Evaluation of treatment results and toxicity in cases of repeated radiation therapy of spinal metastasis

The study evaluates retrospective results and toxicity in repeated radiation therapy in patients with recurrent pain caused by backbone metastasis, having undergone previous radiotherapy in the same body region. Fifty-seven patients were analyzed: 24 women and 33 men, aged 45-74 years (median = 59 years). They underwent a second radiation therapy treatment of the spinal column, between March 2002 and May 2004, performed due to recurrent pain in the previously irradiated region. The radiation used cobalt isotope 60 ((60)Co), to include the metastatically changed vertebrae and the margin of the adjusting healthy upper and lower vertebra. The radiated skin area measured 84-104 cm(2). Patients were divided into 3 groups depending on their treatment schemas: 12 patients -- first course of radiotherapy 4 Gy x 5, second 4 Gy x 5; 16 patients -- first course of radiotherapy 4 Gy x 5, second 8 Gy x 1; 29 patients -- first course of radiotherapy 8 Gy x 1, second 8 Gy x 1. The time delay between the first and the second radiation therapies was between 11 and 766 days (median = 135 days). An analgesic effect was achieved with most treated patients -- 41/57 (71.9%) with the use of second radiotherapy and with an insignificant percentage of complications, unimportant from the clinical point of view. No serious complications such as paralysis, paresis, spinal cord necrosis, neurological dysfunction of urethral or sigmoidorectal sphincters were noted in any of the treated patients. Based on our experience, this retrospective analysis shows usefulness of the second radiotherapy treatment as a safe method of palliative treatment in cases of painful bone metastasis appearing after a previous radiation therapy.     

A prospective study of the development of growth hormone deficiency in children given cranial irradiation, and its relation to statural growth

Although GH deficiency (GHD) is the most frequent hormonal abnormality that occurs after cranial radiation, the natural course of this complication and its relationship to growth in children are not known. Therefore, we undertook a 2-yr prospective study of 16 children, aged 1.7-15 yr at the time of treatment, who received cranial [31-42 Gy (1 Gy = 100 rads)] and spinal radiation for medulloblastoma or ependymoma (group I). Their growth was compared to that of 11 children given similar doses of cranial radiation only (group II). The mean plasma GH response to arginine-insulin test (AITT) was 9.1 +/- 1.5 (+/- SE) micrograms/L in group I and 8.5 +/- 1.8 micrograms/L in group II (P = NS). After 2 yr, 16 of the 27 children had a peak plasma GH value below 8 micrograms/L after AITT, and 10 children had a peak response less than 5 micrograms/L. In addition, in group I, AITT and sleep-related GH secretion were compared; at the 2 yr follow-up only 3 of 13 children had discrepant results. At the 2 yr follow-up children treated by cranial and spinal radiation had a mean height of -1.46 +/- 0.40 SD below the normal mean. In contrast, the children given only cranial radiation had a mean height of -0.15 +/- 0.18 SD; P less than 0.02. Therefore, most of the growth retardation appeared to be due to lack of spinal growth. GHD is thus an early complication of cranial radiation in these children, and no significant growth retardation can be attributed to GHD during the first 2 yr. These data contribute to the organization of follow-up in irradiated children in order to decide when human GH treatment is necessary.     

Combination chemotherapy and radiation therapy. The medical management of epidural spinal cord compression from testicular cancer

Radiation and surgery are the mainstays of treatment for epidural spinal cord compression. There are reports in the literature, however, in which the use of chemotherapy alone or in combination with radiation and surgery has resulted in improved patient response. We present two patients with spinal cord compression from testicular cancer who developed progressive paraplegias that were successfully reversed with combination chemotherapy, steroids, and radiotherapy. In one case, the patient was unable to receive more than 600 rad (6 Gy) of radiation and his improvement was clearly related to the chemotherapy he received. In treating tumors causing spinal cord compression that are thought to be chemosensitive, one should consider adding chemotherapy to radiation or using chemotherapy alone if the options of surgery or radiation are not available.     

Catastrophic transverse myelitis in a patient with systemic lupus erythematosus

A 24-year-old Japanese woman was admitted to our hospital suffering from high fever and progressive paralysis in both legs. Magnetic resonance imaging of the spinal cord showed high-intensity signals from C5 to Th4 and from Th7 to L1 on T2-weighted images. The patient was diagnosed as having acute transverse myelitis , which was a complication of systemic lupus erythematosus based on the serological findings. Despite aggressive immunosuppressive treatments including corticosteroid pulse therapy, plasmapheresis, and intravenous cyclophosphamide, the paralysis of her lower extremities did not improve. In the catastrophic type of lupus-associated TM, which develops extensively and longitudinally along the spinal cord, the prognosis still seems to be poor despite intensive treatments.     

Intramedullary tuberculosis manifested as Brown-Sequard syndrome in a patient with systemic lupus erythematosus

A 25-year-old girl presented with progressive deterioration of right side weakness with decreased sensation on the left trunk. She had been treated with high dose steroid due to autoimmune thrombocytopenia for 2 months. Clinical, laboratory and immunologic studies revealed that she had systemic lupus erythematosus (SLE), MRI of spinal cord showed marginal contrast enhancing and fluid containing mass in the cord of the C5-6 level, suggesting intramedullary abscess. She underwent surgery of mass removal with biopsy. The pathologic findings from cord tissues revealed numerous acid fast bacilli (AFB) in necrotic tissues. After surgery and anti-tuberculous treatment, her neurologic symptoms were markedly improved with restoration of right side motor weakness. To our knowledge, this is the first case report of intramedullary tuberculosis in a patient with SLE. Since intramedullary tuberculosis may sometimes mimic neurologic complication of SLE itself, it may pose diagnostic and therapeutic confusion for clinicians. We report a case of spinal cord tuberculosis affecting C5, 6 level which was manifested as Brown-Sequard syndrome in a patient with SLE.     

造血干细胞移植后继发脑膜造血-1例报告

目的报告1例多发性骨髓瘤患者异基因骨髓造血干细胞移植后发生放射性脊髓炎,1月后又出现髓外脑膜造血的病例,探讨此例髓外脑膜造血的发病因素.方法对该患者在接受非亲缘性供者骨髓移植后7月继发髓外脑膜造血的临床资料进行分析,并结合文献复习.结果脑脊液中发现造血细胞,包括有核红细胞,幼稚粒细胞和巨核细胞,MRI见脊髓T11以下线性增强.结论放射性脊髓炎可能导致髓外脑膜造血,鞘内注射阿糖胞苷和甲氨喋呤治疗使其缓解.     

Spinal cord compression by epidural lipomatosis in juvenile rheumatoid arthritis

Two cases of spinal cord compression secondary to steroid-induced epidural lipomatosis in systemic juvenile rheumatoid arthritis (JRA) patients are reported. This complication of prolonged corticosteroid therapy has not been described previously in children with JRA. Epidural lipomatosis should be considered in the differential diagnosis of JRA patients receiving high-dose and/or prolonged corticosteroid therapy who present with neurologic signs and symptoms referable to the spinal cord.     

Dose-dependent generation of RET/PTC in human thyroid cells after in vitro exposure to gamma-radiation: a model of carcinogenic chromosomal rearrangement induced by ionizing radiation

Ionizing radiation is a well-known risk factor for thyroid cancer in human populations. Chromosomal rearrangements involving the RET gene, known as RET/PTC, are prevalent in thyroid papillary carcinomas from patients with radiation history. We studied the generation of RET/PTC in HTori-3 immortalized human thyroid cells exposed to a range of doses of gamma-radiation and harvested 2, 5-6, and 9 d later. RET/PTC1 and RET/PTC3 were detected by RT-PCR followed by Southern blotting and hybridization with internal oligonucleotide probes. No RET/PTC was found in cells harvested 2 and 5-6 d after irradiation, whereas 59 RET/PTC events were detected in cells collected 9 d after exposure. The average rate of RET/PTC induction was 0.1 x 10(-6) after exposure to 0.1 Gy, 1.6 x 10(-6) after 1 Gy, 3.0 x 10(-6) after 5 Gy, and 0.9 x 10(-6) after 10 Gy. When adjusted for cell survival, the rate after 10 Gy was comparable with those after 5 Gy. RET/PTC1 was more common than RET/PTC3 after each dose, comprising 80% of all rearrangements. In this study, we demonstrate a dose-dependent induction of RET/PTC rearrangements in human thyroid cells after exposure to 0.1-10 Gy gamma-radiation. This provides additional evidence for a direct link between this genetic event and radiation exposure and offers a powerful experimental system for studying radiation-induced carcinogenesis in the thyroid gland.     

Absence of cervical radiation myelitis after hyperfractionated radiation therapy with and without concurrent chemotherapy for locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck

Purpose: To evaluate the risk of developing radiation myelitis after a cervical spinal cord dose of 50.6 Gy given via 1.1 Gy b.i.d. fractionation during a prospective, randomised trial of hyperfractionated radiation therapy (HFX RT) to a total dose of 77 Gy given in 70 fractions of 1.1 Gy b.i.d., with and without concurrent low-dose, daily cisplatin (CDDP) for head and neck cancer. Methods: Of 130 patients with locally advanced, unresectable, nonmetastatic squamous cell carcinoma of the head and neck (SCC H&;N) who entered a prospective, randomised trial, 101 patients received 50.6 Gy to a portion of their spinal cord and survived >1 year following the beginning of therapy. Forty-five patients were treated with HFX RT alone and fifty-six patients also received CDDP. Results: None of these 101 patients developed cervical radiation myelitis. Therefore, it was not possible to investigate the influence of potentially contributing factors on the occurrence of radiation myelitis, such as interfraction interval, cord length, and administration of concurrent CDDP. Conclusions: Given the increasing number of studies with both altered fractionated regimens and concurrent radio-chemotherapy in SCC H&;N, new studies with more patients are needed to gain better insight into the risks of developing cervical radiation myelitis.     

Phase I study of (131)I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome.

Delivery of targeted hematopoietic irradiation using radiolabeled monoclonal antibody may improve the outcome of marrow transplantation for advanced acute leukemia by decreasing relapse without increasing toxicity. We conducted a phase I study that examined the biodistribution of (131)I-labeled anti-CD45 antibody and determined the toxicity of escalating doses of targeted radiation combined with 120 mg/kg cyclophosphamide (CY) and 12 Gy total body irradiation (TBI) followed by HLA-matched related allogeneic or autologous transplant. Forty-four patients with advanced acute leukemia or myelodysplasia received a biodistribution dose of 0.5 mg/kg (131)I-BC8 (murine anti-CD45) antibody. The mean +/- SEM estimated radiation absorbed dose (centigray per millicurie of (131)I) delivered to bone marrow and spleen was 6.5 +/- 0.5 and 13.5 +/- 1.3, respectively, with liver, lung, kidney, and total body receiving lower amounts of 2.8 +/- 0.2, 1.8 +/- 0.1, 0.6 +/- 0.04, and 0.4 +/- 0.02, respectively. Thirty-seven patients (84%) had favorable biodistribution of antibody, with a higher estimated radiation absorbed dose to marrow and spleen than to normal organs. Thirty-four patients received a therapeutic dose of (131)I-antibody labeled with 76 to 612 mCi (131)I to deliver estimated radiation absorbed doses to liver (normal organ receiving the highest dose) of 3.5 Gy (level 1) to 12.25 Gy (level 6) in addition to CY and TBI. The maximum tolerated dose was level 5 (delivering 10.5 Gy to liver), with grade III/IV mucositis in 2 of 2 patients treated at level 6. Of 25 treated patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS), 7 survive disease-free 15 to 89 months (median, 65 months) posttransplant. Of 9 treated patients with acute lymphoblastic leukemia (ALL), 3 survive disease-free 19, 54, and 66 months posttransplant. We conclude that (131)I-anti-CD45 antibody can safely deliver substantial supplemental doses of radiation to bone marrow (approximately 24 Gy) and spleen (approximately 50 Gy) when combined with conventional CY/TBI.     

Irinotecan and S-1 neoadjuvant chemoradiation therapy in patients with advanced rectal cancer

We performed preoperative chemoradiotherapy in locally advanced cases of rectal cancer without distant metastasis. The methods for drug administration and irradiation were as follows: oral administration of S-1 at 80 mg/m2/day on days 1-5, 8-12, 22-26, and 29-33, with periods of 5 days on drug and 2 days off drug and intravascular administration of CPT-11 for 120 minutes on days 1, 8, 22, and 29, at doses of 60 mg/m2/day in Case 1 and 70 mg/m2/day in Case 2. The radiation dosage was a fractionated exposure of 1.8 Gy/day x 5 days/week for 5 weeks, for a total of 45 Gy. No major adverse events were observed in either case, and the treatment was performed as per the protocol. No postoperative complications were observed in either case. Both patients showed complete pathological remission with no evidence of tumor cells in the primary focus and no lymph node metastases. Preoperative chemoradiotherapy with a combination of S-1 and CPT-11 may be a new treatment for rectal cancer.     

An iso-effect table for radiation tolerance of the human thoracic spinal cord. A new approach on the basis of the DFT conception

Forty-four cases of well documented progressive radiation myelopathy of thoracic spinal cord were analyzed in terms of the new DFT conception (Dose-Fraction-Time). The DFT conception is a new radiobiological cell tissue kinetic model comprising explicitly repopulation. The conception has been previously tested against many animal experimental data. Good agreement could be demonstrated. The comparison with clinical data enabled us to establish human thoracic spinal cord tolerance DFT value of DFT = 70. For all cases of thoracic progressive spinal cord radiation myelopathy where the radiation fields were up to 20 cm of the cord length the value of the DFT has been found above the proposed value. Tolerance irradiation doses of various regular irradiation schemes were calculated from the DFT = 70 for practical use. Our predictions are in agreement with tolerance irradiation regimes recommended by various authors on the basis of their clinical experience. Moreover, such an approach enabled to establish safe tolerance doses in cases where currently used NSD or ED conceptions could lead to dangerous consequences--mainly for shorter irradiation schedules. This is the first attempt to utilize the DFT conception in the clinical practice.     

Hereditary spastic paraparesis in adults associated with inborn errors of metabolism: A diagnostic approach

Summary Spastic paraparesis is a general term describing progressive stiffness and weakness in the lower limbs caused by pyramidal tract lesions. This clinical situation is frequently encountered in adult neurology. The diagnostic survey is usually limited to searching for acquired causes (spinal cord compression, inflammatory, metabolic, infectious diseases) and the so-called ‘hereditary spastic paraparesis’. Although poorly recognized by neurologists, spastic paraparesis is also one of the multiple presentations of inborn errors of metabolism (IEMs) in children and adults. Pyramidal signs are usually included in a diffuse neurological or systemic clinical picture; however, in some cases spastic paraparesis remains the only symptom for years. Since these metabolic causes are often treatable, it is essential to include them in the general diagnostic approach to spastic paraparesis. Here we review IEMs causing paraparesis in adults. Competing interests: None declared     

Meningeal hematopoiesis following radiation myelitis in a hematopoietic stem-cell transplant recipient

Extramedullary meningeal hematopoiesis (EMH) represents an uncommon finding after stem-cell transplantation. We describe the case of an allogeneic bone marrow transplantation (BMT) recipient who developed EMH 1 month after radiation myelitis had been diagnosed. A 39-year-old man with multiple myeloma underwent matched unrelated BMT following a myeloablative conditioning regimen of cyclophosphamide and total-body irradiation (200 cGyx6). This was followed by delivery of 40 Gy of involved-field radiation to an extramedullary plasmacytoma compressing the spinal cord. Although transplantation went extremely well, the patient developed radiation myelitis 7 months after transplantation, and EMH ensued 1 month later. Because the patient was not in a disease state known to cause EMH, it is tempting to speculate that radiation-related neural injuries might cause donor cells to migrate to the central nervous system.     

Risk factors for the development of obesity in children surviving brain tumors

Hypothalamic obesity, a syndrome of intractable weight gain due to hypothalamic damage, is an uncommon but devastating complication for children surviving brain tumors. We undertook a retrospective evaluation of the body mass index (BMI) curves for the St. Jude Children's Research Hospital brain tumor population diagnosed between 1965 and 1995 after completion of therapy to determine risk factors for the development of obesity. Inclusion criteria were: diagnosis less than 14 yr of age, no spinal cord involvement, ambulatory, no supraphysiologic hydrocortisone therapy (>12 mg/m(2) x d), treatment and follow-up at St. Jude Children's Research Hospital, and disease-free survival greater than 5 yr (n = 148). Risk factors examined were age at diagnosis, tumor location, histology, extent of surgery, hydrocephalus requiring ventriculoperitoneal shunting, initial high-dose glucocorticoids, cranial radiation therapy, radiation dosimetry to the hypothalamus, intrathecal chemotherapy, and presence of endocrinopathy. Analyses were performed both between groups within a risk factor and against BMI changes for age in normal children older than 5.5 yr (the age of adiposity rebound). Risk factors were: age at diagnosis (P = 0.04), radiation dosimetry to the hypothalamus (51-72 Gy, P = 0.002 even after hypothalamic and thalamic tumor exclusion), and presence of any endocrinopathy (P = 0.03). In addition, risk factors when compared with BMI slope for the general American pediatric population included: tumor location (hypothalamic, P = 0.001), tumor histology (craniopharyngioma, P = 0.009; pilocytic astrocytoma, P = 0.043; medulloblastoma, P = 0.039); and extent of surgery (biopsy, P = 0.03; subtotal resection, P = 0.018). These results verify hypothalamic damage, either due to tumor, surgery, or radiation, as the primary cause of obesity in survivors of childhood brain tumors. In particular, hypothalamic radiation doses of more than 51 Gy are permissive. These results reiterate the importance of the hypothalamus in energy balance, provide risk assessment criteria for preventative measures before the development of obesity in at-risk patients, and suggest therapeutic strategies to reduce the future development of obesity.     

Obesity is a major determinant of radiation dose in patients undergoing pulmonary vein isolation for atrial fibrillation.

OBJECTIVES: This study sought to evaluate the impact of obesity on patient radiation dose during atrial fibrillation (AF) ablation procedures under fluoroscopic guidance. BACKGROUND: Obesity is a risk factor for AF and its recurrence after ablation. It increases patient radiation dose during fluoroscopic imaging, but this effect has not been quantified for AF ablation procedures. METHODS: Effective radiation dose and lifetime attributable cancer risk were calculated from dose-area product (DAP) measurements in 85 patients undergoing AF ablation guided by biplane low-frequency pulsed fluoroscopy (3 frames/s). Three dose calculation methods were used (Monte Carlo simulation, dose conversion coefficients, and depth-profile dose curves). RESULTS: Median DAP for all patients was 119.6 Gy x cm2 (range 13.9 to 446.3 Gy x cm2) for procedures with a median duration of 4 h and 83 +/- 26 min of fluoroscopy. Body mass index was a more important determinant of DAP than total fluoroscopy time (r = 0.74 vs. 0.37, p < 0.001), with mean DAP values per hour of fluoroscopy of 58 +/- 40 Gy x cm2, 110 +/- 43 Gy x cm2, and 184 +/- 79 Gy x cm2 in normal, overweight, and obese patients, respectively. The corresponding effective radiation doses for AF ablation procedures were 15.2 +/- 7.8 mSv, 26.7 +/- 11.6 mSv, and 39.0 +/- 15.2 mSv, respectively (Monte Carlo). Use of conversion coefficients resulted in higher effective dose estimates than other methods, particularly in obese patients. Mean attributable lifetime risk of all-cancer mortality was 0.060%, 0.100%, and 0.149%, depending on weight class. CONCLUSIONS: Obese patients receive more than twice the effective radiation dose of normal-weight patients during AF ablation procedures. Obesity needs to be considered in the risk-benefit ratio of AF ablation and should prompt further measures to reduce radiation exposure.     

Circulating heavy chain IgG,a pathological mediator for coronary artery disease,recognizes platelet surface receptors of both prostacyclin and insulin

Although an increased incidence of premature cardiovascular disease has been determined to be the major cause of mortality in subjects with chronic spinal cord injury the identity of the pathophysiological mediators of cardiovascular disease in spinal cord injury remains obscure. Because both insulin and prostacyclin could be important in the prevention of thrombosis, the status of insulin-induced nitric oxide production and the prostacyclin high-affinity receptor interaction in platelets in subjects with spinal cord injury was studied. It was established that the insulin-induced nitric oxide synthesis in platelets from spinal cord-injured subjects was markedly impaired (0.053-0.058, P = 0.37-0.44) compared to (0.062-0.53 microM/10(8) platelets, P < 0.001) due to the presence of a free heavy chain IgG (Mr 47 kDa) in the circulation of subjects with spinal cord injury. This IgG not only blocked insulin receptor binding sites (without affecting dissociation constant of the hormone binding, Kd1 = 2 x 10(-9) M) for the synthesis of nitric oxide but also blocked the prostacyclin receptor interaction in normal platelets. Since the presence of circulating heavy chain of IgG could block the antithrombotic effect of both insulin and prostacyclin, the free heavy chain of the IgG molecule was thought to be one of the pathological mediators for the increased incidence of cardiovascular disease in individual with spinal cord injury. The cross-reactivity of the free heavy chain with two different receptors antigens was thought to be related to the presence of several regions of homology in the amino acid sequence in the insulin and prostacyclin receptor molecules.     

Carcinomatous leptomeningitis in small cell lung cancer: a clinicopathologic review of the National Cancer Institute experience

CLM developed in 60 of 526 patients (11%) with SCLC seen at the NCI between August 1969 and June 1980. Life table analysis revealed an overall 25% risk of CLM at 3 years. CLM was diagnosed during all phases of the patients' clinical course, but the majority (83%) were cases diagnosed at the time of progressive systemic disease. Univariate log rank analysis indicated that pretreatment factors associated with the development of CLM included: involvement of the brain, spinal cord, bone marrow, liver or bone; extensive disease; and male sex. Patients who did not obtain a complete response to systemic therapy were at greater risk of developing CLM than complete responders. Multivariate analysis of these factors indicated that liver metastases were most strongly associated with the time to development of CLM, followed in order of importance by bone and CNS metastases. Patients usually presented with signs and symptoms reflecting involvement of multiple areas of the neuraxis including the cerebrum, cranial nerves and spinal cord; 51 of the 60 patients had intracerebral metastases and 27 had spinal cord lesions during their clinical course. Autopsy features including focal or diffuse involvement of the leptomeninges with infiltration of the Virchow-Robin spaces were similar to meningeal lymphoma and leukemia, except that CLM was rarely the sole manifestation of CNS tumor. Median survival following the diagnosis of CLM was 7 weeks. However, most deaths were attributed to systemic disease, and treatment with intrathecal chemotherapy and irradiation often provided palliation. With the increased awareness of this complication, an antemortem diagnosis increased from 39% prior to 1977, to 88% of patients after 1977.     

The combination topotecan, temozolomide and dexamethasone associated with radiotherapy as treatment of central nervous system myeloma relapse

A 46-year-old woman with IgA-λ myeloma in partial remission, after a tandem autologous hematopoietic stem cells transplantation, complained of progressive lower back pain associated with paraplegia and neurological bladder 6 months after the second transplant. A lumbar puncture revealed atypical malignant plasma cells in the cerebral spinal fluid associated with multiple foci of altered signal intensity of brain and spinal cord demonstrated by magnetic resonance. Considering the lack of efficacious chemotherapies for neurological myeloma, an experimental systemic treatment with topotecan, temozolamide, and dexamethasone associated with concurrent radiotherapy of brain and spinal cord was initiated. During this treatment, the patient rapidly improved with disappearance of back pain, paresthesia, and urinary incontinence lasting 5 months, before dying of progressive disease. The proposed systemic chemotherapy associated with concurrent radiotherapy may have an antitumor activity against MM with CNS involvement.