Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel.

Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory-motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation (P = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.

Targeting pulmonary metastases of renal cell carcinoma by inhalation of interleukin-2.

INTRODUCTION: Pulmonary metastases of renal cell carcinoma (RCC) are associated with poor prognosis. Inhalation therapy with interleukin-2 (IL-2) is thus an appealing method for palliation. This multicenter study summarizes the national experience of IL-2 inhalation in patients with lung metastases of RCC. PATIENTS AND METHODS: Forty patients (median, 66.5 years of age) with radiologically documented progressing pulmonary metastases were enrolled. All patients had to be able to comply with inhalation technique, and were not candidates for other treatment options. Twenty-eight patients were systemic treatment-naïve. The protocol included three daily inhalations of IL-2 to a total dose of 18 MU. Treatment had to be continued until one of the following occurred: progression; a complete response; a life threatening toxicity; or patient refusal. Response was assessed using the Response Evaluation Criteria in Solid Tumors (RECIST) system. RESULTS: The disease-control rate reached 57.5%, with a partial response rate of 2.5% and a disease stabilization rate of 55%. Median time to progression was 8.7 months. The main side-effects were cough and weakness. CONCLUSIONS: Inhalation of IL-2 for the treatment of pulmonary metastases in RCC is feasible, tolerable and beneficial in controlling progressive disease for considerable periods of time. The definition of response of biological therapy may need to be re-assessed and modified: stable disease should be regarded as a favorable response.

Comparative genomic hybridization analysis of radiation-associated and sporadic meningiomas.

Ionizing irradiation to the skull is a known risk factor for meningioma development. To gain insight into the molecular mechanisms that underlie radiation-associated meningioma (RAM), we characterized the somatic genetic alterations in 16 RAMs by using comparative genomic hybridization and compared the pattern of alterations with 17 nonradiation-associated meningiomas (non-RAM). Most tumors (29/33;87.9%) displayed at least one DNA copy number alteration, and 11 out of 33 (33%) exhibited four or more changes. The mean number of DNA copy number changes was similar in RAMs (2.4+/-1.9) and in non-RAMs (2.5+/-1.9). The most common DNA losses were noted in chromosome 22 (56.2% in RAM, and 47% in non-RAM) and chromosome 1 (37.5% in RAM and 35.3% in non-RAM), with no significant differences between the two groups. Noteworthy, gain in DNA copy number of chromosomes 8 and 12 was detected in two RAM tumors only. In conclusion, no significant differences were noted between RAMs and non-RAMs regarding the number of genetic changes and the extent and frequency of chromosomes 1 and 22 losses. These preliminary data suggest that the tumorogenic pathways of meningioma formation are similar, regardless of previous skull irradiation.

Effect of P-glycoprotein expression on outcome in the Ewing family of tumors.

This study was designed to determine the prognostic significance of multidrug resistance, mediated by P-glycoprotein (Pgp) expression, in Ewing sarcoma. The clinical and laboratory features, treatment protocol, and outcome of 75 patients with Ewing sarcoma or peripheral neuroectodermal tumor treated between 1972 and 1997 were reviewed. Pgp expression was tested with the monoclonal antibody JSB-1. Thirty-four (64%) of the 53 tissue samples from untreated patients stained positive for Pgp. Progression-free and overall survival were 44 and 59%, respectively, in patients with negative findings, and 28 and 41% in those with positive findings; neither difference was significant. Of the 12 relapsed patients, 6 (50%) expressed more Pgp after chemotherapy than at diagnosis and 4 (33%) expressed less. Within these subgroups, 5 out of 6 and 3 out of 4 died from the disease. No correlation was found between Pgp and known prognostic factors of Ewing tumors. Pgp expression is probably an intrinsic factor of Ewing tumors but has no correlation to prognosis.

Diffuse brain stem gliomas. Are we improving outcome?

We reviewed our experience with diffuse brain stem glioma (dBSG) to evaluate whether any improvement of outcome had occurred in our patients over the years. Of the 24 children referred to our department with suspected dBSG from 1981 to 1997, 5 had a different final diagnosis based on the clinical course. Mean survival in the remainder was 16+/-9.8 months from diagnosis. Survival increased with a longer interval from onset of symptoms to diagnosis (12.9+/-9.0 months with an interval of 1-4 weeks; 19.50+/-10.8 months with a longer interval). Visual symptoms at presentation were associated with a poorer prognosis. Survival was better in the 3- to 5-year age group (at diagnosis). Overall, a trend toward a slight improvement in survival was seen over the years, which we presumptively attribute to the introduction of intensive chemotherapy for these patients. We suggest that chemotherapy may be important in the management of dBSG until a better modality is found.

Effect of superoxide dismutase on a rabbit model of chronic allergic asthma.

BACKGROUND: In bronchial asthma, inflammatory cells infiltrating the airway mucosa release oxygen radicals that cause tissue damage and amplify the airway inflammation. Antioxidant enzymes may have a protective effect on the airways. OBJECTIVE: The purpose of this study was to determine whether treatment of a rabbit model of chronic allergic asthma with the antioxidant enzyme superoxide dismutase conjugated to polyethylene glycol will protect the airways from oxygen radical injury, decrease airway inflammation, and attenuate the asthmatic response. METHODS: New Zealand white rabbits were sensitized to ragweed. Baseline histamine PC30, ragweed PD30, and early and late phase asthmatic response to ragweed bronchial challenge were measured. The rabbits were then randomized into two groups that received every 48 hours an intravenous dose of either superoxide dismutase-polyethylene glycol 10,000 U/kg or inactivated superoxide dismutase-polyethylene glycol as control, followed by a 1-hour exposure to aerosolized ragweed extract. After 4 weeks the rabbits had a second bronchial challenge, were sacrificed, and lung histology was studied. RESULTS: On the posttreatment challenge, the superoxide dismutase-polyethylene glycol group had a rise in ragweed PD30, while the control group had no change in ragweed PD30, and two of five rabbits in the superoxide dismutase-polyethylene glycol group did not have an early or late phase asthmatic response, while all rabbits in the control group had an asthmatic response. There was no significant difference in lung histology between both groups. CONCLUSION: A rabbit model of chronic allergic asthma treated with superoxide dismutase-polyethylene glycol showed a trend of improvement in airway responsiveness but no significant effect on airway inflammation.

Antioxidant enzyme activity in murine hematopoietic bone marrow following treatment with interleukin 1 alpha: influence of tumor.

To determine whether non-hematologic tumors influence the bone marrow's antioxidant enzyme response to the radioprotective cytokine interleukin 1 alpha (IL-1), studies were undertaken using BDF1 and Balb/c mice bearing small, medium or large Lewis lung carcinoma (LLCa) or EMT6 mammary carcinoma tumors, respectively. Results demonstrated that, similar to nontumor-bearing mice, treatment of tumor-bearing animals with IL-1 was associated with a significant increase in marrow MnSOD activity. However, the duration of this elevated activity was reduced as tumor burden increased, and this reduction may have an impact on IL-1's ability to radioprotect tumor bearing animals, especially when tumor burden is large. In addition to cytokine-mediated responses, significant tumor-related influences on the marrow's antioxidant enzyme status were seen. Notably, it was observed that the presence of tumor was correlated with a marked suppression of antioxidant enzyme activity. Surprisingly, however, the pattern of enzyme suppression was found to differ between the two tumor models studied both in temporal onset and in the number of enzymes involved. In conclusion, the data obtained from these studies on tumor-bearing animals demonstrate that there are both cytokine-related and tumor-related influences which can effect the antioxidant enzyme status of the hematopoietic marrow-influences which may have the potential to alter the marrow's ability to tolerate free radical-generating events, both endogenous (i.e inflammation, infection) and exogenous (i.e. radiation, certain chemotherapeutic drugs) in origin.

[Malignant epidural cord compression].

Malignant epidural spinal cord compression (MSCC) may appear in 5-10% of adults and 3-5% of children with active malignant disease. Early diagnosis and treatment are imperative to prevent irreversible neurological damage below the level of cord compression. Unfortunately such procedures are often subjected to patient and/or doctor delay, when the emergency nature of MSCC is not understood. 3 women and 2 men, aged 17-74, are described, who illustrate both the variability of the presentation of MSCC and of its clinical course, and also problems related to imaging studies necessary to reach appropriate therapeutic decisions. These cases should increase physicians' awareness of the necessity for its early diagnosis and treatment. In addition, it is suggested that a multidisciplinary team approach be followed when MSCC is suspected (in accord with flow chart in Hebrew text).

Hodgkin disease in children: reduced tailored chemotherapy for stage I-II disease.

PURPOSE: Between January 1982 and January 1994, 46 children with stage I-II Hodgkin disease were treated with a tailored regimen to maintain a high cure rate while reducing toxicity. PATIENTS AND METHODS: Forty-six previously untreated children with stage I-II Hodgkin disease received four to six courses of cyclophosphamide, oncovin, procarbazine, and prednisone (COPP) alternating with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), tailored according to clinical response. Staging was based on various imaging modalities and gallium scan, but surgical staging was not performed. Radiotherapy was given only to bulky mediastinal disease. RESULTS: The median age at diagnosis was 13 years (range 4-18) and only 4 of 46 children had B symptoms. The majority (31 of 46) had stage II disease; 10 had bulky mediastinal disease. Nodular sclerosis histology predominated (32 of 46). Gallium scan was positive in 66% of the patients who were evaluated. Forty-three patients (93%) achieved complete remission after planned therapy. Thirty-six patients (78%) received chemotherapy alone, and 10 (22%) received combined-modality treatment. Fifteen children (33%) completed treatment with only four courses of COPP/ABVD. Overall freedom from relapse was 87% and overall survival was 98% with a median follow-up of 5 1/2 years. Long-term treatment-related morbidity was found mainly in patients receiving radiotherapy. CONCLUSION: Comprehensive clinical staging combined with tailored COPP/ABVD therapy according to response results in excellent disease control and may reduce toxicity.

Hormone receptors in initially excised versus recurrent intracranial meningiomas.

Intracranial meningiomas from 51 surgical patients consecutively treated during an 18-month period were evaluated for the presence of receptors to progesterone and estrogen. Thirty-eight patients underwent initial resection during this time and 13 underwent reoperation for recurrent disease. With positivity defined as receptor levels greater than 10 fmol/mg of cytosol protein, 84% of all the meningiomas were positive for progesterone receptors, whereas only 33% were positive for estrogen receptors. Among the recurrent meningiomas, 92% showed evidence of progesterone receptors and 54% of estrogen receptors; these figures were not significantly different from the corresponding incidence of 82% and 26%, respectively, among the initially excised tumors. However, the mean concentration of progesterone receptors in the recurrent tumor group was significantly higher when compared to the concentration in the initially excised group (p < 0.02). Twenty meningiomas (39%) were considered to be radiation-induced, since they were removed from patients who had received scalp irradiation during childhood. The incidence and concentration of receptors in the radiation-induced tumors were generally comparable to those in the spontaneous meningiomas. This study confirms previous reports of a high incidence of hormone receptors, mainly for progesterone, in meningiomas. In addition, it shows that in recurrent meningiomas these receptors persist and even increase. The results therefore support hormone treatment for nonresectable meningiomas, especially at recurrence.

An evaluation of lateral and medial transposition of the ovaries out of radiation fields.

BACKGROUND: Transposition of the ovaries is practiced in young women before possible radiation to the pelvic fields. In patients with carcinoma of the uterine cervix (Ca cervix), the ovaries are transposed laterally (LOT), whereas in patients with Hodgkin's disease (HD), they are usually transposed medially (MOT). Nevertheless, not all transposed ovaries are successfully protected. METHODS: Computed tomography was performed in 16 patients (7 Ca cervix and 9 HD) after ovarian transposition. The location of all identified ovaries was depicted on diagrams of the respective radiation fields for evaluation of the efficacy of LOT or MOT in relocating the ovaries out of these fields. RESULTS: All 13 ovaries transposed laterally were easily identified by CT, as compared with only 13 of 18 ovaries transposed medially (P = 0.2). Eleven of the 13 ovaries that underwent lateral transposition (6 of 7 patients) were located outside the radiation field. In contrast, only 3 of 13 identified ovaries in the medially transposed group were completely outside the radiation field (P = 0.005). Of the remainder, six were completely within the radiation field, and four were at least partially within the radiation field. CONCLUSIONS: Although LOT achieves its purpose in patients with Ca cervix, the use of MOT in patients with HD should be revised to achieve better protection of the ovaries from the effects of radiation. The authors suggest that LOT is preferred over MOT also in patients with HD if radiation of the pelvic lymph nodes is planned.

The effect of irradiation on expression of HLA class I antigens in human brain tumors in culture.

The immunosuppressive effects of irradiation are well known; however, under certain circumstances irradiation also augments the local immune response by as yet undefined mechanisms. Because of the importance of HLA class I antigen in immune regulation and the fact that killing of tumor cells by cytotoxic T cells is HLA antigen-restricted, the authors studied HLA class I antigen expression in eight glioblastomas multiforme, four meningiomas, and four medulloblastomas. Twenty fragments of each tumor specimen were placed in short-term cultures immediately after resection. For each tumor, control Sample 1 was not irradiated. Sample 2 was irradiated on Day 1, and two groups of the remaining pieces of each tumor (specimens 3 to 10) were irradiated on two consecutive days. Escalating radiation doses were given, starting at 200 cGy/day for Sample 2 up to 1000 cGy/day for Sample 10. The total dose range was 200 to 2000 cGy. Corresponding nonirradiated tumor fragments served as controls. Four hours after irradiation, each sample was processed and stained for HLA class I antigen using the immunoperoxidase technique. The tumor cells were intensely stained in nonirradiated glioblastomas and meningiomas, whereas no staining was observed in medulloblastomas. In four of the eight glioblastomas and in all four meningiomas, irradiation augmented HLA class I antigen expression compared to controls. This effect was dose-dependent and was maximum in the 1200 cGy-treated specimens. No change was observed in the other four glioblastomas or in the medulloblastomas. The data suggest that irradiation does not decrease and may even induce HLA class I antigen expression in some brain tumors. This may be one of the mechanisms by which immunotherapy operates after irradiation. Further studies are required to elucidate optimum radiation doses and fractionation as well as optimum timing of immunotherapy.

An unusual presentation of adenoid cystic carcinoma of the lacrimal gland.

Adenoid cystic carcinoma of the lacrimal gland is a highly malignant tumor usually characterized by symptoms of less than 1 year's duration. Computed tomographic (CT) findings of adjacent bony erosion or focal tumor sclerosis are also suggestive. We present a 57-year-old female patient who manifested symptoms of an enlarging mass in the right lacrimal fossa for almost 3 years prior to the establishment of the diagnosis of adenoid cystic carcinoma. CT findings during those years were not supportive for malignancy. The treatment included en bloc resection of the mass and adjacent bone and radiotherapy.

Hemispheric supratentorial low-grade astrocytoma.

The records of 57 patients who were operated on at the Beilinson Medical Center from 1970 through 1982 for supratentorial low-grade astrocytomas were reviewed. The management of these patients was correlated with survival. Our study demonstrates that a younger age at onset and a negative radionuclide uptake on isotope scan, were the most important factors associated with a better survival rate. Extensive tumor resection combined with radiation therapy also exercised a beneficial effect in prolonging survival.

Radiation-induced cerebellar glioblastoma multiforme subsequent to treatment of an astrocytoma of the cervical spinal cord.

A cerebellar glioblastoma multiforme was diagnosed in a 22-year-old woman. This originated in the zone adjacent to a field irradiated 14 years earlier after the removal of a noncontiguous astrocytoma of the spinal cord. The accepted criteria for radiation-induced tumors of the central nervous system are discussed.

Esophageal obstruction 14 years after treatment for Hodgkin's disease.

The incidence of late radiation injury of the esophagus is not precisely determined but, overall, the occurrence of clinically apparent damage is infrequent. The authors report a complete esophageal obstruction in a 21-year-old man, 14 years after chemo-radiation therapy for Hodgkin's lymphoma. Although endoscopy failed to demonstrate a gross morphologic abnormality, an esophagogram detected abnormal peristalsis and stricture, and esophageal manometry coupled with dynamic isotopic study clearly demonstrated a multilevel secondary neuronal damage. Data in the literature suggest that alteration in motility is by far the most frequent radiologic manifestation. Further prospective studies will probably clarify the actual incidence of late esophageal damage after chemo-radiation therapy.

Soluble histocompatibility antigen class I in breast cancer patients in relation to tumor burden.

Serum beta-2 microglobulin (B-2M) levels were studied in 365 breast cancer patients and 210 age-matched controls. The patients were divided into three groups: Group A, new patients at diagnosis; Group B, patients at follow-up; and Group C, metastatic patients. The mean B-2M of all breast cancer patients plus or minus one standard deviation (3.5 +/- 1.2; range, 1.1 to 5.9) was significantly higher than normal controls (1.29 +/- 0.49; range, 0.3 to 2.3; P less than 0.005). When the three patient groups were compared with each other, the mean B-2M level of Group A (3.0 +/- 1.5; range, 0.9 to 6.9) was similar to that of Group C (4.22 +/- 1.1; range, 2.0 to 6.4). The mean B-2M of both Groups A and C was significantly higher than that of Group B (2.38 +/- 1.02, range, 0.4 to 5.4; P less than 0.001). In Group A the mean B-2M decreased significantly after a 12-month period and reached the mean level of Group B but not that of normal controls. When patients in Group B were analyzed by their stage of disease at diagnosis, there was no significant difference between Stages I and II. There was a significant difference in the mean B-2M levels between Stages I and III. In relapsing patients, mean B-2M levels increased. These findings suggest that serum B-2M levels may reflect tumor burden, and even in patients at follow-up, occult tumor cells may activate the immune system.

Dactinomycin potentiation of radiation pneumonitis: a forgotten interaction.

No mention of dactinomycin potentiation of pulmonary radiation was found in a review of the literature of the past 12 years. Before that, this complication was well described and investigators had calculated that dactinomycin increased the toxic effect of lung radiation by a factor of 1.3 and reduced the radiation tolerance of the lung by at least 20%. An example of such a toxic effect is described in the treatment of a 7-year-old girl with lung metastases from Ewing's sarcoma. The chemotherapy protocol followed contained cyclophosphamide, vincristine, dactinomycin, adriamycin, cisplatinum, VP16, and radiotherapy. The treatment was associated with fatal pulmonary fibrosis following the reintroduction of dactinomycin after radiotherapy. Our experience suggests that there is clinical significance to this complication in sarcoma therapy when dactinomycin-containing protocols are used with radiation in the treatment of pulmonary metastases.