent high grade cervical intraepithelial neoplasia after definitive surgical therapy: Post-hoc analysis from a randomised controlled trial
ABSTRACT
We evaluated the efficacy of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in preventing HPV-related disease after surgery for cervical lesions in a post-hoc analysis of the PApilloma TRIal against Cancer In young Adults (PATRICIA; NCT00122681). Healthy women aged 15-25 years were randomised (1:1) to receive vaccine or control at months 0, 1, and 6 and followed for 4 years. Women were enrolled regardless of their baseline HPV DNA status, HPV-16/18 serostatus, or cytology, but excluded if they had previous or planned colposcopy. The primary and secondary endpoints of PATRICIA have been reported previously; the present post-hoc analysis evaluated efficacy in a subset of women who underwent an excisional procedure for cervical lesions after vaccination. The main outcome was the incidence of subsequent HPV-related cervical intraepithelial neoplasia grade 2 or greater (CIN2+) 60 days or more post-surgery. Other outcomes included the incidence of HPV-related CIN1+, and vulvar or vaginal intraepithelial neoplasia (VIN/VaIN) 60 days or more post-surgery. Of the total vaccinated cohort of 18,644 women (vaccine=9,319; control=9,325), 454 (vaccine=190, control=264) underwent an excisional procedure during the trial. Efficacy 60 days or more post-surgery for a first lesion, irrespective of HPV DNA results, was 88.2% (95% CI: 14.8, 99.7) against CIN2+ and 42.6% (-21.1, 74.1) against CIN1+. No VIN was reported and one woman in each group had VaIN2+ 60 days or more post-surgery. Women who undergo surgical therapy for cervical lesions after vaccination with the HPV-16/18 vaccine may continue to benefit from vaccination, with a reduced risk of developing subsequent CIN2+. This article is protected by copyright. All rights reserved.
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Role of isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan in locally advanced extremity soft tissue sarcoma
The management of locally advanced extremity soft tissue sarcoma of the limbs is challenging, particularly for recurrent tumors and those adjacent to neurovascular bundles and joints. Typically, the tumors are large, below the fascia, and high-grade (T2b or stage III according to the American Joint Committee on Cancer) and thus require multimodal therapy. Treatment options must be tailored to patient and tumor characteristics. Isolated limb perfusion with recombinant human tumor necrosis factor α and melphalan (TNF-ILP) adds a therapeutic option to radiation therapy (RT) and systemic chemotherapy. Although the procedure is somewhat sophisticated to learn, it is a safe method and has been used now for almost 2 decades at more than 50 centers worldwide. TNF-ILP yields a high rate of complete or nearly complete pathologic tumor remission. In combination with surgical resection of the tumor remnant after isolated limb perfusion, the limb salvage rate is close to 90%. Often, patients can be spared adjuvant RT without long-term local tumor control rates being compromised. Nevertheless, TNF-ILP has never been compared with another treatment regimen in a randomized trial. This review summarizes the mode of action and standard application of TNF-ILP and focuses on a critical discussion of the role of TNF-ILP in the multimodal treatment of locally advanced primary and recurrent extremity sarcoma. Cancer 2016. © 2016 American Cancer Society. Cancer 2016;122:2624–2632. © 2016 American Cancer Society.
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Tracheobronchomalacia diagnosed by tracheobronchography in ventilator-dependent infants
Abstract
Background
Tracheobronchomalacia prevalence in premature infants on prolonged mechanical ventilation is high.
Objective
To examine the prevalence of tracheobronchomalacia diagnosed by tracheobronchography in ventilator-dependent infants, and describe the demographic, clinical and dynamic airway characteristics of those infants with tracheobronchomalacia.
Materials and methods
This retrospective review studies 198 tracheobronchograms performed from 1998 to 2011 in a cohort of 158 ventilator-dependent infants <2 years of age. Dynamic airway assessment during tracheobronchography determined the optimal positive end-expiratory pressure to maintain airway patency at expiration in those infants with tracheobronchomalacia.
Results
Tracheobronchograms were performed at a median age of 52 weeks post menstrual age. The primary diagnoses in these infants were bronchopulmonary dysplasia (53%), other causes of chronic lung disease of infancy (28%) and upper airway anomaly (13%). Of those with bronchopulmonary dysplasia, 48% had tracheobronchomalacia. Prematurity (P=0.01) and higher baseline - pre-tracheobronchogram positive end-expiratory pressure (P=0.04) were significantly associated with tracheobronchomalacia. Dynamic airway collapse during tracheobronchography showed statistically significant airway opening at optimal positive end-expiratory pressure (P < 0.001). There were no significant complications noted during and immediately following tracheobronchography.
Conclusion
The overall prevalence of tracheobronchomalacia in this cohort of ventilator-dependent infants is 40% and in those with bronchopulmonary dysplasia is 48%. Infants born prematurely and requiring high pre-tracheobronchogram positive end-expiratory pressure were likely to have tracheobronchomalacia. Tracheobronchography can be used to safely assess the dynamic function of the airway and can provide the clinician the optimal positive end-expiratory pressure to maintain airway patency.
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Prognostic value of HER2 status in bladder transitional cell carcinoma revealed by both IHC and BDISH techniques
Abstract
Background
Her2/neu is an oncogene that plays an important role in the pathogenesis of many cancer types. In bladder carcinoma (BC), the clinical significance of Her2/neu status remains under-investigated and poorly linked to the patients' clinic-pathological features and survival status. Thus, the current study was conducted to assess Her2/neu status in a cohort of patients' in Saudi Arabia, and to explore its prognostic value in BC.
Methods
A total of 160 consent patients of transitional cell carcinoma (TCC) of bladder were arranged on a tissue microarray (TMA) and stained by immunohistochemistry (IHC) and bright-field dual in situ hybridization (BDISH) methods. The intensity of Her2/neu protein receptor immunostaining was evaluated, correlated to Her2/neu gene amplification status in TCC and assessed for potential clinical value by correlation measures.
Results
IHC data demonstrated that Her2/neu protein is expressed in 60 % (2+ and 3+) of our TCC patient's cohort from Saudi Arabia. Her2/neu gene amplification is detected in 25 % by BDISH. There was a strong association between Her2/neu protein levels and lymph node invasion (p = 0.04), tumor stage (p = 0.002), vascular invasion and borderline significance with distant metastasis (p = 0.07). Amplification of Her2/neu gene was associated with tumor grade (p = 0.03) and poor disease-specific survival (p = 0.02), in that, patients with non-amplified Her2/neu gene live longer. Interestingly, there was a reasonable concordance rate (71 %) between IHC and BDISH data in the analyzed cohort.
Conclusion
The study showed that 25 % of our patients' cohort has Her2/neu over-expression. This Her2/neu (over-expression/amplification) status was concordant using either IHC or BDISH and significantly associated with disease aggressiveness and poor outcome. These findings suggested a potential impact of anti-Her2 targeted therapy in the treatment of bladder cancer with amplified/overexpressed HER2 that needs further investigation.
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Connect MDS/AML: design of the myelodysplastic syndromes and acute myeloid leukemia disease registry, a prospective observational cohort study
Abstract
Background
Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are myeloid neoplasms in which outgrowth of neoplastic clones disrupts normal hematopoiesis. Some patients with unexplained persistent cytopenias may not meet minimal diagnostic criteria for MDS but an alternate diagnosis is not apparent; the term idiopathic cytopenia of undetermined significance (ICUS) has been used to describe this state. MDS and AML occur primarily in older patients who are often treated outside the clinical trial setting. Consequently, our understanding of the patterns of diagnostic evaluation, management, and outcomes of these patients is limited. Furthermore, there are few natural history studies of ICUS. To better understand how patients who have MDS, ICUS, or AML are managed in the routine clinical setting, the Connect MDS/AML Disease Registry, a multicenter, prospective, observational cohort study of patients newly diagnosed with these conditions has been initiated.
Methods/Design
The Connect MDS/AML Disease Registry will capture diagnosis, risk assessment, treatment, and outcomes data for approximately 1500 newly diagnosed patients from approximately 150 community and academic sites in the United States in 4 cohorts: (1) lower-risk MDS (International Prognostic Scoring System [IPSS] low and intermediate-1 risk), with and without del(5q); (2) higher-risk MDS (IPSS intermediate-2 and high risk); (3) ICUS; and (4) AML in patients aged ≥ 55 years (excluding acute promyelocytic leukemia). Diagnosis will be confirmed by central review. Baseline patient characteristics, diagnostic patterns, treatment patterns, clinical outcomes, health economics outcomes, and patient-reported health-related quality of life will be entered into an electronic data capture system at enrollment and quarterly for 8 years. A tissue substudy to explore the relationship between karyotypes, molecular markers, and clinical outcomes will be conducted, and is optional for patients.
Discussion
The Connect MDS/AML Disease Registry will be the first prospective, observational, non-interventional study in the United States to collect clinical information, patient-reported outcomes, and tissue samples from patients with MDS, ICUS, or AML receiving multiple therapies. Results from this registry may provide new insights into the relationship between diagnostic practices, treatment regimens, and outcomes in patients with these diseases and identify areas for future investigation.
Trial registration
Connect MDS/AML Disease Registry (NCT01688011). Registered 14 September 2012.
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Comprehensive analysis of clinical development and regulatory submission promotion schemes for oncologic drugs as the Japanese national projects
Summary
To reduce the delay in marketing authorization of drugs in Japan, four Japanese national projects were instituted. We examined all oncologic drugs for adult patients approved or discussed through these schemes, for the first time. All the data are publicly available. In total, 197 applications/demands (181 indications and 16 dosages/uses) were collected. As of December 31, 2015, 64 indications and 10 dosages/uses were approved as off-label drugs through these schemes without conducting additional registration trials in Japan. Furthermore, 46 indications and two dosages/uses were approved after registration trials in Japan requested by the national scheme councils. Regarding the following 23 indications of the 197 applications/demands, registration trials in Japan were commenced after the national scheme council's request: 17 hematological malignancies and six orphan solid tumors. Moreover, 54 indications and three dosages/uses, for which demands were submitted, were regarded as not a high medical priority by the national scheme council. Regarding two hematological malignancy indications, the dosage approved in foreign countries was intolerable for the Japanese patients in Japanese registration trials and this stopped the clinical development in Japan. Our analysis showed that 110 indications and 12 dosages/uses were approved in Japan through these schemes. These national projects have provided numerous therapeutic options for Japanese patients and may be meaningful for promoting clinical development and regulatory approval especially in orphan diseases in countries other than Japan.
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Analysis of prognostic factors for pancreatic head cancer according to para-aortic lymph node
Abstract
This study was designed to investigate the relationship between prognosis of pancreatic head cancer and status of para-aortic lymph node (PALN). A total of 233 patients with pancreatic head cancer who underwent surgical resection between February 2008 and October 2015 were enrolled in this study. Univariate and multivariate analyses were used to reveal the prognostic factors. Prognostic factors for patients with and without metastasis of PALN were analyzed, respectively. The 5-year overall survival (OS) rate was 19.0% for all patients, and the positive rate of PALN metastasis was 18.9% (44/233). The 1-, 2-, 3-, and 5-year OS rates in patients without metastasis of PALN were 79.4%, 54.8%, 36.4%, and 22.9%, respectively, whereas the 1-, 2-, and 3-year survival rates were 54.0%, 14.8%, and 0%, respectively, in patients with metastasis of PALN. Preoperative CA19-9 level, tumor size, T status, N status, and adjuvant therapy were independent prognostic factors for all patients confirmed by multivariate analysis. For patients without PALN metastasis, back pain, tumor size, T status, N status, portal or superior mesenteric vein invasion, and adjuvant therapy were independent prognostic factors, while the only one influence factor for 2-year OS was adjuvant therapy for patients with metastasis of PALN. Metastasis of PALN was associated with poor prognosis for patients with pancreatic head cancer. Patients with and without metastasis of PALN had different prognostic factors, and adjuvant therapy was the only prognostic factor for patients with metastasis of PALN.
There were few reports on analysis of prognostic factors for pancreatic head cancer according to para-aortic lymph node. Different prognostic factors for pancreatic cancer had been confirmed by our study.
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Novel dual-mode nanobubbles as potential targeted contrast agents for female tumors exploration
Abstract
The purpose of this study was to prepare tumor-specific dual-mode nanobubbles as both ultrasound contrast agents (UCAs) and near-infrared fluorescence (NIRF) imaging agents for female tumors. Recent studies have demonstrated the conjugation of anti-tumor ligands on the surface of nanobubbles for use as molecule-targeting ultrasound contrast agents for tumor visualization. However, this complicated procedure has also posed a challenge to nanobubble stability. Thus, in the present study, we combined the fluorescent dye, NIRF IR-780 iodide, which has lipid solubility and tumor-targeting characteristics, with the phospholipid film of nanobubbles that we constructed. We then characterized the physical features of the IR-780-nanobubbles, observed their tumor-targeting capacity in multiple female tumor cell types in vitro, and verified their capability for use in tumor-specific ultrasound contrast imaging and NIRF imaging in vivo. The results showed that the new IR-780-nanobubbles had a uniform nano-size (442.5 ± 48.6 nm) and stability and that they were safe and effective at NIRF imaging and ultrasound imaging in vitro. The IR-780-nanobubbles were found to automatically accumulate on different female tumor cells in vitro with a considerable targeting rate (close to 40 %) but did not accumulate on cardiac muscle cells used as a negative control. Importantly, the IR-780-nanobubbles can detect female tumors precisely via dual-mode imaging in vivo. In conclusion, the new dual-mode IR-780-nanobubbles are stable and have potential advantages in non-invasive tumor-specific detection for female tumors via contrast-enhanced ultrasound and NIRF imaging.
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Current Progress in Immunotherapy for the Treatment of Biliary Cancers
Abstract
Purpose
Biliary tract cancers (BTC) remain one of the poorest groups of malignancies in terms of long-term survival, with only limited success in improvements by the use of systemic chemotherapy and our current repertoire of molecularly targeted therapies. Treatments that aim to adapt the patient's own immune system to target cancer cell have shown tremendous promise in treating solid tumors such as melanoma and non-small cell lung cancer, and there are many recently completed and ongoing studies looking to move immunotherapy into the treatment of BTC. We review here both preclinical and early clinical studies of immune therapies for BTC, including autologous cell transfer, vaccinations, and immunomodulatory approaches (e.g., immune checkpoint inhibitors).
Methods
Published abstracts and articles from peer-reviewed journals as well as ongoing trial information were obtained from PubMed, Google Scholar, and Clinicaltrials.gov.
Results
The use of immune-mediated or immunomodulatory therapies in BTC are supported by observations that many chronic inflammatory states are associated with their development. Although success in treating BTC by the active manipulation of the immune system has been limited to date, we note many recent and ongoing areas of preclinical and clinical investigation that may translate to further clinical trials.
Conclusions
As we continue to follow subgroup analyses and results from specific studies that include BTC patients, we will hopefully be able to combine these with focused preclinical investigations providing further rationale for future trial success in treating BTC.
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Analysis of predictability of F-18 fluorodeoxyglucose-PET/CT in the recurrence of papillary thyroid carcinoma
Abstract
Whether preoperative F-18 fluorodeoxyglucose (FDG)-positron emission tomography/computed tomography (PET/CT) can predict recurrence of papillary thyroid carcinoma (PTC) remains unclear. Herein, we evaluated the potential of primary tumor FDG avidity for the prediction of tumor recurrence in PTC patients. A total of 412 PTC patients (72 males, 340 females; age: 47.2 ± 12.2 years; range: 17–84 years) who underwent FDG-PET/CT prior to total thyroidectomy (n = 350), subtotal thyroidectomy (n = 2), or lobectomy (n = 60) from 2007 to 2011 were analyzed. The predictive ability for recurrence was investigated among various clinicopathological factors, BRAFV600E mutation, and preoperative FDG avidity of the primary tumor using Kaplan–Meier (univariate) and Cox proportional hazards regression (multivariate) analyses. Of the 412 patients, 19 (4.6%) experienced recurrence, which was confirmed either by pathology (n = 17) or high serum thyroglobulin level (n = 2), during a mean follow-up period of 43.9 ± 16.6 months. Of the 412 patients, 237 (57.5%) had FDG-avid tumors (maximum standardized uptake value, 7.1 ± 7.0; range: 1.6–50.5). Kaplan–Meier analysis revealed that tumor size (P = 0.0054), FDG avidity of the tumor (P = 0.0049), extrathyroidal extension (P = 0.0212), and lymph node (LN) stage (P < 0.0001) were significant predictors for recurrence. However, only LN stage remained a significant predictor in the multivariate analysis (P < 0.0001). Patients with FDG-avid tumors had higher LN stage (P < 0.0001), larger tumor size (P < 0.0001), and more frequent extrathyroidal extension (P < 0.0001). In conclusion, FDG avidity of the primary tumor in preoperative FDG-PET/CT could not predict the recurrence of PTC. LN stage was the only identified predictor of PTC recurrence.
FDG (fluorodeoxyglucose)-avid papillary thyroid carcinomas showed worse pathological prognostic factors. Lymph node metastasis was the only predictor of papillary thyroid carcinoma (PTC) recurrence. Preoperative FDG-PET/CT may play a potential role for the prediction of papillary thyroid carcinoma recurrence.
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Applying a RapidPlan model trained on a technique and orientation to another: a feasibility and dosimetric evaluation
Abstract
Background
The development of a dose-volume-histogram (DVH) estimation model for knowledge-based planning is very time-consuming and it could be inefficient if it was only used for similar upcoming cases as supposed. It is clinically desirable to explore and validate other potential applications for a configured model. This study tests the hypothesis that a supine volumetric modulated arc therapy (VMAT) model can optimize intensity modulated radiotherapy (IMRT) plans of other patient setup orientations.
Methods
Based on RapidPlan, a DVH estimation model was trained using 81 supine VMAT rectal plans and validated on 10 similar cases to ensure the robustness of its designed purpose. Attempts were then made to apply the model to re-optimize the dynamic MLC-sequences of the duplicated IMRT plans from 30 historical patients (20 prone and 10 supine) that were treated with the same prescription as for the model (50.6 and 41.8 Gy to 95 % of PGTV and PTV simultaneously/22 fractions). The performance of knowledge-based re-optimization and the impact of setup orientations were evaluated dosimetrically.
Results
The VMAT model validation on similar cases showed comparable target dose distribution and significantly improved organ sparing (by 10.77 ~ 18.65 %) than the original plans. IMRT plans of either setup can be re-optimized using the supine VMAT model, which significantly reduced the dose to the bladder (by 25.88 % from 33.85 ± 2.96 to 25.09 ± 1.32 Gy for D50 %; by 22.77 % from 33.99 ± 2.77 to 26.25 ± 1.22 Gy for mean dose) and femoral head (by 12.27 % from 15.65 ± 3.33 to 13.73 ± 1.43 Gy for D50 %; by 10.09 % from 16.26 ± 2.74 to 14.62 ± 1.10 Gy for mean dose), all P < 0.01. Although the dose homogeneity and PGTV conformity index (CI_PGTV) changed slightly (≤0.01), CI_PTV of IMRT plans was significantly increased (Δ = 0.17, P < 0.01) by the manually defined target-objectives in the VMAT optimizer. The semi-automated IMRT planning increased the global maximum dose and V107 % due to the missing of hot spot suppression by specific manual optimizing or fluence map editing.
Conclusions
The Varian RapidPlan model trained on a technique and orientation can be used for another. Knowledge-based planning improves organ sparing and quality consistency, yet the target-objectives defined for VMAT-optimizer should be readapted to IMRT planning, followed by manual hot spot processing.
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Id4 promotes cisplatin resistance in lung cancer through the p38 MAPK pathway.
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Overall prognostic impact of C-reactive protein level in patients with metastatic renal cell carcinoma treated with sorafenib.
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Antitumoral action of icaritin in LNCaP prostate cancer cells by regulating PEA3/HER2/AR signaling.
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