Prediction of Acute Radiation Mucositis using an Oral Mucosal Dose Surface Model in Carbon Ion Radiotherapy for Head and Neck Tumors

Purpose

To evaluate the dose-response relationship for development of acute radiation mucositis (ARM) using an oral mucosal dose surface model (OMDS-model) in carbon ion radiotherapy (C-ion RT) for head and neck tumors.

Methods

Thirty-nine patients receiving C-ion RT for head and neck cancer were evaluated for ARM (once per week for 6 weeks) according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0, and the Radiation Therapy Oncology Group (RTOG) scoring systems. The irradiation schedule typically used was 64 Gy [relative biological effectiveness (RBE)] in 16 fractions for 4 weeks. Maximum point doses in the palate and tongue were compared with ARM in each patient.

Results

The location of the ARM coincided with the high-dose area in the OMDS-model. There was a clear dose-response relationship between maximum point dose and ARM grade assessed using the RTOG criteria but not the CTCAE. The threshold doses for grade 2–3 ARM in the palate and tongue were 43.0 Gy(RBE) and 54.3 Gy(RBE), respectively.

Conclusions

The OMDS-model was useful for predicting the location and severity of ARM. Maximum point doses in the model correlated well with grade 2–3 ARM.     

Brain-Sparing Methods for IMRT of Head and Neck Cancer

Purpose

Radical radiotherapy for head and neck cancer (HNC) may deliver significant doses to brain structures. There is evidence that this may cause a decline in neurocognitive function (NCF). Radiation dose to the medial temporal lobes, and particularly to the hippocampi, seems to be critical in determining NCF outcomes. We evaluated the feasibility of two alternative intensity-modulated radiotherapy (IMRT) techniques to generate hippocampus- and brain-sparing HNC treatment plans to preserve NCF.

Methods and Materials

A planning study was undertaken for ten patients with HNC whose planning target volume (PTV) included the nasopharynx. Patients had been previously treated using standard (chemo)-IMRT techniques. Bilateral hippocampi were delineated according to the RTOG atlas, on T1w MRI co-registered to the RT planning CT. Hippocampus-sparing plans (HSRT), and whole-brain/hippocampus-sparing fixed-field non-coplanar IMRT (BSRT) plans, were generated. DVHs and dose difference maps were used to compare plans. NTCP calculations for NCF impairment, based on hippocampal dosimetry, were performed for all plans.

Results

Significant reductions in hippocampal doses relative to standard plans were achieved in eight of ten cases for both HSRT and BSRT. EQD2 D40% to bilateral hippocampi was significantly reduced from a mean of 23.5 Gy (range 14.5–35.0) in the standard plans to a mean of 8.6 Gy (4.2–24.7) for HSRT (p = 0.001) and a mean of 9.0 Gy (4.3–17.3) for BSRT (p < 0.001). Both HSRT and BSRT resulted in a significant reduction in doses to the whole brain, brain stem, and cerebellum.

Conclusion

We demonstrate that IMRT plans for HNC involving the nasopharynx can be successfully optimised to significantly reduce dose to the bilateral hippocampi and whole brain. The magnitude of the achievable dose reductions results in significant reductions in the probability of radiation-induced NCF decline. These results could readily be translated into a future clinical trial.     

A Review of Clinical Radioprotection and Chemoprotection for Oral Mucositis

The first tenet of medicine, “primum non nocere” or “first, do no harm”, is not always compatible with oncological interventions e.g., chemotherapy, targeted therapy and radiation, since they commonly result in significant toxicities. One of the more frequent and serious treatment-induced toxicities is mucositis and particularly oral mucositis (OM) described as inflammation, atrophy and breakdown of the mucosa or lining of the oral cavity. The sequelae of oral mucositis (OM), which include pain, odynodysphagia, dysgeusia, decreased oral intake and systemic infection, frequently require treatment delays, interruptions and discontinuations that not only negatively impact quality of life but also tumor control and survivorship. One potential strategy to reduce or prevent the development of mucositis, for which no effective therapies exist only best supportive empirical care measures, is the administration of agents referred to as radioprotectors and/or chemoprotectors, which are intended to differentially protect normal but not malignant tissue from cytotoxicity. This limited-scope review briefly summarizes the incidence, pathogenesis, symptoms and impact on patients of OM as well as the background and mechanisms of four clinical stage radioprotectors/chemoprotectors, amifostine, palifermin, GC4419 and RRx-001, with the proven or theoretical potential to minimize the development of mucositis particularly in the treatment of head and neck cancers.     

Tooth Loss and Risk of Head and Neck Cancer: A Meta-Analysis

Background

Observational studies suggest an association between tooth loss and risk of head and neck cancer. However, whether tooth loss is an independent risk factor for head and neck cancer still remains controversial. The aim of this study is to assess the association between tooth loss and head and neck cancer risk.

Methods

Eligible studies were searched in PubMed and Embase databases from their inception to March 2013. A random-effects model or fixed-effects model was used to calculate the overall combined risk estimates.

Results

Eight case-control studies and one cross-sectional study involving 5,204 patients and 5,518 controls were included in the meta-analysis. The overall combined odds ratio for tooth loss and head and neck cancer was 2.00 (95% confidence interval, 1.28–3.14). Similar results yielded both in the moderate and severe tooth loss group. Sensitivity analysis based on various exclusion criteria maintained this significance with respect to head and neck cancer individually. Little evidence of publication bias was observed.

Conclusion

This meta-analysis suggests that tooth loss is associated with increased risk of head and neck cancer. This increase is probably independent of conventional head and neck cancer risk factors.     

Tea Consumption and Risk of Head and Neck Cancer

Background

The current study evaluated the association between tea consumption and head and neck cancer (HNC) in Taiwan, where tea is a major agricultural product and a popular beverage.

Methods

Interviews regarding tea consumption (frequency, duration, and types) were conducted with 396 HNC cases and 413 controls. Unconditional logistic regression was performed to estimate the odds ratio (OR) and 95% confidence interval (CI) of HNC risk associated with tea drinking, adjusted for sex, age, education, cigarette smoking, betel quid chewing, and alcohol drinking.

Results

A reduced HNC risk associated with tea drinking (OR for every cup per day = 0.96, 95% CI: 0.93–0.99; OR for ≧5 cups per day = 0.60, 95% CI: 0.39–0.94) was observed. The association was especially significant for pharyngeal cancer (OR for every cup per day = 0.93, 95% CI: 0.88–0.98; OR for ≧5 cups per day = 0.32, 95% CI: 0.16–0.66). A significant inverse association between HNC and tea consumption was observed particularly for green tea.

Conclusions

This study suggests that tea drinking may reduce the risk of HNC. The anticancer property of tea, if proven, may offer a natural chemopreventive measure to reduce the occurrence of HNC.     

GSTM3 A/B Polymorphism and Risk for Head and Neck Cancer: A Meta-Analysis

Background

Glutathione S-transferase M3 (GSTM3) is an important member of the GSTs that plays a critical role in the development of head and neck cancer (HNC). Several studies have investigated between the GSTM3 A/B polymorphism and risk of HNC, however, the results remain controversial. The aim of this meta-analysis is to evaluate the association between the GSTM3 A/B polymorphism and the risk of HNC.

Methods

All eligible case-control studies published up to July 2013 were identified by searching PubMed and Web of Science. The HNC risk associated with the GSTM3 A/B polymorphism was estimated for each study by odds ratios (OR) together with its 95% confidence interval (CI), respectively.

Results

Fourteen studies from ten publications with 2110 patients and 2259 controls were included. Overall, the GSTM3 A/B polymorphism was associated with a decreased risk of HNC using the dominant model, homozygote comparison model and heterozygote comparison model (OR = 0.82, 95%CI: 0.71–0.94; OR = 0.67, 95%CI: 0.49–0.94; and OR = 0.84, 95%CI: 0.73–0.97, respectively); besides, in stratification analyses by ethnicity, similar results were observed in Caucasian populations. Stratification by tumor site indicated that the GSTM3 polymorphism was associated with a decreased risk of laryngeal cancer under recessive model and homozygote comparison (OR = 0.52, 95%CI: 0.30–0.89; and OR = 0.50, 95%CI: 0.29–0.87, respectively); By stratifying source of control, decreased cancer risk was observed in hospital-based population under all genetic models (OR = 0.67, 95%CI: 0.56–0.81 for the dominant model; OR = 0.66, 95%CI: 0.46–0.95 for the recessive model; OR = 0.55, 95%CI: 0.37–0.83 for the homozygote comparison model, and OR = 0.70, 95%CI: 0.58–0.84 for the heterozygote comparison model).

Conclusions

This meta-analysis suggests that the GSTM3 A/B polymorphism may be an important protective factor for HNC, especially of laryngeal cancer and Caucasian populations.     

Tooth Loss and Head and Neck Cancer: A Meta-Analysis of Observational Studies

Backgroud

Epidemiological studies have shown that tooth loss is associated with risk of head and neck cancer (HNC); however, the results were inconsistent. Therefore, we conducted a meta-analysis to ascertain the relationship between tooth loss and HNC.

Methods

We searched for relevant observational studies that tested the association between tooth loss and risk of HNC from PubMed and were conducted up to January 30, 2013. Data from the eligible studies were independently extracted by two authors. The meta-analysis was performed using the Comprehensive Meta-Analysis 2.2 software. Sensitivity and subgroup analyses were conducted to evaluate the influence of various inclusions. Publication bias was also detected.

Results

Ten articles involving one cohort and ten case-control studies were yielded. Based on random-effects meta-analysis, an association between tooth loss and HNC risk was identified [increased risk of 29% for 1 to 6 teeth loss (OR = 1.29, 95% CI = 0.52–3.20, p = 0.59), 58% for 6 to 15 teeth loss (OR = 1.58, 95% CI = 1.08–2.32, p = 0.02), 63% for 11+ teeth loss (OR = 1.63, 95% CI = 1.23–2.14, p<0.001), 72% for 15+ teeth loss (OR = 1.72, 95% CI = 1.26–2.36, p<0.001), and 89% for 20+ teeth loss (OR = 1.89, 95% CI = 1.27–2.80, p<0.001)]. The sensitivity analysis shows that the result was robust, and publication bias was not detected.

Conclusions

Based on the current evidence, tooth loss is probably a significant and dependent risk factor of HNC, which may have a dose-response effect. People who lost six or more teeth should pay attention to symptoms of HNC, and losing 11 teeth or 15 teeth may be the threshold.     

一种特异性识别小细胞肺癌细胞的小分子肽

应用“一个珠子一个化合物”的组合化学肽库技术,筛选得到特异性识别小细胞肺癌细胞(DMS53)的小分子肽.初次筛选共得到32个与DMS53阳性结合的珠子,经氨基酸序列分析后发现,含有cNGRXXXc或cXNGRXXc肽链结构的序列共有10个.再次合成三种有代表性的小分子肽,发现cFNGRQQc与DMS53的结合率明显高于其他小分子肽.选择cFNGRQQc作进一步的细胞特异性研究,发现cFNGRQQc与DMS53的粘附特异性明显高于其他细胞系,对cFNGRQQc的结构分析显示,-NGR-及六肽长度对小分子肽与DMS53细胞的粘附非常重要.用抗整合素、E-cadherin、NCAM及ICAM的抗体或多肽阻断小分子肽与DMS53细胞表面的相应受体结合,未见明显的阻断效应.小分子肽与DMS53细胞表面的结合位点有待于进一步证实.     

A Novel Magnetic Nanoparticle Drug Carrier for Enhanced Cancer Chemotherapy

Background

Magnetic nanoparticles (NPs) loaded with antitumor drugs in combination with an external magnetic field (EMF)-guided delivery can improve the efficacy of treatment and may decrease serious side effects. The purpose of this study was 1) to investigate application of PEG modified GMNPs (PGMNPs) as a drug carrier of the chemotherapy compound doxorubicin (DOX) in vitro; 2) to evaluate the therapeutic efficiency of DOX-conjugated PGMNPs (DOX-PGMNPs) using an EMF-guided delivery in vivo.

Methods

First, DOX-PGMNPs were synthesized and the cytotoxicity of DOX-PGMNPs was assessed in vitro. Second, upon intravenous administration of DOX-PMGPNs to H22 hepatoma cell tumor-bearing mice, the DOX biodistribution in different organs (tissues) was measured. The antitumor activity was evaluated using different treatment strategies such as DOX-PMGPNs or DOX-PMGPNs with an EMF-guided delivery (DOX-PGMNPs-M).

Results

The relative tumor volumes in DOX-PGMNPs-M, DOX-PGMNPs, and DOX groups were 5.46±1.48, 9.22±1.51, and 14.8±1.64, respectively (each p<0.05), following treatment for 33 days. The life span of tumor-bearing mice treated with DOX-PGMNPs-M, DOX-PGMNPs, and DOX were 74.8±9.95, 66.1±13.5, and 31.3±3.31 days, respectively (each p<0.05).

Conclusion

This simple and adaptive nanoparticle design may accommodate chemotherapy for drug delivery optimization and in vivo drug-target definition in system biology profiling, increasing the margin of safety in treatment of cancers in the near future.     

Pharmacodynamic and Pharmacokinetic Properties of AFPep,a Novel Peptide for the Treatment of Breast Cancer

AFPep is a small synthetic cyclized peptide derived from alpha-fetoprotein that has been shown to have anti-estrogenic and anti-breast cancer activity. The purpose of this study was to establish blood levels of AFPep that are associated with biological activity. Blood levels of AFPep were measured by LC/MS/MS. Once daily treatment of mice with 4 mg/kg i.p. AFPep yielded a C_max of 7 µg/ml and was sufficient to inhibit estrogen-stimulated growth of mouse uterus and of human breast cancer xenografts even though the half-life of this drug was only 11 min in mice, suggesting that its biological effects last much longer than its chemical half-life. In dose de-escalation studies, blood levels of 100 ng/ml of AFPep were still found to be biologically active. AFPep was effective by parenteral routes and with dose escalation also by the oral route. Blood levels of AFPep that were biologically effective in mice were readily achieved in dogs through parenteral as well as oral routes with no apparent evidence of host toxicity. In conclusion, AFPep blood levels can be measured by LC/MS/MS with accuracy into the ng/ml range. Blood levels in the 100 ng/ml range are associated with efficacious biological activity. This drug shows great promise for the treatment as well as prevention of breast cancer.     

Significance of Lymph Node Metastasis in Cancer Dissemination of Head and Neck Cancer

Lymph node metastasis (LNM) in many solid cancers is a well-known prognostic factor; however, it has been debated whether regional LNM simply reflects tumor aggressiveness or is a source for further tumor dissemination. Similarly, the metastatic process in head and neck cancer (HNC) has not been fully evaluated. Thus, we aimed to investigate the relative significance of LNM in metastatic cascade of HNC using functional imaging of HNC patients and molecular imaging in in vivo models. First, we analyzed ¹⁸Fluorodeoxyglucose positron emission tomography (PET) parameters of 117 patients with oral cancer. The primary tumor and nodal PET parameters were measured separately, and survival analyses were conducted on the basis of clinical and PET variables to identify significant prognostic factors. In multivariate analyses, we found that only the metastatic node PET values were significant. Next, we compared the relative frequency of lung metastasis in primary ear tumors versus lymph node (LN) tumors, and we tested the rate of lung metastasis in another animal model, in which each animal had both primary and LN tumors that were expressing different colors. As a result, LN tumors showed higher frequencies of lung metastasis compared to orthotopic primary tumors. In color-matched comparisons, the relative contribution to lung metastasis was higher in LN tumors than in primary tumors, although both primary and LN tumors caused lung metastases. In summary, tumors growing in the LN microenvironment spread to systemic sites more commonly than primary tumors in HNC, suggesting that the adequate management of LNM can reduce further systemic metastasis.     

Fenretinide: A Novel Treatment for Endometrial Cancer

Resistance to progestin treatment is a major hurdle in the treatment of advanced and reoccurring endometrial cancer. Fenretinide is a synthetic retinoid that has been evaluated in clinical trials as a cancer therapeutic and chemo-preventive agent. Fenretinide has been established to be cytotoxic to many kinds of cancer cells. In the present study, we demonstrate that fenretinide decreased cell viability and induced apoptosis in Ishikawa cells, which are an endometrial cancer cell line, in dose dependent manner in-vitro. This effect was found to be independent of retinoic acid nuclear receptor signaling pathway. Further, we have shown that this induction of apoptosis by fenretinide may be caused by increased retinol uptake via STRA6. Silencing of STRA6 was shown to decrease apoptosis which was inhibited by knockdown of STRA6 expression in Ishikawa cells. Results of an in-vivo study demonstrated that intraperitoneal injections of fenretinide in endometrial cancer tumors (created using Ishikawa cells) in mice inhibited tumor growth effectively. Immunohistochemistry of mice tumors showed a decrease in Ki67 expression and an increase in cleaved caspase-3 staining after fenretinide treatment when compared to vehicle treated mice. Collectively, our results are the first to establish the efficacy of fenretinide as an antitumor agent for endometrial cancer both in-vitro and in-vivo, providing a valuable rationale for initiating more preclinical studies and clinical trials using fenretinide for the treatment of endometrial cancer.     

Periodontal Disease and Risk of Head and Neck Cancer: A Meta-Analysis of Observational Studies

Background

Many epidemiological studies have found a positive association of periodontal disease (PD) with risk of head and neck cancer (HNC), but the findings are varied or even contradictory. In this work, we performed a meta-analysis to ascertain the relationship between PD and HNC risk.

Methods

We searched the PubMed, Embase, and Cochrane Library databases for relevant observational studies on the association between PD and HNC risk published up to March 23, 2013. Data from the included studies were extracted and analyzed independently by two authors. Meta-analysis was performed using RevMan 5.2 software.

Results

We obtained seven observational studies involving two cohort and six case-control studies. Random-effects meta-analysis indicated a significant association between PD and HNC risk (odds ratio = 2.63, 95% confidence interval = 1.1.68 - 4.14; p < 0.001), with sensitivity analysis showing that the result was robust. Subgroup analyses based on adjustment for covariates, study design, PD assessment, tumor site, and ethnicity also revealed a significant association.

Conclusions

Based on currently evidence, PD is probably a significant and independent risk factor of HNC.     

Dental Management of the Geriatric Head and Neck Cancer Patient1

The geriatric patient presenting with cancer of the head and neck region constitutes slightly less than half of all oral cancers diagnosed. Cancers of this region are generally treated with surgery, radiation, chemotherapy or combinations of these three. These patients not only present with special problems due to their age but also with challenging ones resulting from treatment of their disease. The dentist plays an important role in evaluating the patient's oral health and providing necessary services prior to any curative treatment. The dental diagnosis and treatment protocol practiced at Memorial Hospital are discussed for each therapeutic modality along with the measures taken for follow up care.     

一种用于肿瘤药物治疗的新型人源性穿膜肽的优化及其应用

细胞穿膜肽(cell-penetrating peptide,CPP)作为一种体内大分子药物跨膜运输载体被广泛研究和应用。中期因子Midkine(MK)是人体的一种带有肝素结合域(heparin-binding domain,HBD)的生长因子。报道了MK中HBD的部分富含碱性氨基酸的基因序列(命名为MK-S0)与绿色荧光蛋白(EGFP)基因融合表达后,能将EGFP有效地转运入胞内,且其穿膜转运效率高于经典穿膜肽Tat。将MK-S0序列进一步突变优化改造得到的midkine-mutantΔ4(MK-Δ4),其穿膜效率比天然序列来源的MK-S0提高16倍以上,且MK-Δ4的穿膜转运作用适用于多种肿瘤细胞。穿膜机制分析研究结果显示,MK-Δ4可与细胞表面硫酸乙酰肝素结合,随之以巨胞饮形式内吞入胞。采用MTT方法检测的细胞生长抑制试验结果显示,连接有MK-Δ4的苦瓜来源的核糖体失活蛋白MAP30比单独的MAP30对HeLa肿瘤细胞的药效可提升5.8倍,大大提高了这种药物蛋白抑杀肿瘤细胞的效果。由此表明,源于MK的这种经过突变改造的MK-Δ4,可作为一种新型高效的细胞穿膜肽,将药物蛋白有效运输到细胞内发挥抗肿瘤效应。     

功能与分子影像在头颈部肿瘤放射治疗计划和疗效评价中的应用

目前临床普遍采用功能与分子影像检测手段能来评价头颈部肿瘤的放射治疗计划和疗效,可指导个体化治疗从而提高疗效。文章概述了功能与分子影像技术CT,MRI,PET-CT,超声检测技术在头颈部肿瘤放射治疗计划制定和疗效评价中的应用进展。结果显示,不同分子影像检测方法如在检查时机的选择、诊断和鉴别诊断的价值、观察放射治疗后肿瘤的残存和复发、预测放射治疗效果、指导后续治疗等方面均可起到重要作用。采用图像融合技术进行联合应用,如PET-CT和MRI-CT等,可提高检测的准确率。临床医生需在常规影像学手段的基础上,根据头颈部肿瘤患者病情和治疗方法的不同选用正确的功能和分子影像检测手段,更好地指导制定放射治疗计划及综合评价放射治疗后的疗效。