Radiation therapy may increase metastatic potential in alveolar rhabdomyosarcoma.

BACKGROUND: We previously determined that radiation could be safely administered using a mouse-flank in vivo model to both alveolar (Rh30) and embryonal (Rh18) rhabdomyosarcoma xenografts. Mice from both tumor lines in this experiment developed metastases, an event not previously described with these models. We sought to determine if radiation-induced changes in gene expression underlie an increase in the metastatic behavior of these tumor models. PROCEDURE: Parental Rh18 and Rh30 xenografts, as well as tumor that recurred locally after radiotherapy (Rh18RT and Rh30RT), were grown subcutaneously in the flanks of SCID mice and then subjected to either fractionated radiotherapy or survival surgery alone. Metastasis formation was monitored and recorded. Gene expression profiling was also performed on RNA extracted from parental, recurrent, and metastatic tissue of both tumor lines. RESULTS: Rh30 and Rh30RT xenografts demonstrated metastases only if they were exposed to fractionated radiotherapy, whereas Rh18 and Rh18RT xenografts experienced significantly fewer metastatic events when treated with fractionated radiotherapy compared to survival surgery alone. Mean time to metastasis formation was 40 days in the recurrent tumors and 73 days in the parental xenografts. Gene expression profiling noted clustering of Rh30 recurrent and metastatic tissue that was independent of the parental Rh30 tissue. Rh18RT xenografts lost radiosensitivity compared to parental Rh18. CONCLUSION: Radiation therapy can significantly decrease the formation of metastases in radio-sensitive tumors (Rh18) and may induce a more pro-metastatic phenotype in radio-resistant lines (Rh30).

Tumor-to-tumor metastasis from pituitary carcinoma to radiation-induced meningioma.

Radiation-induced meningioma and pituitary carcinoma are both uncommon. Tumor-to-tumor metastasis (TTM) from pituitary carcinoma to meningioma, to our knowledge, has not been previously reported. A 67-year old man presented with a previous history of transcranial subtotal resection of pituitary adenoma, at the age of 36, followed by radiotherapy. The follow-up was uneventful for the following 31 years. The patient presented with worsening sight and numbness of the right arm. Three separate lesions were found on MRI. Histological examinations revealed pituitary carcinomas and TTM from pituitary carcinoma to meningioma. A constant surveillance is necessary for patients with pituitary tumor, especially those followed by radiotherapy.

Neonatal UVB exposure accelerates melanoma growth and enhances distant metastases in Hgf-Cdk4(R24C) C57BL/6 mice.

Genetically engineered mouse models offer new opportunities to experimentally investigate the impact of UV on melanoma pathogenesis. Here we irradiated a cohort of newborn 15 Hgf-Cdk4(R24C) mice on the pigmented C57BL/6 background with one erythemogenic dose of 6 kJ/m(2) UVB and compared the development of nevi and melanoma with a cohort of 30 untreated Hgf-Cdk4(R24C) mice. Neonatal UVB exposure decreased the latency and accelerated the growth of primary melanomas resulting in a significantly decreased time from melanoma onset to melanoma-related death (61 days vs. 96 days). Interestingly, we did not observe differences in the development of melanocytic nevi. Histopathological investigations revealed that UVB irradiation shifted the spectrum of melanomas toward a more aggressive phenotype with increased tumor cell proliferation, invasive growth and enhanced angiogenesis. Accordingly, we observed distal melanoma metastases in the lungs more frequently in the UV-irradiated than in the untreated cohort of Hgf-Cdk4(R24C) mice (73% vs. 47%). UVB-induced melanomas only contained very few infiltrating immune cells and expressed very low levels of proinflammatory chemokines. Taken together, our results demonstrate that neonatal UVB exposure promoted the early appearance of rapidly enlarging primary melanomas in Hgf-Cdk4(R24C) C57BL/6 mice which showed enhanced invasive and metastatic behaviour without a persistent tumor-associated inflammatory response. The preferential impact of UVB irradiation on the progression of melanoma without an effect on the development of nevi supports the hypothesis that the molecular targets of UVB are involved in bypassing the proliferative arrest of transformed melanocytes without alerting a cellular immune response.

Postirradiation primary vaginal angiosarcoma with widespread intra-abdominal metastasis.

We report a primary vaginal angiosarcoma with widespread intra-abdominal metastasis occurring in a 73-yr-old woman 13 yr after vaginal brachytherapy for an endometrial carcinoma. This is an extremely rare phenomenon with only 7 previously reported cases of vaginal angiosarcoma, 5 of which were associated with earlier irradiation. All of the earlier reported cases have been localized to the pelvis without metastatic disease.

Radiation-induced occult insufficiency fracture or bone metastasis after radiotherapy for cervical cancer? The nomogram based on quantitative apparent diffusion coefficients for discrimination.

BACKGROUND: Radiation-induced insufficiency fractures (IF) is frequently occult without fracture line, which may be mistaken as metastasis. Quantitative apparent diffusion coefficient (ADC) shows potential value for characterization of benign and malignant bone marrow diseases. The purpose of this study was to develop a nomogram based on multi-parametric ADCs in the differntiation of occult IF from bone metastasis after radiotherapy (RT) for cervical cancer. METHODS: This study included forty-seven patients with cervical cancer that showed emerging new bone lesions in RT field during the follow-up. Multi-parametric quantitative ADC values were measured for each lesion by manually setting region of interests (ROIs) on ADC maps, and the ROIs were copied to adjacent normal muscle and bone marrow. Six parameters were calculated, including ADCmean, ADCmin, ADCmax, ADCstd, ADCmean ratio (lesion/normal bone) and ADCmean ratio (lesion/muscle). For univariate analysis, receiver operating characteristic curve (ROC) analysis was performed to assess the performance. For combined diagnosis, a nomogram model was developed by using a multivariate logistic regression analysis. RESULTS: A total of 75 bone lesions were identified, including 48 occult IFs and 27 bone metastases. There were significant differences in the six ADC parameters between occult IFs and bone metastases (p < 0.05), the ADC ratio (lesion/ muscle) showed an optimal diagnostic efficacy, with an area under ROC (AUC) of 0.887, the sensitivity of 95.8%, the specificity of 81.5%, respectively. Regarding combined diagnosis, ADCstd and ADCmean ratio (lesion/muscle) were identified as independent factors and were selected to generate a nomogram model. The nomogram model showed a better performance, yielded an AUC of 0.92, the sensitivity of 91.7%, the specificity of 96.3%, positive predictive value (PPV) of 97.8% and negative predictive value (NPV) of 86.7%, respectively. CONCLUSIONS: Multi-parametric ADC values demonstrate potential value for differentiating occult IFs from bone metastasis, a nomogram based on the combination of ADCstd and ADCmean ratio (lesion/muscle) may provide an improved classification performance.

Incidental Orbital Neuroendocrine Metastases on 111In-OctreoScan and MRI.

Neuroendocrine tumors have a propensity to metastasize, but rarely to the orbits. A 69-year-old woman with history of neuroendocrine tumor of pancreatic primary underwent routine follow-up In-pentetreotide (OctreoScan) imaging, with 24-hour whole-body planar images showing subtle right periorbital tracer uptake that localized to extraocular muscles on subsequent SPECT/CT. Orbital MRI further defined the location of these highly suspicious orbital metastases, which were treated with external radiation, with follow-up MRI showing decreased size of the orbital metastases. Early identification and treatment of orbital metastases is critical to help preserve vision and quality of life.

Secondary carcinogenesis in patients treated with radiation: a review of data on radiation-induced cancers in human, non-human primate, canine and rodent subjects.

Concern for risk of radiation-induced cancer is growing with the increasing number of cancer patients surviving long term. This study examined data on radiation transformation of mammalian cells in vitro and on the risk of an increased cancer incidence after irradiation of mice, dogs, monkeys, atomic bomb survivors, occupationally exposed persons, and patients treated with radiation. Transformation of cells lines in vitro increased linearly with dose from approximately 1 to approximately 4-5 Gy. At <0.1 Gy, transformation was not increased in all studies. Dose-response relationships for cancer incidence varied with mouse strain, gender and tissue/organ. Risk of cancer in Macaca mulatta was not raised at 0.25-2.8 Gy. From the atomic bomb survivor study, risk is accepted as increasing linearly to 2 Sv for establishing exposure standards. In irradiated patients, risk of cancer increased significantly from 1 to 45 Gy (a low to a high dose level) for stomach and pancreas, but not for bladder and rectum (1-60 Gy) or kidney (1-15 Gy). Risk for several organs/tissues increased substantially at doses far above 2 Gy. There is great heterogeneity in risk of radiation-associated cancer between species, strains of a species, and organs within a species. At present, the heterogeneity between and within patient populations of virtually every parameter considered in risk estimation results in substantial uncertainty in quantification of a general risk factor. An implication of this review is that reduced risks of secondary cancer should be achieved by any technique that achieved a dose reduction down to approximately [corrected] 0.1 Gy, i.e. dose to tissues distant from the target. The proportionate gain should be greatest for dose decrement to less than 2 Gy.

Ultraviolet radiation-induced malignant skin melanoma in melanoma-susceptible transgenic mice.

A new mouse model of UV radiation-induced melanoma is described. Unlike previous models, melanoma induction requires only short-term irradiation, does not require the application of chemical carcinogens, and does not cause any other tumors. The model takes advantage of the fact that Tyr-SV40E (C57BL/6 strain) transgenic mice are all melanoma-susceptible, and that different inbred lines are susceptible to different extents. Four-day-old mice of a moderately susceptible line (line 9 transgenic homozygotes) were exposed for 20 min/day to 328 mJ/cm2 to UVB (280-320 nm wavelength, comprising 70% of the total irradiance) for up to 4 consecutive days. Melanocytic lesions resembling macules, nevi, or early melanomas gradually appeared in the irradiated mice that were not seen in unirradiated transgenic controls of similar age. To afford ongoing observation beyond the short life span of line 9 homozygous mice, skin samples containing a total of 26 selected lesions were grafted at 20 weeks after UV radiation to longer-lived unirradiated hosts of transgenic line 12, in which melanoma susceptibility is low. Ten lesions in the grafts became melanomas; all melanomas had ulcerated and two had metastasized. At the stages examined, all the tumors were deeply melanotic. The remaining 16 lesions were still indolent when the experiment was terminated at 57 weeks post-UV radiation. The present protocol lends itself to variations in the choice of transgenic line, the age of the treated mice, and the intensity and duration of ultraviolet light; appropriate combinations of these variables would be expected to yield melanomas in relatively long-lived transgenic mice without skin grafting. The new model provides an opportunity to determine the melanoma action spectrum, to characterize at the molecular level the melanomas induced by ultraviolet light in comparison with those of other origins, and to investigate in vivo the photoprotective role of melanin.

Metastatic cutaneous melanoma promoted by ultraviolet radiation in mice with transgene-initiated low melanoma susceptibility.

An inbred-strain (C57BL/6) transgenic (Tyr-SV40E) mouse model of ultraviolet radiation (UVR)-induced metastatic cutaneous melanoma was produced without the use of chemical carcinogens and without resulting in other skin malignancies. Expression of this transgene occurs specifically in melanocytic-lineage cells. In untreated hemizygous mice of transgenic line 12 there are no skin melanomas, and the oncogenic sequence, which is expressed at a very low level, functions solely as a weak initiating stimulus. UVR [including 65% ultraviolet B (280-320 nm wavelength)] supplied the necessary promoting stimulus leading to melanomas. Of various trial protocols, eight were successful and involved exposure of 112 mice for a limited time on each of 3-10 days starting at 2-3 days of age and totalling 1.1-3.7 J/cm2 UVR. Fourteen of these animals developed a total of 15 invasive skin melanomas on the head and body, arising between 37-115 weeks of age and, therefore, often after a relatively long latency. The tumors were melanotic and in five of the mice they yielded macrometastases in regional and distant sites. The single most favorable protocol (1.9 J/cm2 total UVR, at 0.38 J/cm2/day for 5 days starting at 3 days of age) led to the highest incidence of melanoma (5 of 19 mice) and one of the lowest mortality rates (2 of 19). No melanomas occurred in UVR-treated nontransgenic C57BL/6 controls. Benign skin keratoacanthomas arose and often regressed in treated transgenic as well as nontransgenic mice. This new transgenic mouse model introduces many novel possibilities for experimental analysis of the melanoma-promoting mechanisms of UVR and also of the ability of specific genetic changes to impede or facilitate the UVR effect.

Immune response to progressor variants derived from transfection of an ultraviolet radiation-induced C3H mouse regressor tumor cell line with activated Harvey-ras oncogene.

Skin cancers induced in mice by UV radiation often exhibit a regressor phenotype. In order to determine how tumors escape the immune defenses of the normal immunocompetent host, we sought to isolate progressor variants from a UV radiation-induced C3H mouse regressor fibrosarcoma cell line, UV-2240, by transfection with an activated Ha-ras oncogene. A cotransfection protocol using pSV2-neo DNA, which confers resistance to the antibiotic G418, was used to select transfected cells. Injection of Ha-ras-transfected UV-2240 cells s.c. into immunocompetent C3H mice produced tumors in four of 36 animals. In contrast, UV-2240 cells transfected with pSV2-neo DNA alone or mock transfected with CaPO4 did not produce tumors in normal C3H mice. DNAs from cell lines established from Ha-ras-induced tumors contained unique Ha-ras sequences in addition to those sequences endogenous to UV-2240 cells. However, the Ha-ras-induced progressor variants did not overexpress the Mr 21,000 protein. The Ha-ra-induced progressor variants produced experimental lung metastasis in both normal C3H and nude mice, although they induced more lung nodules in nude mice than in normal C3H mice. In addition, all four Ha-ras-induced progressor variants produced significantly more experimental lung metastases in nude mice than did the parent UV-2240 cell line. However, both the parental UV-2240 cell line and the Ha-ras-induced progressor variants expressed similar levels of H-2Kk and H-2Dk antigens and were immunologically cross-reactive, as determined by in vitro cytotoxic T-lymphocyte and in vivo immunization-challenge assays. These results indicate that the progressor phenotype of the Ha-ras-induced tumor variants is not due to loss of tumor-specific transplantation or Class I major histocompatibility complex antigens. This implies that some tumor cells can escape the immune defenses of the normal immunocompetent host by mechanisms other than loss of tumor-specific transplantation and Class I major histocompatibility antigens.

Detection of metastatic tumors after γ-irradiation using longitudinal molecular imaging and gene expression profiling of metastatic tumor nodules.

A few recent reports have indicated that metastatic growth of several human cancer cells could be promoted by radiotherapy. C6-L cells expressing the firefly luciferase (fLuc) gene were implanted subcutaneously into the right thigh of BALB/c nu/nu mice. C6-L xenograft mice were treated locally with 50-Gy γ-irradiation (γ-IR) in five 10-Gy fractions. Metastatic tumors were evaluated after γ-IR by imaging techniques. Total RNA from non-irradiated primary tumor (NRPT), γ-irradiated primary tumor (RPT), and three metastatic lung nodule was isolated and analyzed by microarray. Metastatic lung nodules were detected by BLI and PET/CT after 6-9 weeks of γ-IR in 6 (17.1%) of the 35 mice. The images clearly demonstrated high [18F]FLT and [18F]FDG uptake into metastatic lung nodules. Whole mRNA expression patterns were analyzed by microarray to elucidate the changes among NRPT, RPT and metastatic lung nodules after γ-IR. In particular, expression changes in the cancer stem cell markers were highly significant in RPT. We observed the metastatic tumors after γ-IR in a tumor-bearing animal model using molecular imaging methods and analyzed the gene expression profile to elucidate genetic changes after γ-IR.

Impact of stereotactic radiosurgery dose on control of cerebral metastases from renal cell carcinoma.

AIM: Renal cell carcinoma (RCC) is a relatively radioresistant tumor and may require for higher radiation doses than other tumor types. PATIENTS AND METHODS: Nineteen patients treated with 20 Gy of stereotactic radiosurgery (SRS) alone for one to three cerebral metastases were compared to nine patients treated with 16-18 Gy. RESULTS: SRS with 20 Gy led to significantly better local control than did 16-18 Gy (81% vs. 50% at 12 months; p<0.001). Results were also significant on multivariate analysis (risk ratio: 6.30; p=0.033). SRS dose did not associate with freedom from new cerebral metastases (75% vs. 62% at 12 months; p=0.42) or survival (16% vs. 56% at 12 months; p=0.46). On multivariate analyses, better survival was associated with higher Karnofsky performance score (p<0.001) and absence of extracranial metastatic disease (p=0.006). CONCLUSION: In patients treated with SRS alone, local control of cerebral metastases from RCC was better after 20 Gy than after 16-18 Gy.

A new allogeneic model for metastatic melanoma.

Metastatic melanoma cells, clonally derived from an affected lymph node of an ultraviolet-irradiated laboratory opossum, were allografted subcutaneously into suckling young, juveniles and adults to determine their tumorigenicity and metastatic potential. All injected 1- and 3-week-old suckling young survived well beyond weaning at 8 weeks. One died 12 weeks after injection from the effects of rampant metastatic involvement, while the rest were killed 13 to 26 weeks after injection. At necropsy, most animals showed extensive primary tumour growth, many showed metastasis to nodes and/or lungs, and in some there was dissemination to distant sites including liver and spleen. Animals injected as juveniles or adults rejected the allografts. Injection of allogeneic malignant melanoma cells during early postnatal development facilitates successful, long-term allografting and metastasis without concomitant immunosuppressive agents. Developmental lack of self-recognition (immunological immaturity) or induced tolerance may be responsible. This unique model system will be useful for further metastasis studies and may be valuable for investigations of novel antineoplastic therapies.

[Multiple primary vaginal tumors following the radiation treatment of cervical cancer]. / Pervichno-mnozhestvennye opukholi vlagalishcha posle luchevogo lecheniia raka sheiki matki.

The analysis of the data on 3225 irradiated patients with cervical cancer was performed to evaluate the probability of development of primary multiple tumors of the vagina. The actual risk of second tumor development within the mean period of survival of the treated patients (30 years) was 200 times higher than the expected risk of vaginal cancer in the general population. Local radiation injury and overdose proved the main factors of risk. Basic differences between these tumors, and primary vaginal malignancies and late metastases and relapses of cervical cancer are discussed. They were used as basis for the identification of a separate entity, namely radiation-induced cancer of the vagina. Patients irradiated for cervical cancer should be followed for their life-time.

Microdosimetry measurements characterizing the radiation fields of 300 MeV/u 12C and 185 MeV/u 7Li pencil beams stopping in water.

In order to characterize the complex radiation field produced by heavy-ion beams in water, in particular the lateral dose fall-off and the radiation quality, microdosimetry measurements were performed at GSI Darmstadt using pencil-like beams of 300 MeV/u (12)C and 185 MeV/u (7)Li ions delivered by the heavy-ion synchrotron SIS-18. The ion beams (range in water about 17 cm) were stopped in the center of a 30 x 30 x 30 cm(3) water phantom and their radiation field was investigated by in-phantom measurements using a tissue-equivalent proportional chamber (TEPC). The chamber was placed at 35 different positions in the central plane at various depths along the beam axis and at radial distances of 0, 1, 2, 5 and 10 cm. The off-axis measurements for both (12)C and (7)Li ions show very similar distributions of the lineal energy, all peaking between 1 and 10 keV microm(-1) which is a typical range covered by secondary hydrogen fragments and neutrons. The radiation quality given by the dose-mean lineal energy [Formula in text] was found to be at a constant level of 1-2 keV microm(-1) at radial distances larger than 2 cm. The relative absorbed dose at each position was obtained by integration of the measured spectra normalized to the number of incident primary beam particles. The results confirm that the lateral dose profile of heavy ions shows an extremely steep fall-off, with relative values of about 10(-3), 10(-4) and 10(-5) at the 2, 5 and 10 cm distance from the beam axis, respectively. The depth-dose curves at a fixed distance from the beam axis slowly rise until they reach the depth of the Bragg peak, reflecting the build-up of secondary fragments with increasing penetration depth. The measured (12)C dose profiles were found to be in good agreement with a similar experimental study at HIMAC (Japan).

Clinical behavior of radiation-induced thyroid cancer: factors related to recurrence.

BACKGROUND: Whether thyroid cancer is more aggressive in radiation-exposed patients is not resolved. The frequency of aggressive features in post-Chernobyl patients suggests this may be the case. Our aim was to address this question by re-examining the pattern of risk factors for recurrence of thyroid cancers found in a cohort exposed to external radiation. METHODS: The study population was drawn from a cohort of 4296 people, followed since 1974, who were treated before the age of 16 with conventional external radiation for benign conditions of the head and neck between 1939 and the early 1960s. The study group consisted of 390 patients who had surgically verified thyroid cancer. Potential risk factors for recurrence were evaluated by proportional hazards analysis. RESULTS: Fifty patients had recurrences an average of 8.7 years after diagnosis while the other 340 patients were followed for an average of 19.7 years. The sooner after radiation exposure the cancer occurred, the more likely it was to recur (hazard ratio, 0.96/year; 95% confidence interval [CI] 0.91-0.99). Taking into account the effect of the onset of screening in 1974, the features predictive of recurrence were younger age at the initial diagnosis (hazard ratio, 0.95/year; 95% CI, 0.91-0.99) and the size of the thyroid cancer (hazard ratio, 1.2/cm; 95% CI, 1.0-1.6). CONCLUSION: Although not based on a direct comparison, we conclude that thyroid cancers following external radiation exposure are not, on average, more aggressive than other thyroid cancers. The similarity of risk factors for recurrence suggests that they should be treated and followed in the same way as non-radiation-induced thyroid cancers.

Post-irradiation malignant fibrous histiocytoma of the larynx: A case report with an unusual metastatic spread pattern.

We report a case of a laryngeal malignant fibrous histiocytoma (MFH) that showed an uncommon clinical behavior. This tumor occurred in a 70-year-old male patient 5 years after radiation treatment for laryngeal squamous cell carcinoma, and unusual metastases were spread unusually to the pleural cavity. The interval between the end of radiotherapy and the onset of MFH can be justified by the development of laryngeal stenosis by fibrotic tissue as a late complication of radiotherapy. Laryngeal fibrosis after radiotherapy probably triggered the MFH. Neither computed tomography nor magnetic resonance imaging differentiate between fibrotic tissue and MFH, and only repeated biopsy was definitive to give us the correct diagnosis.