Enhancement of radiosensitivity in human glioblastoma cells by the DNA N-mustard alkylating agent BO-1051 through augmented and sustained DNA damage response

<p>Abstract</p> <p>Background</p> <p>1-{4-[Bis(2-chloroethyl)amino]phenyl}-3-[2-methyl-5-(4-methylacridin-9-ylamino)phenyl]urea (BO-1051) is an N-mustard DNA alkylating agent reported to exhibit antitumor activity. Here we further investigate the effects of this compound on radiation responses of human gliomas, which are notorious for the high resistance to radiotherapy.</p> <p>Methods</p> <p>The clonogenic assay was used to determine the IC₅₀and radiosensitivity of human glioma cell lines (U87MG, U251MG and GBM-3) following BO-1051. DNA histogram and propidium iodide-Annexin V staining were used to determine the cell cycle distribution and the apoptosis, respectively. DNA damage and repair state were determined by γ-H2AX foci, and mitotic catastrophe was measure using nuclear fragmentation. Xenograft tumors were measured with a caliper, and the survival rate was determined using Kaplan-Meier method.</p> <p>Results</p> <p>BO-1051 inhibited growth of human gliomas in a dose- and time-dependent manner. Using the dosage at IC₅₀, BO-1051 significantly enhanced radiosensitivity to different extents [The sensitizer enhancement ratio was between 1.24 and 1.50 at 10% of survival fraction]. The radiosensitive G₂/M population was raised by BO-1051, whereas apoptosis and mitotic catastrophe were not affected. γ-H2AX foci was greatly increased and sustained by combined BO-1051 and γ-rays, suggested that DNA damage or repair capacity was impaired during treatment. <it>In vivo </it>studies further demonstrated that BO-1051 enhanced the radiotherapeutic effects on GBM-3-beared xenograft tumors, by which the sensitizer enhancement ratio was 1.97. The survival rate of treated mice was also increased accordingly.</p> <p>Conclusions</p> <p>These results indicate that BO-1051 can effectively enhance glioma cell radiosensitivity <it>in vitro </it>and <it>in vivo</it>. It suggests that BO-1051 is a potent radiosensitizer for treating human glioma cells.</p

Effect of Granulocyte-Macrophage Colony-Stimulating Factor on Oral Mucositis in Head and Neck Cancer Patients After Cisplatin, Fluorouracil, and Leucovorin Chemotherapy

These beneficial effects continued into the second cycle of PFL chemotherapy after crossover to no GM-CSF. The incidence of severe mucositis was reduced when GM-CSF was given in the second cycle of PFL. Analysis of variance indicated significant direct GM-CSF treatment effects on the mean AUC of gross/functional scores and duration of moderate gross mucositis (grade -2) over both periods. There was a significant period effect in favor of giving GM-CSF in the first cycle of chemotherapy. Conclusion: GM-CSF can significantly reduce the severity and duration of chemotherapy-induced oral mucositis after PFL chemotherapy

Safety and efficacy of fluoxetine on functional outcome after acute stroke (AFFINITY): a randomised, double-blind, placebo-controlled trial

Background Trials of fluoxetine for recovery after stroke report conflicting results. The Assessment oF FluoxetINe In sTroke recoverY (AFFINITY) trial aimed to show if daily oral fluoxetine for 6 months after stroke improves functional outcome in an ethnically diverse population. Methods AFFINITY was a randomised, parallel-group, double-blind, placebo-controlled trial done in 43 hospital stroke units in Australia (n=29), New Zealand (four), and Vietnam (ten). Eligible patients were adults (aged ≥18 years) with a clinical diagnosis of acute stroke in the previous 2–15 days, brain imaging consistent with ischaemic or haemorrhagic stroke, and a persisting neurological deficit that produced a modified Rankin Scale (mRS) score of 1 or more. Patients were randomly assigned 1:1 via a web-based system using a minimisation algorithm to once daily, oral fluoxetine 20 mg capsules or matching placebo for 6 months. Patients, carers, investigators, and outcome assessors were masked to the treatment allocation. The primary outcome was functional status, measured by the mRS, at 6 months. The primary analysis was an ordinal logistic regression of the mRS at 6 months, adjusted for minimisation variables. Primary and safety analyses were done according to the patient's treatment allocation. The trial is registered with the Australian New Zealand Clinical Trials Registry, ACTRN12611000774921. Findings Between Jan 11, 2013, and June 30, 2019, 1280 patients were recruited in Australia (n=532), New Zealand (n=42), and Vietnam (n=706), of whom 642 were randomly assigned to fluoxetine and 638 were randomly assigned to placebo. Mean duration of trial treatment was 167 days (SD 48·1). At 6 months, mRS data were available in 624 (97%) patients in the fluoxetine group and 632 (99%) in the placebo group. The distribution of mRS categories was similar in the fluoxetine and placebo groups (adjusted common odds ratio 0·94, 95% CI 0·76–1·15; p=0·53). Compared with patients in the placebo group, patients in the fluoxetine group had more falls (20 [3%] vs seven [1%]; p=0·018), bone fractures (19 [3%] vs six [1%]; p=0·014), and epileptic seizures (ten [2%] vs two [<1%]; p=0·038) at 6 months. Interpretation Oral fluoxetine 20 mg daily for 6 months after acute stroke did not improve functional outcome and increased the risk of falls, bone fractures, and epileptic seizures. These results do not support the use of fluoxetine to improve functional outcome after stroke

Strategic Study of Development of Boron Neutron Capture Therapy on Cancer Radiotherapy in Taiwan

　　自民國七零年代起，癌症即成為國人主要之致死原因，近年來，每年因癌病死亡之國人數已突破四萬人，國內外醫學界亦均以突破癌病治療為臨床及基礎研究之主要目標。放射治療的臨床運用甚早，至今已超過百年，在目前及預估未來癌病治療一重要角色，極具效益。其主要特色主要建立在原子科學的成熟發展，透過有效之放射線粒子作用，得以有效摧毀並破壞腫瘤細胞，因此很多結合放射線與腫瘤治療的概念應運而生，從早期普遍利用鈷六十所產生的加馬射線(gamma ray)，直到現今普遍利用直線加速器所產生之X-rays以及電子射束等，均提供臨床腫瘤治療一種穩定有效之腫瘤治療方式。然誠如很多腫瘤臨床醫療工作者的觀察，放射線治療並不全然是腫瘤治療的萬靈丹藥，仍有其限制，及待突破之處。主要因素除包含放射線本身物理條件之限制外，其主要亦包括腫瘤細胞本身對於放射射源之反應敏感程度，相較於放射敏感之腫瘤(如淋巴瘤lymphoma、生殖細胞瘤germinoma等)，很多具放射抗性之腫瘤(如黑色素細胞瘤melanoma，惡性腦瘤malignant glioma，惡性肉瘤sarcoma等)，對於傳統放射線射源(加馬線或X射線)腫瘤不會明顯消退，侷限了放射線治療的臨床效果。因此具有強大放射生物效應且較低正常組織傷害性的放射線射源，尤其是能專門針對腫瘤的 ”標靶放射治療 ”，成為現今放射腫瘤醫學熱門發展之目標。 　　舉凡現今國際知名之重粒子治療(heavy particle radiotherapy)及硼中子捕獲治療(boron neutron capture therapy; BNCT)等，均是建立在此治療概念及實務應用。透過結合較佳之輻射生物反應，以及精準之放射物理技術，可使此放射技術療法對特定的癌症提供較傳統放療有更佳之治療成效。亦可結合現有各類先進之癌症治療方法提供多元治療之選擇與結合，而有最佳之效益及突破。 本研究建立於目前癌症先進設備技術及逐漸進步的放射治療成果經驗，結合多年來國內唯一，世界上少數的硼中子捕獲治療的研究團隊，所共同完成此令人期待矚目的標靶放射治療臨床試驗研究。以此再進一步探討如何讓此極具發展潛力及效益的標靶放射治療，如何在未來更廣泛的使用。實務發展可設置於醫院的加速器型設備，其應用發展及可與各類治療結合應用推廣的發展策略，在未來是具創新突破性且可落實。本研究於國內立於先基，希此研究及初步成果能更激勵同儕於標靶放射治療研究努力，期對癌症治療有進一步之突破。Since 1980s, cancer has become the principal cause of death in Taiwan. The mortality number is higher than 40,000 each year. Both clinical and basic cancer researchers worldwide are eager to overcome this intractable disease. Radiotherapy plays a very important role in cancer treatment for more than one hundred years. The most important characteristic of radiotherapy is that it destroys cancer cells via DNA damage. Therefore, a lot of new radiotherapy techniques, such as gamma-ray (generated by cobalt 60) and X-rays (generated by linear accelerator) had been developed, They all make stable and reliable contributions for cancer treatment. However, not every types of caner can be overcome entirely by conventional radiotherapy due to dismal response contributed by radioresistance. For some radiosensitive tumors, including lymphoma or germinoma, tumor bulk will disappear soon after radiotherapy. But for some tumors with poor radiosensitivity, such as melanoma in skin or glioblastoma in brain (malignant brain tumor), conventional radiotherapy only has little impact and cannot work efficiently. Therefore, if we can develop some new “targeted radiotherapy” which can provide higher radiation effectiveness with relatively less normal tissue toxicity, it’ll become the most popular goal for the modern radiotherapy development. Up to now, the most well-established heavy particle radiotherapies globally, such as Boron Neutron Capture Therapy (BNCT) and so on, are all based on the modern concepts and practical use. It can combine the excellent radiobiological effectiveness and precise radiation physical technique which can also make better clinical results in current cancer treatment. Therefore, we strongly believe that it will provide a new option and breakthrough for future cancer treatment with higher benefits. This research project is based on the clinical results of cancer treatment at Taipei Veterans General Hospital and National Tsing-Hua University using BNCT. Our group is one of the few teams in the world who are capable to conduct this state-of-the-art cancer treatment. We will take advantage of our encouraging results as well as experiences to further develop this promising therapy. In the foreseeable future, hospital-based BNCT will be available for widespread utilization of this treatment. Our efforts had laid the groundwork for future development of BNCT in Taiwan. We are hoping these initial results could give our fellow researchers confidence in continuing development of “Targeted Radiotherapy”, thereby bringing breakthrough to cancer treatment

Lung Cancer Associated with Rheumatoid Arthritis Does Not Shorten Life Expectancy

The incidence of lung cancer (LC) is reported to be higher in patients with rheumatoid arthritis (RA). The present study investigated whether or not RA altered the clinical manifestation of LC. Methods: In this retrospective, cohort study, a total of 23 patients with both RA and LC (RA + LC group), and 6,570 patients with primary LC alone (LCA group), were identified from records at Taipei Veterans General Hospital between 1993 and 2002. Data about clinical characteristics, smoking habit, tumor location, LC histology, staging, and survival, were compared between the 2 groups. Results: There was no significant difference in mean age at LC diagnosis between the RA + LC and LCA groups (70.2 vs 67.6 years; p = 0.154). Adenocarcinoma was the major histologic type in both groups, especially among women. There was no significant difference in histology, location, or staging of LC between the RA + LC and LCA groups. In the RA + LC group, all patients had RA before LC was diagnosed; pulmonary fibrosis was noted in 3 patients, 1 of whom had secondary Sjogren's syndrome. Median survival in the LCA group was not significantly different from that in the RA + LC group (10 [95% confidence interval, CI, 9.6, 10.4] vs 11 [95% CI, 3.7, 18.3] months; p = 0.69); the relative risk of LCA compared with RA + LC for survival was 0.938 (95% CI, 0.555, 1.585). The incidence of LC in RA patients in our hospital was 1.32% (23 of 1,740 patients). Conclusion: RA has no influence on LC stage and does not shorten the survival of LC patients

The Lifetime Cost of Hepatocellular Carcinoma: A Claims Data Analysis from a Medical Centre in Taiwan

Background: Hepatocellular carcinoma (HCC) is the second most common cancer in Taiwan. For males in Taiwan, it is the most dangerous cancer, with both the highest incidence and mortality rate. Objective: To determine cancer-related medical care costs for long-term survivors of HCC. Methods: The estimation of the lifetime cost was based on the insurer perspective and adopted an incidence-based approach. Data was sourced from the 1999-2002 cancer registry statistics of patients with HCC and the claims data of Taipei Veterans General Hospital (TVGH). In total there were 2873 HCC patients at TVGH. In addition to this data, the research used population National Health Insurance claims data from the National Health Research Institutes (1996-2002) as the comparison group. The probabilities of survival, dying of cancer or dying of other causes were estimated using cancer registry statistics. To estimate lifetime (10-year) cost, we divided the disease process into three phases: initial, continuing and terminal. The cost of HCC was calculated as the sum of the average cost of each phase. The expected lifetime cost for treatment of an HCC patient was estimated by incorporating the phase-specific costs with the survival and mortality rates. Results: The results showed that 895 patients survived =1 year, the terminal phase of treatment resulted in the highest costs, $NT237_032. On average, for each patient, the initial phase cost was$NT140_403 and the monthly cost for the continuing phase was $NT8687. For the average HCC patient, the 10-year lifetime cost was$NT418_554 (in nominal $NT). Conclusion: Our study showed that the terminal phase cost the most out of the three treatment phases. The aggregate lifetime cost of HCC is useful for health policy making and clinical decision making. DOI: 10.2165/0148365-200806010-00005Cost-of-illness, Liver-cancer

Preliminary dosimetric study on feasibility of multi-beam boron neutron capture therapy in patients with diffuse intrinsic pontine glioma without craniotomy.

Diffuse intrinsic pontine glioma is a very frustrating disease. Since the tumor infiltrates the brain stem, surgical removal is often impossible. For conventional radiotherapy, the dose constraint of the brain stem impedes attempts at further dose escalation. Boron neutron capture therapy (BNCT), a targeted radiotherapy, carries the potential to selectively irradiate tumors with an adequate dose while sparing adjacent normal tissue. In this study, 12 consecutive patients treated with conventional radiotherapy in our institute were reviewed to evaluate the feasibility of BNCT. NCTPlan Ver. 1.1.44 was used for dose calculations. Compared with two and three fields, the average maximal dose to the normal brain may be lowered to 7.35 ± 0.72 Gy-Eq by four-field irradiation. The mean ratio of minimal dose to clinical target volume and maximal dose to normal tissue was 2.41 ± 0.26 by four-field irradiation. A therapeutic benefit may be expected with multi-field boron neutron capture therapy to treat diffuse intrinsic pontine glioma without craniotomy, while the maximal dose to the normal brain would be minimized by using the four-field setting

Use of a Rich Internet Application Solution to Present Medical Images

[[abstract]]Browser with Rich Internet Application (RIA) Web pages could be a powerful user interface for handling sophisticated data and applications. Then the RIA solutions would be a potential method for viewing and manipulating the most data generated in clinical processes, which can accomplish the main functionalities as general picture archiving and communication system (PACS) viewing systems. The aim of this study is to apply the RIA technology to present medical images. Both Digital Imaging and Communications in Medicine (DICOM) and non-DICOM data can be handled by our RIA solutions. Some clinical data that are especially difficult to present using PACS viewing systems, such as ECG waveform, pathology virtual slide microscopic image, and radiotherapy plan, are as well demonstrated. Consequently, clinicians can use browser as a unique interface for acquiring all the clinical data located in different departments and information systems. And the data could be presented appropriately and processed freely by adopting the RIA technologies

Can mixed pure hepatocellular carcinoma and germinoma arise together in the brain?

Intracranial germ-cell tumors (GCTs) represent 10–15% of all pediatric brain tumors in East Asia. There is a wide histopathological spectrum of intracranial GCTs. Germinomas and nongerminomatous GCTs are the two major classifications. It is difficult to distinguish different subtypes of intracranial GCTs based solely on imaging studies, however, some tumor markers, such as α-fetoprotein or β-human chorionic gonadotropin, are helpful for diagnosis. In this study we present the case of a 13-year-old girl with an intracranial mixed GCT containing a hepatocellular carcinoma and germinoma without a primary liver tumor. Based on this unique pathological diagnosis, a series of treatments were applied, including surgery for gross tumor removal, adjuvant radiotherapy, and chemotherapy. Long-term follow up indicates fair disease control