Preliminary Clinical Experience with Intraoperative Radiotherapy

Intraoperative radiotherapy is the term applied to the irradiation of unresectable tumors, partially resectable tumors, and regional lymph nodes with external beam radiation at the time of surgical exposure. Since only one treatment is given at the time of surgery, one should consider the intraoperative technique as “boost” therapy which may allow us to raise the conventional external beam dose to the tumor by 50 to 100 percent. At Howard University Hospital and Cancer Research Center, seven advanced-stage cancer patients have been treated since 1976 with single doses of electron beam irradiation in the range of 1,300 to 2,000 rad. The preliminary evaluation of these patients has shown no serious acute radiation reactions.     

Skin Metastasis of Hypopharyngeal Carcinoma to the Nasal Tip

Head and neck squamous cell carcinoma (SCC) rarely metastasizes to the skin. Metastases to the nasal tip from hypopharyngeal malignancies are extremely rare. We present a patient with nasal tip metastasis from hypopharyngeal SCC. A 74-year-old man with hypopharyngeal and esophageal carcinomas had a red nodule on his nasal tip (so-called “clown nose”). Histopathologically, atypical squamoid cell nests had proliferated in a lobular fashion from the dermis to subcutaneous tissue. Those atypical cells were identical to primary tumor cells in the hypopharynx. Based on these findings, a diagnosis of skin metastasis from hypopharyngeal SCC was made. In patients with malignant disease, biopsy should be performed for any suspicious skin lesion. In a patient like ours, “clown nose” might be a symptom of cutaneous metastasis. When clinicians note a “clown nose”, they should consider malignancies in the neck and chest areas.     

Thyroid tumors and thyroid function in women exposed to internal and external radiation

The frequency of tumors and other conditions of the thyroid gland were examined in 686 female radium dial workers first employed before 1930, who had a radium body-burden measurement while living (1958-76). If one assumed that the two thyroid cancers ascertained were radiation-induced and that a linear dose-response relationship existed, the estimated thyroid cancer risk was 69 (4-124, 95% confidence range) per 10(6) person-rem thyroid dose equivalent from internal and external radiation. Using data from the Connecticut tumor registry to obtain expected numbers of thyroid cancer, the estimated risk (2 observed vs. 0.67 expected cases) was 46 (95% confidence interval = -19 to 101) excess cases per 10(6) person-rem. Risk estimates were based on crude estimates of external radiation exposure and uncertain quality factors for internal radiation from alpha particles ingested. The frequencies of benign tumor (adenoma), nodules, and goiters were not significantly higher in the higher thyroid-dose groups (5-19, greater than or equal to 20 or greater than or equal to 50 rem) than in the lowest dose group (less than 5 rem). In 1237 female dial workers first employed before 1930, with or without a radium body-burden measurement, no deaths due to thyroid cancer (underlying cause of death on death certificates) were observed during 1950-76, when 0.4 deaths were expected. In a subgroup of 84 Illinois female dial workers who were long-term survivors, means for thyroid function test (T3 resin uptake and free thyroxine index) results did not differ among the thyroid-dose groups.     

Self-consistent tumor control probability and normal tissue complication probability models based on generalized EUD

Traditional methods to compute the tumor control probability (TCP) or normal tissue complication probability (NTCP) typically require a heterogeneous radiation dose distribution to be converted into a simple uniform dose distribution with an equivalent biological effect. Several power-law type dose-volume-histogram reduction schemes, particularly Niemierko's generalized equivalent uniform dose model [Med. Phys. 26, 1000 (1999)], have been proposed to achieve this goal. In this study, we carefully examine the mathematical outcome of these schemes. We demonstrate that (1) for tumors, with each tumor cell independently responding to local radiation dose, a closed-form analytical solution for tumor survival fraction and TCP can be obtained; (2) for serial structured normal tissues, an exponential power-law form relating survival to functional sub-unit (FSU) radiation is required, and a closed-form analytical solution for the related NTCP is provided; (3) in the case of a parallel structured normal tissue, when NTCP is determined solely by the number of the surviving FSUs, a mathematical solution is available only when there is a non-zero threshold dose and/or a finite critical dose defining the radiotherapy response. Some discussion is offered for the partial irradiation effect on normal tissues in this category; (4) for normal tissues with alternative architectures, where the radiation response of FSU is inhomogeneous, there is no exact global mathematical solution for SF or NTCP within the available schemes. Finally, numerical fits of our models to some experimental data are also presented.     

Treatment of multiple brain metastases with a divide-and-conquer spatial fractionation radiosurgery approach

Brain metastases are a common problem, managed with surgery, stereotactic radiosurgery (SRS), whole brain irradiation (WBI), or a combination. SRS targets individual tumors with large dosages of radiation. There is a trend toward using more SRS and less WBI, due to a reduction in cognitive damage, shorter treatment course, and improved tumor control. In conventional radiation a total dose of radiation is frequently divided over time into several smaller “fractions”, which helps spare normal tissues such as the brain. Two doses of 10 Gy each given on separate days will result in 45% less damage to normal brain tissue than a single dose of 20 Gy, according to the linear quadratic model for biologically effective dose (BED). Unfortunately, standard fractionation also reduces the effective dose to the tumor. It would therefore be highly beneficial to be able to fractionate the dose to the normal brain, but not fractionate the tumor dose. When a tumor is irradiated, there are dozens of beams that pass through the skull and converge on the tumor, also irradiating healthy brain tissue in the beam paths. If multiple tumors are irradiated, there are areas of brain that are overlapped by beams that are targeting separate tumors. If these tumors were treated on separate days, then on any given day portions of normal brain may only see the radiation beams for one tumor instead of 2 or more. That is how spatial fractionation of multiple metastases works. By treating groups of tumors on separate days the beams are spread out over time, reducing areas of beam overlap, and effectively fractionating the dose to healthy brain. Yet, each tumor still receives a single treatment. The hypothesis is that an array of metastases may be divided into 2–5 different groups that are treated on different days such that the BED to normal brain tissue is minimized. This should benefit patients by reducing side effects, allowing greater numbers of tumors to be treated, and making retreatment safer. An algorithm is discussed, which places the largest tumors and tumors situated close together into different groups. Modifications for axial beam delivery systems such as helical tomotherapy are discussed.     

Multiplication of Mycobacterium tuberculosis Within Normal and "Immune" Mouse Macrophages Cultivated With and Without Streptomycin

Acquired cellular immunity to infection with Mycobacterium tuberculosis is believed to reside in the capacity of mononuclear phagocytes of immunized animals to inhibit intracellular multiplication of the parasite. However, in macrophage tissue culture systems, it has been customary to employ streptomycin in the medium for the purpose of restricting extracellular, but not intracellular, growth of M. tuberculosis. In contrast, our data show that small amounts of streptomycin markedly inhibit intracellular as well as extracellular growth of M. tuberculosis in normal mouse peritoneal macrophages, and that the degree of this inhibition is directly proportional to the concentration of streptomycin used. In the absence of streptomycin, virulent tubercle bacilli grew as rapidly in “immune” macrophages as in normal macrophages. “Immune” macrophages, however, were slightly more resistant to destruction by the intracellularly multiplying mycobacteria. In the presence of streptomycin, however, intracellular mycobacterial growth was inhibited more in “immune” macrophages than in normal macrophages, and this effect also was directly proportional to the concentration of streptomycin used. Virulent mycobacteria grew somewhat more slowly within mouse peritoneal macrophages obtained after induction of a peritoneal exudate with glycogen than in noninduced cells. The rate of multiplication, though, was the same within normal and “immune” induced peritoneal cells except in the presence of streptomycin. As with noninduced macrophages, this drug inhibited the intracellular multiplication of virulent tubercle bacilli more effectively within “immune” induced than within normal induced cells. It would appear, therefore, that the greater inhibition of intracellular multiplication of virulent tubercle bacilli in “immune” macrophages in tissue culture noted by a number of investigators in the past may have been an artifact created by the use of streptomycin in the tissue culture medium.     

Radiation‐induced genomic instability in breast carcinomas of the Swedish hemangioma cohort

Radiation‐induced genomic instability (GI) is hypothesized to persist after exposure and ultimately promote carcinogenesis. Based on the absorbed dose to the breast, an increased risk of developing breast cancer was shown in the Swedish hemangioma cohort that was treated with radium‐226 for skin hemangioma as infants. Here, we screened 31 primary breast carcinomas for genetic alterations using the OncoScan CNV Plus Assay to assess GI and chromothripsis‐like patterns associated with the absorbed dose to the breast. Higher absorbed doses were associated with increased numbers of copy number alterations in the tumor genome and thus a more unstable genome. Hence, the observed dose‐dependent GI in the tumor genome is a measurable manifestation of the long‐term effects of irradiation. We developed a highly predictive Cox regression model for overall survival based on the interaction between absorbed dose and GI. The Swedish hemangioma cohort is a valuable cohort to investigate the biological relationship between absorbed dose and GI in irradiated humans. This work gives a biological basis for improved risk assessment to minimize carcinogenesis as a secondary disease after radiation therapy.     

Dental enamel as an in vivo radiation dosimeter

The determination of the radiation exposure history of the population has become increasingly important in the study of the effects of low-level radiation. The present work was started to try to obtain an in vivo dosimeter that could give an indication of radiation exposure. Dental enamel is the only living tissue which retains indefinitely its radiation history, and electron spin resonance measurements have shown that the radiation signal can be resolved down to about 10 cGy. Measurements on samples from the general population give radiation exposure estimates that are reasonable, and one measurement on a patient who had radiotherapy to the mouth area showed a good correlation with tumor dose. We believe that this is an important new indicator of radiation dose and taken together with exposure histories should provide important data for epidemiological studies as well as accidental exposures.     

胸上段食管癌调强放疗和三维适形放疗剂量学研究

目的:比较分析胸上段食管癌调强适形(IMRT)放疗和三维适形(3D-CRT)放疗的剂量学差异。方法:选择10例胸上段食管癌患者,应用三维治疗计划系统(TPS)分别为每例患者设计2种治疗计划(A:调强适形放疗;B:三维适形放疗),在规定PTV至少达到95%处方剂量前提下根据体积直方图(DVH)比较2种计划靶区剂量分布及脊髓、肺、心脏等正常组织受量的差异。结果:2种计划的靶区适形度指数(CI)、均匀性指数(HI)、处方剂量覆盖PTV百分比均以IM-RT计划为好,IMRT同时减少了脊髓最大所受剂量,差异均有统计学意义(P0.05);2种计划的双肺受照剂量V20、心脏平均剂量均在可耐受的范围内,差异无统计学意义(P0.05)。结论:胸上段食管癌采用IMRT优于3DCRT放疗,是目前较好的一种放疗方法。     

Radium traffic: radiation,science and spiritualism in early twentieth-century Japan

The emergence of modern health-related commodities and tourism in the late Meiji and Taishō eras (1900s–1920s) was accompanied by a revival of spiritualist religions, many of which had their origins in folk belief. What helped this was the people’s interpretation of radiation. This article underscores the linkages between radiation, science and spiritualism in Japan at the time of modernisation and imperialism. In the early twentieth century, the general public came to know about radiation because it was deemed to have special efficacy in healing the human body. In Japan, the concept of radiation harmonised with both Western culture and Japanese traditional culture. One can see the fusion of Western and traditional culture both in people’s lives and commercial culture through the popularity and availability of radium hot springs and radioactive commodities. Radium hot springs became fashionable in Japan in the 1910s. As scholars reported that radium provided the real potency of hot springs, local hot springs villages seized on the scientific explanation and connected their developments with national policies and industries. This paper illustrates how the discourse about radium, which came from the field of radiation medicine, connected science and spiritualism in modern Japan.     

基于FDK算法的数字合成X线体层成像

目的:放射治疗是恶性肿瘤病人的主要治疗手段之一。放疗的基本目标是最大限度地将放射线的剂量集中到病变(靶区)内,杀灭肿瘤细胞,而使周围正常组织和器官少受或免受不必要的照射。放疗过程中的一些不确定性因素,可以影响到靶区的几何形态,进而影响肿瘤实际照射剂量的分布,造成肿瘤脱靶和(或)危及器官损伤增加。因此,放射治疗中摆位的准确性和重复性成为影响肿瘤放疗疗效的关键性因素之一,特别是当高剂量梯度存在的时候。提高放疗摆位精度核心就是要及时获取并修正摆位误差。方法:测量摆位误差,需要比较治疗位置图像与模拟定位时的图像。研究成像剂量低,图像质量好的成像模式可以更好的提高放射治疗的摆位精度。数字合成X线体层成像(Digital Tomosynthesis,DTS)是一种基于有限角度的二维投影图像获取三维图像的重建方法。本文提出利用与FDK(Feldkamp-Davis-Kress)相似的算法重建治疗位置DTS图像,并对DTS图像质量的影响因素进行研究。结果:DTS图像比传统千伏射野验证片显示更多的解剖信息,骨结构和软组织清晰度明显提高。结论:DTS可以替代传统射野验证片和CBCT,作为放疗摆位校正的另一种方法。     

Physical aspects of yttrium-90 microsphere therapy for nonresectable hepatic tumors

Administration of yttrium-90 microspheres via the hepatic artery is an attractive approach to selectively deliver therapeutic doses of radiation to liver malignancies. This procedure allows delivering radiation absorbed doses in excess of 100 Gy to the tumors without significant liver toxicity. The microsphere therapy involves different specialties including medical oncology, radiation oncology, nuclear medicine, interventional radiology, medical physics, and radiation safety. We have treated 80 patients with nonresectable hepatic tumors with yttrium-90 microspheres during the past two years on an institutional study protocol. The nominal radiation absorbed dose to the tumor in this study was 150 Gy. Required activity was calculated based on the nominal radiation absorbed dose and patient's liver volume obtained from the CT scan, assuming a uniform distribution of the microspheres within the liver. Microspheres were administered via a catheter placed into the hepatic artery. The actual radiation absorbed doses to tumors and normal liver tissue were calculated retrospectively based on the patient's 99mTc-MAA study and CT scans. As expected, the activity uptake within the liver was found to be highly nonuniform and multifold tumor to nontumor uptake was observed. A partition model was used to calculate the radiation absorbed dose within each region. For a typical patient the calculated radiation absorbed doses to the tumor and liver were 402 and 118 Gy, respectively. The radiation safety procedure involves confinement of the source and proper disposal of the contaminated materials. The average exposure rates at 1 m from the patients and on contact just anterior to the liver were 6 and 135 uSv/h, respectively. The special physics and dosimetry protocol developed for this procedure is presented.     

Is Mechanism and Symptom-Based Analgesia an Answer to Opioid-Induced Hyperalgesia?

“Cancer Pain” and “Pain in cancer patient” are not synonymous. Opioid-induced Hyperalgesia (OIH) is a paradoxical state of nociceptive sensitization caused by exposure to opioids. Neuropathic pain is only partially responsive to opioids; injudicious increase in dose of opioids in neuropathic pain may not only result in inadequate pain relief but also OIH. Majority of literature on OIH is in non-cancer pain with systemic use of opioids. We describe the development and successful treatment of OIH in a 55-year-old male patient with Small cell Carcinoma Lung. Opioid tapering, rotation, systemic desensitization helps in combatting OIH. The use of anti-neuropathic adjuvant analgesics helps not only in preventing and treating OIH but also in understanding putative mechanisms underlying neuropathic pain and OIH.     

Radiation-induced galectin-1 by endothelial cells: a promising molecular target for preferential drug delivery to the tumor vasculature

The present study reports on a new strategy for selective, radiation therapy-amplified drug delivery using an antiangiogenic 33-a.a., tumor vasculature-targeting ligand, anginex, to improve the therapeutic ratio for strategies developed against solid tumors. Our findings indicate that galectin-1 is (a) one of the major receptors for anginex (b) overexpressed by tumor neovasculature and (c) further specifically upregulated in endothelial cells in response to radiation exposure as low as 0.5 Gy. An investigation of [18]-F-labeled anginex biodistribution in SCK tumors indicates that anginex is an effective targeting molecule for image and radiation-guided therapy of solid tumors. An anginex-conjugated liposome capable of being loaded with drug was shown to selectively target endothelial cells post-radiation. The presence of endothelial cells in a three-dimensional co-culture system with tumor cells developed to study tumor/endothelial cell interactions in vitro led to higher levels of galectin-1 and showed a further increase in expression upon radiation exposure when compared to tumor cell spheroids alone. Similar increase in galectin-1 was observed in tumor tissue originating from the tumor‐endothelial cell spheroids in vivo and radiation exposure further induced galectin-1 in these tumors. The overall results suggest feasibility of using a clinical or subclinical radiation dose to increase expression of the galectin-1 receptor on the tumor microvasculature to promote delivery of therapeutics via the anginex peptide. This approach may reduce systemic toxicity, overcome drug resistance, and improve the therapeutic efficacy of conventional chemo/radiation strategies.     

Analytic solution for source distributions in brachytherapy to obtain uniform dose rates in spherical tumor models

Interstitial brachytherapy involves implanting many small radioactive sources into a tumor, with the goal of delivering a uniform radiation dose to the target volume. As a guide for the optimal placement of these sources, we assumed a spherical tumor irradiated by a continuously distributed radiation source. The solution of the ensuing integral equation shows that the source density is very low near the center of the sphere, increases rapidly toward the surface and becomes infinite at the surface. Integration of the source density over a given spherical sub-volume shows that only about 6% of the total activity is contained in the central core up to 50% of the tumor radius, while about one-half of the activity has to be placed in the outer spherical shell having a thickness of one-tenth of the tumor radius. Since attenuation is not taken into account, the results are applicable to highly penetrating radiation of isotopes such as 192Ir and 137Cs and tumor radii of a few cm. This situation is approximated in the high dose rate (HDR) treatment of the prostate using 192Ir. The results are in good agreement with the recommendations given in the traditional Paterson-Parker tables for radium and cesium treatments and a numerical solution to the problem.     

Gene Therapy for Pediatric Cancer: State of the Art and Future Perspectives

While modern treatments have led to a dramatic improvement insurvival for pediatric malignancy, toxicities are high and a significant proportion of patients remain resistant. Gene transfer offers the prospect of highly specific therapies for childhood cancer. “Corrective” genes may be transferred to overcome the genetic abnormalities present in the precancerous cell. Alternatively, genes can be introduced to render themalignant cell sensitive to therapeutic drugs. The tumor can also be attacked by decreasing its blood supply with genes that inhibit vascular growth. Another possible approach is to modify normal tissues with genes that make them more resistant to conventional drugs and/or radiation, thereby increasing thetherapeutic index. Finally, it may be possible to attack the tumor indirectly by using genes that modify the behavior of the immune system, either by making the tumor more immunogenic, or by rendering host effector cells more efficient. Several gene therapy applications have already been reported for pediatric cancer patients in preliminary Phase 1 studies. Although no majorclinical success has yet been achieved, improvements in gene delivery technologies and a better understanding of mechanisms of tumor progression and immune escape have opened new perspectives for the cure of pediatric cancer by combining gene therapy with standard therapeutic available treatments.     

Can juvenile scoliosis be corrected by circumscribed radium-irradiation of the spine?

In 1936 scoliosis was produced in growing animals by exposing one side of one or more vertebrae to radium action. The purpose of this treatment was to recurve existing curvatures of the spine on the same principle. No attempt has been made so far to correct congenital scoliosis of infants by this method. Hundreds of infants treated by X-ray for Wilms' tumor developed incidental spinal curvatures. In none of these cases was there any recorded mention of damage to the spinal cord or any other organ. Since the epiphyseal plate is much more sensitive to radiation than is the Wilms' tumor and radium radiation can be more easily controlled than X-radiation, it is suggested that scoliosis of genetic or other etiology might be successfully treated by radium or possibly other gamma rays. The choice of the rays and the dosage must be left to the experts.     

前列腺癌调强计划改变多叶准直器角度对直肠和膀胱剂量的影响

目的:常规放疗的前列腺癌,由于直肠和膀胱的剂量限制,治疗结束后活检阳性率较多。剂量递增实验证明,高剂量照射能提高前列腺癌的局部控制率和生存率。本文以前列腺癌为例,在保证肿瘤区域剂量的前提下,探讨调强计划中改变多叶准直器角度对减少直肠和膀胱剂量的影响。材料方法:选取10例已放疗患者的CT作为研究对象,用调强技术比较改变多叶准直器角度对直肠和膀胱的剂量影响。结果:直肠的D25、D50、V60和膀胱的D30、D50、V60在改变多叶准直器角度后都有明显减少。结论:在前列腺癌靶区复杂,且计划因肿瘤剂量和正常组织剂量不能同时满足时,应用此方法可以一定程度上减少正常组织的受照剂量。