Effects of shielding on pelvic and abdominal IORT dose distributions

PurposeTo study the impact of shielding elements in the proximity of Intra-Operative Radiation Therapy (IORT) irradiation fields, and to generate graphical and quantitative information to assist radiation oncologists in the design of optimal shielding during pelvic and abdominal IORT.MethodAn IORT system was modeled with BEAMnrc and EGS++ Monte Carlo codes. The model was validated in reference conditions by gamma index analysis against an experimental data set of different beam energies, applicator diameters, and bevel angles. The reliability of the IORT model was further tested considering shielding layers inserted in the radiation beam. Further simulations were performed introducing a bone-like layer embedded in the water phantom. The dose distributions were calculated as 3D dose maps.ResultsThe analysis of the resulting 2D dose maps parallel to the clinical axis shows that the bevel angle of the applicator and its position relative to the shielding have a major influence on the dose distribution. When insufficient shielding is used, a hotspot nearby the shield appears near the surface. At greater depths, lateral scatter limits the dose reduction attainable with shielding, although the presence of bone-like structures in the phantom reduces the impact of this effect.ConclusionsDose distributions in shielded IORT procedures are affected by distinct contributions when considering the regions near the shielding and deeper in tissue: insufficient shielding may lead to residual dose and hotspots, and the scattering effects may enlarge the beam in depth. These effects must be carefully considered when planning an IORT treatment with shielding.     

Cancer stem cells in glioblastoma — molecular signaling and therapeutic targeting

Glioblastomas (GBMs) are highly lethal primary brain tumors. Despite current therapeutic advances in other solid cancers, the treatment of these malignant gliomas remains essentially palliative. GBMs are extremely resistant to conventional radiation and chemotherapies. We and others have demonstrated that a highly tumorigenic subpopulation of cancer cells called GBM stem cells (GSCs) promotes therapeutic resistance. We also found that GSCs stimulate tumor angiogenesis by expressing elevated levels of VEGF and contribute to tumor growth, which has been translated into a useful therapeutic strategy in the treatment of recurrent or progressive GBMs. Furthermore, stem cell-like cancer cells (cancer stem cells) have been shown to promote metastasis. Although GBMs rarely metastasize beyond the central nervous system, these highly infiltrative cancers often invade into normal brain tissues preventing surgical resection, and GSCs display an aggressive invasive phenotype. These studies suggest that targeting GSCs may effectively reduce tumor recurrence and significantly improve GBM treatment. Recent studies indicate that cancer stem cells share core signaling pathways with normal somatic or embryonic stem cells, but also display critical distinctions that provide important clues into useful therapeutic targets. In this review, we summarize the current understanding and advances in glioma stem cell research, and discuss potential targeting strategies for future development of anti-GSC therapies.     

宫颈癌的治疗进展

宫颈癌是全世界妇女中第二常见的恶性肿瘤,在非洲、亚洲以及南美洲,是妇女最常见的恶性肿瘤。其发病率和死亡率仅次于乳腺癌。宫颈癌的传统治疗是根治性手术（包括广泛全子宫切除＋盆腔淋巴结清扫术）和放疗,化疗主要用于晚期或复发转移的患者。近些年,随着科学技术的发展,其手术方式及放化疗方式都有了新的进展,同时,还出现了靶向治疗、基因治疗及疫苗预防等综合防治体系。     

The efficiency of the radiobiological and clinical of the intraoperative radiation therapy in combination with distant gamma-radiation therapy of malignant tumors

The efficiency of the radiobiological and the clinical planning of the combination of the intraoperative radiation therapy (IORT) and the external beam radiation therapy (EBRT) was assessed according to the incidence of local recurrences and to the level of radiation-induced damages during 5 years for patients with malignant tumors of head and neck, lung and soft tissues. Criteria of radiobiological planning for performing IORT + EBRT using the modified model of TDF (time-dose-fractionation) for calculating a single IORT dose and total radiation doses was defined among 169 patients of the studied group. The control group included 115 patients who were treated with surgery followed by photon radiation therapy at the total dose of 40-45 Gy. The Clinical critetia for performing the combined treatment with IORT and EBRT were such like: locally-advanced tumors, multicentrical location of tumor sites and the necessity of the increasing of the total doses of the combination of IORT and EBRT. The Average rates of total doses of IORT and EBRT were 67 +/- 2.1 Gy for patients with cancer of nasal cavity and of accessory nasal sinus, 50 +/- 1.8 Gy for patients with oral cavity cancer, 60 +/- 0.7 Gy for patients with lung cancer and 75 +/- 2.0 Gy for patients with sarcomas of soft tissues. Radiation-induced damages for normal tissues such as mandible osteomyelitis, neuritis and pathological bone fracture occurred among 16.8% of patients from the studied group if the TDF factor was exceeded over 100 conventional units. The combined treatment with IORT and EBRT resulted the significant reduction of recurrence rate among 5-year as compared with the combined treatment fot the control group: 37.5 +/- 5.3% and 65 +/- 5.1% of patients with cancer of nasal cavity and accessory nasal sinus; 55.8 +/- 6.3% and 80 +/- 5.9% of patients with oral cavity cancer; 57.8 +/- 6.7% and 75 +/- 5.8% of patients with non-small cell lung cancer and 32.7 +/- 6.1% and 72 +/- 6.7% of patients with sarcomas of soft tissues, respectively. The use of criteria for radiobiological and clinical planning of the combined treatment with IORT and EBRT promotes the improvement of long-term treatment results.     

Monte Carlo evaluation of the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy in pelvic area

The aim of this study was to evaluate the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy (IORT) in pelvic area. A GATE Monte Carlo model of the INTRABEAM® was adapted for the study. Simulations were performed in the CT scan of a cadaver considering a homogeneous segmentation (water) and an inhomogeneous segmentation (5 tissues from ICRU44). Measurements were performed in the cadaver using EBT3 Gafchromic® films. Impact of inhomogeneities on dose calculation in cadaver was 6% for soft tissues and greater than 300% for bone tissues. EBT3 measurements showed a better agreement with calculation for inhomogeneous media. However, dose discrepancy in soft tissues led to a sub-millimeter (0.65 mm) shift in the effective point dose in depth. Except for bone tissues, the effect of inhomogeneities on dose calculation for low energy photons intra-operative radiation therapy in pelvic area was not significant for the studied anatomy.     

A Mouse Tumor Model of Surgical Stress to Explore the Mechanisms of Postoperative Immunosuppression and Evaluate Novel Perioperative Immunotherapies

Surgical resection is an essential treatment for most cancer patients, but surgery induces dysfunction in the immune system and this has been linked to the development of metastatic disease in animal models and in cancer patients. Preclinical work from our group and others has demonstrated a profound suppression of innate immune function, specifically NK cells in the postoperative period and this plays a major role in the enhanced development of metastases following surgery. Relatively few animal studies and clinical trials have focused on characterizing and reversing the detrimental effects of cancer surgery. Using a rigorous animal model of spontaneously metastasizing tumors and surgical stress, the enhancement of cancer surgery on the development of lung metastases was demonstrated. In this model, 4T1 breast cancer cells are implanted in the mouse mammary fat pad. At day 14 post tumor implantation, a complete resection of the primary mammary tumor is performed in all animals. A subset of animals receives additional surgical stress in the form of an abdominal nephrectomy. At day 28, lung tumor nodules are quantified. When immunotherapy was given immediately preoperatively, a profound activation of immune cells which prevented the development of metastases following surgery was detected. While the 4T1 breast tumor surgery model allows for the simulation of the effects of abdominal surgical stress on tumor metastases, its applicability to other tumor types needs to be tested. The current challenge is to identify safe and promising immunotherapies in preclinical mouse models and to translate them into viable perioperative therapies to be given to cancer surgery patients to prevent the recurrence of metastatic disease.     

肿瘤干细胞的光动力治疗研究进展

肿瘤干细胞(cancerstem cells,CSCs)是在肿瘤组织中具有干细胞特性的细胞亚群,它具有正常干细胞的多向分化潜能,能够无限增值和自主分化为各种具有异质性的肿瘤细胞。CSCs在肿瘤的发生、生长、转移中起着重要作用。同时,CSCs对目前大多数治疗如化疗、放疗不敏感,甚至具有耐药性,这也就导致了恶性肿瘤在治疗后容易复发。鉴于此,针对肿瘤干细胞的治疗日益受到关注,光动力疗法(photodynamictherapy,PDT)由于其微创性,不良反应少,靶向性强等特点在肿瘤的治疗研究中不断得到发展。本文将从CSCs的特性入手,结合PDT治疗的最新进展,探讨PDT治疗在肿瘤干细胞治疗中的应用。     

Intraoperative radiation therapy-induced sarcomas in dogs

In a canine model the tolerance of normal and surgically manipulated tissue to intraoperative radiotherapy (IORT) was investigated to provide guidelines for the clinical use of IORT in human cancer patients. A dose of 20 Gy IORT, with or without external beam radiotherapy, was generally well tolerated without significant increased treatment morbidity. Higher doses of IORT (over 30 Gy) have produced radiation-induced sarcomas in some animals followed over a long period. Therefore IORT should be used only in human cancer patients in well controlled studies, in which complications are well documented, and the possibility of radiation-induced malignancies in long-term survival should be considered.     

Radiation therapy after radical prostatectomy: why patience is a virtue! The case for salvage radiation therapy

Without reliable clinical or pathologic predictors of local recurrence, selection of patients for adjuvant radiotherapy based on any combination of clinical or pathological parameters is bound to lead to the unnecessary treatment of significant numbers of patients whose disease might not have ultimately recurred or who might have been destined to have recurrence with extrapelvic metastatic disease, for which pelvic radiation would be ineffective. Furthermore, new ultrasensitive prostate-specific antigen (PSA) assays can identify patients actually failing surgery with a detectable and rising PSA earlier than ever, when disease volume is low and still amenable to salvage radiation therapy, and can allow the calculation of the PSA doubling time, which is gaining widespread acceptance as a proven predictor of response to salvage radiation therapy in this setting. Therefore, the rationale for preemptive adjuvant radiation therapy after radical prostatectomy is weaker than ever.     

A model of using magnetic resonance imaging in osteoarticular tumor lesion in case of giant cell tumors

Fifty-eight patients with giant cell tumors (GCT) underwent a comprehensive radiation diagnosis involving X-ray study and magnetic resonance imaging (MRI). The obtained MR images indicated the high efficiency of this combination of radiation diagnostic techniques in solving the problems in the visualization of osteoarticular tumor lesions. GCT is characterized by well-known primary X-ray semiotics; MR images are also rather pathognomonic of these tumors and they illustrate the process of morphogenesis of these masses. MRI made it possible to solve the specific problems facing a physician (a radiation diagnostician), to determine the site, shape, sizes, volume, and local extent of a tumor, which permitted the planning of surgical treatment policy; to assess its results, to reveal possible inflammatory complications; and to visualize a local recurrence and on-going growth of a tumor, including the signs of GCT malignancy.     

原发性肝癌临床分期的对比探讨

原发性肝癌严重威胁着人类的健康,全球每年新增的病例数约为50万,其中54％发生在我国,且患者在3年内复发率高于60％,可见诊治形势十分严峻。肝癌的临床分期系统对于患者的预后评估以及选择何种治疗方案有着极其重要的意义。国内外虽有此类研究的相关内容,但将各种分期的评价及适用范围、发展趋势相结合进行分析的较少。本文对国际上多种常用的分期方案（TNM分期、Child-Pu曲分期、Okuda分期、CLIP评分、JIS分期、CUPI指标、CIS记分）进行探讨,论述各种方案间的差异及相互关系,并对未来可能发展方向进行展望。经本文分析多项研究发现：TNM分期更适用于外科病人,Child—Pugh对肝功能受损的患者具有较好的预后价值,而Okuda、CLIP、JIs分期适用于不适合手术治疗的进展期病人,CUPI指数则对慢性乙肝患者有疗效,CIS适用于非手术治疗的患者。随着肿瘤分子生物学技术的进步,肝癌分期有可能上升到分子病理学的水平,肝癌切除的根治程度将划分得更为细致,以反映患者肝癌切除后所处状态的多种可能性,分子指标也将更加客观、敏感,有利于患者早期的诊断与治疗。     

Intraoperative breast radiotherapy: survival,local control and risk factors for recurrence

BackgroundWhole breast irradiation reduces loco-regional recurrence and risk of death in patients submitted to breast-conserving treatment. Data show that radiation to the index quadrant alone may be enough in selected patients.AimTo report the experience with intra-operative radiotherapy (IORT) with Electron-beam Cone in Linear Accelerator (ELIOT) and the results in overall survival, local control and late toxicity of patients submitted to this treatment.Materials and Methods147 patients treated with a median follow up of 6.9 years (0.1?11.5 years). The actuarial local control and overall survival probabilities were estimated using the Kaplan Meier method. All tests were two-sided and p ? 0.05 was considered statistically significant.ResultsOverall survival of the cohort in 5 years, in the median follow up and in 10 years was of 98.3%, 95.1% and 95.1%, respectively, whereas local control in 5 years, in the median follow up and in 10 years was of 96%, 94.9% and 89.5%, respectively. Two risk groups were identified for local recurrence depending on the estrogen or progesterone receptors, axillary or margin status and lymphovascular invasion (LVI) (p = 0.016).ConclusionsIORT is a safe and effective treatment. Rigorous selection is important to achieve excellent local control results.     

肿瘤干细胞与表观遗传学调控

关于恶性肿瘤发生、复发与转移机制的研究由来已久,但目前的临床治疗方法依然不能克服肿瘤复发与转移的难题,肿瘤患者的生存率并未得到显著改善。近年来的研究提示肿瘤的起源、复发与转移的真正原因可能是存在于肿瘤内的极少数具有干细胞特性的细胞,即肿瘤干细胞（cancer stem cells,CSC）。与此同时,越来越多的研究表明,对于肿瘤干细胞的发生与功能维持,表观遗传学的调控机制可能发挥着极其重要的作用。该文简要综述目前肿瘤干细胞和表观遗传学相关领域的研究进展,并对肿瘤干细胞形成及发展过程中表观遗传学的调控作用及机制进行重点介绍。     

Revisiting p53 for cancer-specific chemo- and radiotherapy

Despite intense studies, highly effective therapeutic strategies against cancer have not yet been fully exploited, because few true cancer-specific targets have been identified. Most modalities, perhaps with the exception of radiation therapy, target proliferating cells, which are also abundant in normal tissues. Thus, most current cancer treatments have significant side effects. More than 10 years ago, the tumor suppressor p53 was first explored as a cancer-specific target. At the time, the approach was to introduce a normal p53 gene into mutant p53 (mp53) tumor cells to induce cell cycle arrest and apoptosis. However, this strategy did not hold up and mostly failed in subsequent clinical studies. Recent research developments have now returned p53 to the limelight. Several studies have reported that mutant or null p53 tumor cells undergo apoptosis more easily than genetically matched, normal p53 counterparts when inhibiting a specific stress kinase in combination with standard chemotherapy or when exposed to an ataxia-telangiectasia mutated (ATM) kinase inhibitor and radiation, thus achieving true cancer specificity in animal tumor models. This short review highlights several of these recent studies, discusses possible mechanism(s) for mp53-mediated “synthetic lethality,” and the implications for cancer therapy.     

Primary Kaposi sarcoma of the subcutaneous tissue

Background

Tumor recurrence following radical cystectomy for a low-grade superficial transitional cell carcinoma (TCC) is exceedingly uncommon and has not been reported previously.

Case presentation

We describe a case of a young male presenting with anorexia, weight loss and a large, painful locally destructive pelvic recurrence, ten years after radical cystoprostatectomy. The pathology was consistent with a low-grade urothelial carcinoma. After an unsuccessful treatment with cisplatin-based chemotherapy, the patient underwent a curative intent hemipelvectomy with complete excision of tumor and is disease free at one year follow-up.

Conclusion

A literature review related to this unusual presentation is reported and a surgical solutions over chemotherapy and radiotherapy is proposed.     

Characterizing mutational heterogeneity in a glioblastoma patient with double recurrence

Human cancers are driven by the acquisition of somatic mutations. Separating the driving mutations from those that are random consequences of general genomic instability remains a challenge. New sequencing technology makes it possible to detect mutations that are present in only a minority of cells in a heterogeneous tumor population. We sought to leverage the power of ultra-deep sequencing to study various levels of tumor heterogeneity in the serial recurrences of a single glioblastoma multiforme patient. Our goal was to gain insight into the temporal succession of DNA base-level lesions by querying intra- and inter-tumoral cell populations in the same patient over time. We performed targeted "next-generation" sequencing on seven samples from the same patient: two foci within the primary tumor, two foci within an initial recurrence, two foci within a second recurrence, and normal blood. Our study reveals multiple levels of mutational heterogeneity. We found variable frequencies of specific EGFR, PIK3CA, PTEN, and TP53 base substitutions within individual tumor regions and across distinct regions within the same tumor. In addition, specific mutations emerge and disappear along the temporal spectrum from tumor at the time of diagnosis to second recurrence, demonstrating evolution during tumor progression. Our results shed light on the spatial and temporal complexity of brain tumors. As sequencing costs continue to decline and deep sequencing technology eventually moves into the clinic, this approach may provide guidance for treatment choices as we embark on the path to personalized cancer medicine.     

Bone in the breast? Long term toxicity 21 years after interstitial brachytherapy as a boost

An 81-year-old patient developed an exulcerous tumor in her left breast 21 years after breast cancer treatment with lumpectomy and adjuvant radiotherapy. At the time of the initial treatment 21 years ago, whole breast irradiation was performed with a prescribed dose of 48?Gy and a maximal dose of 69?Gy. In addition, the patient received a 14.7?Gy boost with multicatheter brachytherapy as partial breast irradiation.In general, fat necrosis after radiotherapy, surgery or trauma is a minor problem for patients, but can lead to diagnostic difficulties. The incidence varies: the literature indicates that it occurs in up to 34% of cases. The direct pathogenesis is not clear; it can be due to high radiation dose to the breast, dosimetric inhomogeneities or surgical complications (seromas and inflammation).The tumor in the case described here, occurring more than two decades after the primary treatment, is a rarity in this extent and is an unusual clinical, radiological, and histological finding. It provides a good example of the need for an individualized approach to treatment.     

非小细胞肺癌低分割放疗研究进展

肺癌是全球发病率和死亡率第一的恶性肿瘤,虽然放疗在NSCLC的治疗中具有可观的局部疗效,但临床上仍有部分患者出现治疗失败。放疗失败的主要原因是局部未控、复发或远处转移。与常规分割相比,大分割放疗可在不增加放疗次数的情况下提高总的放疗剂量;对于接受相同BED照射的NSCLC患者,大分割放疗除了能带来局部控制率上的增加外,还可减少治疗次数,节省治疗时间和费用,增加病人的便捷,提高医用加速器的使用效率。L-Q模型的数据在预测大分割放疗疗效时存在许多局限。除经典L-Q模型所模拟的机制外,还可能有其他机制的参与。分子影像是无创性评价放疗疗效的可靠手段,利用不同分子显像剂结合胞内特定靶分子,能够对恶性肿瘤的代谢水平、乏氧状态、增殖能力等情况进行较为准确的评估,为大分割放疗提供良好的疗效评估手段并成为研究其特殊放射生物效应的有力工具。     

Ecological Therapy for Cancer: Defining Tumors Using an Ecosystem Paradigm Suggests New Opportunities for Novel Cancer Treatments

We propose that there is an opportunity to devise new cancer therapies based on the recognition that tumors have properties of ecological systems. Traditionally, localized treatment has targeted the cancer cells directly by removing them (surgery) or killing them (chemotherapy and radiation). These modes of therapy have not always been effective because many tumors recur after these therapies, either because not all of the cells are killed (local recurrence) or because the cancer cells had already escaped the primary tumor environment (distant recurrence). There has been an increasing recognition that the tumor microenvironment contains host noncancer cells in addition to cancer cells, interacting in a dynamic fashion over time. The cancer cells compete and/or cooperate with nontumor cells, and the cancer cells may compete and/or cooperate with each other. It has been demonstrated that these interactions can alter the genotype and phenotype of the host cells as well as the cancer cells. The interaction of these cancer and host cells to remodel the normal host organ microenvironment may best be conceptualized as an evolving ecosystem. In classic terms, an ecosystem describes the physical and biological components of an environment in relation to each other as a unit. Here, we review some properties of tumor microenvironments and ecological systems and indicate similarities between them. We propose that describing tumors as ecological systems defines new opportunities for novel cancer therapies and use the development of prostate cancer metastases as an example. We refer to this as “ecological therapy” for cancer.