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1.
Cancer Med ; 9(22): 8676-8684, 2020 11.
Article in English | MEDLINE | ID: mdl-33068336

ABSTRACT

Ibrutinib-based combination therapy with high-dose methotrexate (HD-MTX) has recently shown clinical activity against relapse/refractory (R/R) primary central nervous system lymphoma (PCNSL). Herein, we report our real-world experience of treating 11 newly diagnosed PCNSL patients with the ibrutinib/MTX combination. HD-MTX was given at 3.5 g/m2 every 2-week for eight doses. Ibrutinib was held upon HD-MTX infusion until clearance and was administered daily post-induction until disease progression, intolerable toxicity, or death. Nine out of 11 patients completed the induction phase and received ibrutinib as maintenance therapy. An objective response rate (ORR) of 82% (9/11) was observed including complete response (64%) and partial response (18%). The median progression-free survival (PFS) was 7.4 months while the median overall survival (OS) was not reached. The ibrutinib/MTX combination was well tolerated in these treatment-naïve PCNSL patients with an acceptable safety profile. Moreover, the longitudinal analysis of cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) revealed that CSF ctDNA detection was closely associated with tumor response, and sustained tumor responses correlated with the clearance of ctDNA from the CSF. In sum, our data not only demonstrated the clinical benefit of the ibrutinib and HD-MTX combination regimen in treating newly diagnosed PCNSL patients in a real-world setting, but also highlighted the significance of liquid biopsy including CSF ctDNA in tracing tumor burden and assessing treatment response.


Subject(s)
Adenine/analogs & derivatives , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/drug therapy , Lymphoma/drug therapy , Off-Label Use , Piperidines/therapeutic use , Protein Kinase Inhibitors/therapeutic use , Adenine/adverse effects , Adenine/therapeutic use , Adult , Agammaglobulinaemia Tyrosine Kinase/antagonists & inhibitors , Agammaglobulinaemia Tyrosine Kinase/metabolism , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/enzymology , Central Nervous System Neoplasms/mortality , Disease Progression , Female , Humans , Lymphoma/enzymology , Lymphoma/mortality , Male , Methotrexate/therapeutic use , Middle Aged , Piperidines/adverse effects , Progression-Free Survival , Protein Kinase Inhibitors/adverse effects , Retrospective Studies , Time Factors
2.
Hematol Oncol ; 38(3): 277-283, 2020 Aug.
Article in English | MEDLINE | ID: mdl-32101329

ABSTRACT

Overexpression of bcl-2 and c-myc are defining features of double-expressor-lymphoma (DEL) but may also occur separately in patients with primary central nervous system lymphoma (PCNSL). Despite all progress in optimizing treatment regimen, there is lack of sufficient risk stratification models. Here, we first describe the relationship between DEL biology, the National Comprehensive Cancer Network International Prognostic Index (NCCN-IPI), treatment response, disease progression, and mortality in PCNSL. In this study, we determined c-myc and bcl-2 status immunohistochemically in samples of 48 patients with newly diagnosed PCNSL and followed these patients for a median interval of 6.2 years. Twelve, 18, and 17 patients harbored none, one, or both DEL features. Corresponding overall response rates after first-line therapy were strongly associated with DEL biology (100%, 42%, and 44% in patients with 0, 1, or 2 DEL features). Patients with one or both DEL features had a 5-fold and 13-fold higher 5-year risk of progression and/or death than patients without DEL features. These associations prevailed after adjusting for the NCCN-IPI. DEL improved the discriminatory capability of the NCCN-IPI (P = .0001). Furthermore, we could show that addition of DEL biology to the NCCN-IPI significantly improved the score's discriminatory potential both toward progression-free survival (increase in Harell's c = 0.15, P = .005) and overall survival (increase in Harell's c = 0.11, P = .029). In conclusion, DEL biology is a strong and simple-to-use predictor of adverse outcome in PCNSL. Addition of DEL to the NCCN-IPI improves its prognostic potential. Disease progression from PCNSL harboring both DEL features is invariably fatal. This defines a novel PCNSL patient subset with a great unmet need for improved therapy.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/metabolism , Central Nervous System Neoplasms/mortality , Immunohistochemistry/methods , Neoplasm Recurrence, Local/mortality , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Aged , Aged, 80 and over , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/pathology , Cytarabine/administration & dosage , Disease Progression , Female , Follow-Up Studies , Humans , Male , Methotrexate/administration & dosage , Middle Aged , Neoplasm Recurrence, Local/drug therapy , Neoplasm Recurrence, Local/metabolism , Neoplasm Recurrence, Local/pathology , Prognosis , Retrospective Studies , Risk Assessment , Survival Rate
3.
J Neurooncol ; 140(2): 427-434, 2018 Nov.
Article in English | MEDLINE | ID: mdl-30109672

ABSTRACT

OBJECTIVE: This prospective, randomized, controlled and open-label clinical trial sought to evaluate the tolerability and efficacy of the FTD regimen (fotemustine, teniposide and dexamethasone) compared to HD-MA therapy (high-dose methotrexate plus cytarabine) and to elucidate some biomarkers that influence outcomes in patients with newly diagnosed primary CNS lymphoma. METHODS: Participants were stratified by IELSG risk score (low versus intermediate versus high) and randomly assigned (1:1) to receive four cycles of FTD or HD-MA regimen. Both regimens were administered every 3 weeks and were followed by whole-brain radiotherapy. The primary endpoints were overall response rate (ORR), progression-free survival (PFS) and overall survival (OS). RESULTS: Between June 2012, and June 2015, 52 patients were enrolled, of whom 49 patients were randomly assigned and analyzed. Of the 49 eligible patients, no significant difference was observed in terms of ORR between FTD (n = 24) and HD-MA (n = 25) groups (88% versus 84%, respectively, P = 0.628). Neither the 2-year PFS nor the 3-year OS rate differed significantly between FTD and HD-MA groups (37% versus 39% for 2-year PFS, P = 0.984; 51% versus 46% for 3-year OS, P = 0.509; respectively). The HD-MA group showed more serious neutropenia (P = 0.009) than the FTD group. High Bcl-6 expression correlated with longer OS (P = 0.038). CONCLUSIONS: FTD chemotherapy appeared to be safe and effective for PCNSL patients. High Bcl-6 expression correlated with longer survival.


Subject(s)
Antineoplastic Agents/administration & dosage , Central Nervous System Neoplasms/drug therapy , Lymphoma/drug therapy , Adolescent , Adult , Aged , Antineoplastic Agents/adverse effects , Antineoplastic Combined Chemotherapy Protocols , Biomarkers, Tumor/metabolism , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/mortality , Cytarabine/administration & dosage , Cytarabine/adverse effects , Dexamethasone/administration & dosage , Dexamethasone/adverse effects , Female , Humans , Lymphoma/metabolism , Lymphoma/mortality , Male , Methotrexate/administration & dosage , Methotrexate/adverse effects , Middle Aged , Nitrosourea Compounds/administration & dosage , Nitrosourea Compounds/adverse effects , Organophosphorus Compounds/administration & dosage , Organophosphorus Compounds/adverse effects , Proto-Oncogene Proteins c-bcl-6/metabolism , Teniposide/administration & dosage , Teniposide/adverse effects , Treatment Outcome , Young Adult
4.
Zhonghua Bing Li Xue Za Zhi ; 47(1): 32-38, 2018 Jan 08.
Article in Chinese | MEDLINE | ID: mdl-29325248

ABSTRACT

Objective: To investigate the impact of clinicopathological features, gene rearrangements and protein expression of bcl-6, bcl-2, C-MYC and chemotherapy regime on the prognosis of patients with primary central nervous system diffuse large B-cell lymphoma (PCNS-DLBCL). Methods: Thirty-three cases of PCNS-DLBCL diagnosed from January 2006 to December 2016 at Zhejiang Cancer Hospital were collected. The expression of CD10, bcl-6, bcl-2, MUM1 and MYC were detected by immunohistochemical staining (IHC). The presence of EB virus was detected by in situ hybridization(EBER). Copy number variation (ICN) and translocation status of bcl-6, bcl-2 and C-MYC genes were detected by fluorescence in situ hybridization (FISH). The relationship between the above indexes and the prognosis was analyzed by univariate, bivariate survival analysis and multiple Cox hazard regression analysis. Results: The study included 33 patients of PCNS-DLBCL, without evidence of primary or secondary immunodeficient disease. Male to female ratio was 1.36∶1.00, and the average age was 56 years. Twenty cases had single lesion while 13 had multiple lesions. Deep brain involvement was seen in 12 cases. All patients underwent partial or total tumor resection. Five patients received whole brain post-surgery radiotherapy, nine patients received high-dose methotrexate (HD-MTX) based chemotherapy, and 12 patients received whole-brain radiotherapy combined with HD-MTX based chemotherapy. Severn patients received no further treatment and rituximab was used in 8 patients. According to the Hans model, 27 cases were classified as non-GCB subtypes (81.8%). Bcl-2 was positive in 25 cases (75.8%, 25/33) and highly expressed in 8 (24.2%). MYC was positive in 12 cases (36.4%) and double expression of bcl-2 and MYC was seen in 6 cases. EBER positive rate was 10.0%(3/30), all of which had multiple lesions. Two bcl-6 gene translocations and 3 amplifications were found in 28 patients. Two translocations, 3 ICN or with both bcl-2 gene translocation and ICN were found in 30 patients. Four ICNs of C-MYC gene were found in 28 patients. Elevated protein in cerebrospinal fluid (CSF) was found in 13 patients. LDH increased in 10 cases. Follow-up period was 2-90 months with the average survival time of (23.0±3.7) months and two-year survival rate of 39.0%. Univariate survival analysis showed that overexpression of bcl-2 protein (≥70%) and MYC protein (≥40%), bcl-2 gene abnormality (including copy number increase and translocation), C-MYC gene copy number increased were adverse factors for survival. C-MYC/ bcl-2 gene double hit was seen in 2 cases. Bivariate survival analysis found that of bcl-2/MYC protein double expression and bcl-2 and C-MYC genes double aberration were significantly associated with adverse outcomes. Cox multivariate risk regression analysis found that gender, cerebrospinal fluid protein increasing, and ICN of C-MYC gene were independent poor prognostic factors. DH-MTX based comprehensive chemotherapy was associated with better prognosis. Conclusions: Double hit at genomic level (copy number variations and gene rearrangements) and double protein expression of bcl-2 and C-MYC in PCNS-DLBCL are significantly associated with an adverse outcome. DH-MTX based comprehensive treatment may prolong the patient survival.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/mortality , Gene Rearrangement , Lymphoma, Large B-Cell, Diffuse/mortality , Proto-Oncogene Proteins c-bcl-2/metabolism , Proto-Oncogene Proteins c-myc/metabolism , Antimetabolites, Antineoplastic/therapeutic use , Brain Neoplasms/metabolism , Brain Neoplasms/mortality , Brain Neoplasms/pathology , Brain Neoplasms/therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/therapy , DNA Copy Number Variations , Female , Gene Dosage , Genes, bcl-2 , Genes, myc , Herpesvirus 4, Human/isolation & purification , Humans , In Situ Hybridization, Fluorescence , Interferon Regulatory Factors/metabolism , Lymphoma, Large B-Cell, Diffuse/genetics , Lymphoma, Large B-Cell, Diffuse/metabolism , Lymphoma, Large B-Cell, Diffuse/therapy , Male , Methotrexate/therapeutic use , Middle Aged , Neprilysin/metabolism , Prognosis , Proto-Oncogene Mas , Proto-Oncogene Proteins c-bcl-6/genetics , Proto-Oncogene Proteins c-bcl-6/metabolism , Survival Analysis , Survival Rate , Translocation, Genetic
5.
Arch Iran Med ; 18(9): 577-81, 2015 Sep.
Article in English | MEDLINE | ID: mdl-26317598

ABSTRACT

BACKGROUND: We assessed the outcome of high-dose methotrexate (HD-MTX) chemotherapy with or without radiotherapy (RT) in primary central nervous system lymphoma (PCNSL) patients. METHODS: Fifty-one HIV-negative patients with an average age of 50.3 years were treated with chemotherapy regimen included 2500 mg/m(2) MTX with Leucovorin rescue and 1.4 mg/m(2) vincristine (day two), which was administered every other week for 6 weeks. Only the patients who were younger than 60 years received RT. All patients received two cycles of 3000 mg/m(2) cytarabine at the end of the treatment for two successive days. RESULTS: Diffuse large B-cell lymphoma was the most common histologic subtype (90.2%), and twenty-six (51.0%)patients had multiple brain lesions. The median survival of patients who were younger than 60 years was 37 months. For patients who were older than 60 years, the median survival was 20 months. The median survival of men and women were 30 and 34 months, respectively. There was no significant difference in survival of patients in terms of age and sex. Overall, sixteen patients (31%) out of fifty-one patients died, five of them were older than 60 years and eleven were younger than 60 years. Twenty-five (49%) of all patients experienced relapse, and 10 (40%) of them died after rechemotherapy. CONCLUSIONS: The base of our chemotherapy regimen was HD-MTX as the regular doses of MTX cannot penetrate the blood brain barrier (BBB). Our results indicated that the combination of HD-MTX with RT may not influence the outcome of PCNSL; thus, RT cannot be the first line therapy.


Subject(s)
Antimetabolites, Antineoplastic/administration & dosage , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/therapy , Lymphoma/mortality , Lymphoma/therapy , Methotrexate/administration & dosage , Antineoplastic Agents, Phytogenic/therapeutic use , Cytarabine/therapeutic use , Dose-Response Relationship, Drug , Female , Humans , Leucovorin/therapeutic use , Male , Middle Aged , Radiotherapy, Adjuvant , Retrospective Studies , Vincristine/therapeutic use
6.
Neuro Oncol ; 17(7): 1016-21, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25817328

ABSTRACT

BACKGROUND: We investigated the prognostic significance of B-cell differentiation status and common B-cell differentiation markers in a post hoc analysis of 119 patients with primary CNS lymphoma (PCNSL) homogeneously receiving high-dose methotrexate (HDMTX)-based chemotherapy within the prospective G-PCNSL-SG1 trial. METHODS: We evaluated protein expression of B-cell lymphoma 2 (BCL2), BCL6, CD10, and multiple myeloma oncogene 1/interferon regulatory factor 4 (MUM1/IRF4) by immunohistochemistry and analyzed the association with survival. RESULTS: The median follow-up of all patients was 67.5 months. Median progression-free survival (PFS) was 10.61 months (95% CI: 4.23-17.00). Median overall survival (OS) was 28.85 months (95% CI: 17.96-39.73). Eighty-nine tumors expressed BCL2 (92.7%), 24 (20.5%) expressed CD10, 60 (54.1%) expressed BCL6, and 87 (79.0%) expressed MUM1/IRF4. On the basis of the Hans algorithm, 80 tumors (73.4%) were classified to the non-germinal center B group, suggesting a post-germinal center origin of PCNSL. Expression of BCL6 (cutoff point 30%), but none of the other markers, was associated with shorter PFS (P = .047) and OS (P = .035). On multivariate analysis, BCL6 expression was associated with shorter PFS (hazard ratio: 1.95, 95% CI: 1.22-3.12, P = .005) but not OS (hazard ratio: 1.85, 95% CI: 0.71-4.80, P = .21). Classification according to Hans algorithm and expression status of the single B-cell markers BCL2, CD10, and MUM1/IRF4 did not correlate with prognosis. CONCLUSION: The findings are limited by the fact that only 23% of all G-PCNSL-SG1 patients could be included in the analysis. If validated in an independent cohort, BCL6 may assume clinical relevance as an unfavorable prognostic biomarker in PCNSL.


Subject(s)
Central Nervous System Neoplasms/diagnosis , Lymphoma, B-Cell/diagnosis , Proto-Oncogene Proteins c-bcl-6/metabolism , Adult , Aged , Biomarkers/metabolism , Central Nervous System Neoplasms/metabolism , Central Nervous System Neoplasms/mortality , Female , Humans , Interferon Regulatory Factors/metabolism , Kaplan-Meier Estimate , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/mortality , Male , Middle Aged , Neprilysin/metabolism , Prognosis , Proto-Oncogene Proteins c-bcl-2/metabolism
7.
J Natl Cancer Inst ; 106(8): dju166, 2014 Aug.
Article in English | MEDLINE | ID: mdl-25178694

ABSTRACT

BACKGROUND: Adolescents and young adults (AYAs; aged 15-39 years) have inferior survival in comparison with younger (aged 0-14 years) cancer patients. Impact of care at specialized centers such as National Cancer Institute-designated Comprehensive Cancer Centers (NCICCC) for AYAs of all ages or the Children's Oncology Group (COG) for AYAs aged 15 to 21 years with central nervous system (CNS) tumors remains unstudied. METHODS: We constructed a cohort of 560 children and 784 AYAs with CNS tumors reported to the Los Angeles cancer registry from 1998 to 2008. Cox and logistic regression models were used, with two-sided P values from Wald χ(2) tests. RESULTS: In Cox regression analysis restricted to World Health Organization (WHO) grade II tumors, patients of all ages saw worse outcome if not treated at NCICCC/COG sites (non-NCICCC/COG vs NCICCC/COG: hazard ratio [HR] =1.73; 95% confidence interval [CI] = 1.09 to 2.72). Furthermore, the worse outcome for AYAs compared with children (HR = 1.90; 95% CI = 1.21 to 2.98; P = .005) was abrogated (HR = 1.35; 95% CI = 0.79 to 2.29; P = .27) by care at NCICCC/COGs. Those less likely to receive care at NCICCC/COG sites included young AYAs (aged 15-21 years vs children: odds ratio [OR] = 0.23; 95% CI = 0.11 to 0.48; P < .001) and older AYAs (aged 22-39 years) with low socioeconomic status (OR = 0.39; 95% CI = 0.17 to 0.89; P = .02), public/no insurance (OR = 0.30; 95% CI = 0.12 to 0.71; P < .01), and distance to care greater than 5 miles (OR = 0.29; 95% CI = 0.15 to 0.57; P < .001). CONCLUSIONS: Population-based data reveal that care at NCICCC/COG sites mitigates inferior outcome in AYAs with WHO grade II CNS tumors compared with children. Compared with children, AYAs are less likely to receive care at NCICCC/COGs. Insurance, socioeconomic status, and distance serve as barriers to care at NCICCCs for older AYAs.


Subject(s)
Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/therapy , Health Services Accessibility , Healthcare Disparities/statistics & numerical data , Insurance, Health , Social Class , Adolescent , Adult , Age Factors , Cancer Care Facilities , Central Nervous System Neoplasms/ethnology , Central Nervous System Neoplasms/pathology , Child , Child, Preschool , Cohort Studies , Female , Humans , Infant , Logistic Models , Los Angeles/epidemiology , Male , Neoplasm Grading , Odds Ratio , Prognosis , Proportional Hazards Models , Registries , Survival Analysis , Young Adult
8.
Am J Ind Med ; 56(11): 1262-71, 2013 Nov.
Article in English | MEDLINE | ID: mdl-24009194

ABSTRACT

BACKGROUND: Nuclear workers may be exposed to a variety of chemical hazards, in addition to radiation. We examined the effect of chemical exposures on cancer mortality among French uranium processing workers at the AREVA NC Pierrelatte facility. METHODS: A cohort of 2,897 uranium processing workers employed for at least 6 months was followed from 1968 through 2006. Exposure to uranium and potentially carcinogenic chemicals was assessed with a plant-specific job-exposure matrix. Mortality hazard ratios (HRs) for cancers of the lung, lymphohematopoietic system, kidney and bladder, brain and central nervous system (BCNS), and prostate were estimated for each specific chemical exposure, with Cox regression models stratified for sex and calendar period and adjusted for socioeconomic status. Additional adjustments enabled us to examine the effect of co-exposure to uranium and other chemicals. RESULTS: Exposure to aromatic solvents was associated with increased risk of BCNS malignancies after adjustment for other chemicals (HR=6.53, 95% CI=1.14-37.41; n=6) and for other chemicals and uranium (HR=7.26, 95% CI=0.90-58.19) in the annual exposure status model. Selected groups of lymphohematopoietic cancers were found associated with solvent exposure. Inconclusive results were found regarding chromium (VI) exposure, since only 2 workers died from lung cancer among 109 exposed. CONCLUSION: Based on our pilot study, it seemed important to take into account chemical exposures in the analyses of cancer mortality among French uranium processing workers.


Subject(s)
Extraction and Processing Industry , Hazardous Substances/poisoning , Neoplasms, Radiation-Induced/mortality , Neoplasms/mortality , Occupational Diseases/mortality , Occupational Exposure , Uranium/poisoning , Asbestos/poisoning , Carcinogens , Central Nervous System Neoplasms/mortality , Chromium Compounds/poisoning , Cohort Studies , Female , France , Hematologic Neoplasms/mortality , Humans , Kidney Neoplasms/mortality , Longitudinal Studies , Lung Neoplasms/mortality , Male , Middle Aged , Proportional Hazards Models , Prostatic Neoplasms/mortality , Solvents/poisoning , Urinary Bladder Neoplasms/mortality
9.
J Clin Oncol ; 31(25): 3061-8, 2013 Sep 01.
Article in English | MEDLINE | ID: mdl-23569323

ABSTRACT

PURPOSE: Concerns regarding neurocognitive toxicity of whole-brain radiotherapy (WBRT) have motivated development of alternative, dose-intensive chemotherapeutic strategies as consolidation in primary CNS lymphoma (PCNSL). We performed a multicenter study of high-dose consolidation, without WBRT, in PCNSL. Objectives were to determine: one, rate of complete response (CR) after remission induction therapy with methotrexate, temozolomide, and rituximab (MT-R); two, feasibility of a two-step approach using high-dose consolidation with etoposide plus cytarabine (EA); three, progression-free survival (PFS); and four, correlation between clinical and molecular prognostic factors and outcome. PATIENTS AND METHODS: Forty-four patients with newly diagnosed PCNSL were treated with induction MT-R, and patients who achieved CR received EA consolidation. We performed a prospective analysis of molecular prognostic biomarkers in PCNSL in the setting of a clinical trial. RESULTS: The rate of CR to MT-R was 66%. The overall 2-year PFS was 0.57, with median follow-up of 4.9 years. The 2-year time to progression was 0.59, and for patients who completed consolidation, it was 0.77. Patients age > 60 years did as well as younger patients, and the most significant clinical prognostic variable was treatment delay. High BCL6 expression correlated with shorter survival. CONCLUSION: CALGB 50202 demonstrates for the first time to our knowledge that dose-intensive consolidation for PCNSL is feasible in the multicenter setting and yields rates of PFS and OS at least comparable to those of regimens involving WBRT. On the basis of these encouraging results, an intergroup study has been activated comparing EA consolidation with myeloablative chemotherapy in this randomized trial in PCNSL, in which neither arm involves WBRT.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/drug therapy , Immunotherapy , Lymphoma, Non-Hodgkin/drug therapy , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Central Nervous System Neoplasms/mortality , Child , DNA-Binding Proteins/analysis , Disease-Free Survival , Female , Humans , Lymphoma, Non-Hodgkin/mortality , Male , Middle Aged , Prognosis , Prospective Studies , Proto-Oncogene Proteins c-bcl-6
10.
J Invest Dermatol ; 126(12): 2658-63, 2006 Dec.
Article in English | MEDLINE | ID: mdl-16946711

ABSTRACT

Vitiligo, an autoimmune skin disorder, was evaluated in 49 metastatic melanoma patients treated with an immunotherapy regimen of maintenance biotherapy (mBT) following induction concurrent biochemotherapy (cBCT). Patients receiving mBT demonstrated a stable or better response to cBCT. The mBT regimen consisted of outpatient subcutaneous injections of low-dose IL-2 (1 MIU/m(2)) 5/7 days weekly, GM-CSF (125 mcg/m(2)) 14 days monthly, and high-dose pulses of in-patient continuous infusion decrescendo IL-2 (54 MIU/m(2)) over 48 hours monthly for the first 6 months and every 2 months thereafter. The majority of patients had poor prognostic features. Forty-nine patients were without evidence of vitiligo at the start of mBT. Of these, 21 patients (43%) developed vitiligo during mBT and had a median overall survival from the start of mBT of 18.2 months (95% CI, 12.3-N/A) compared to 8.5 months (95%CI <6.7-12.7) for 28 non-vitiligo patients (P=0.027). Six of 21 vitiligo patients (29%) expressed IgG antibody titers to tyrosinase-related protein-2 compared to four of 28 non-vitiligo patients (14%) (P=NS). The development of vitiligo in metastatic melanoma patients on cBCT/mBT immunotherapy correlates with a better therapeutic outcome.


Subject(s)
Biological Therapy/adverse effects , Central Nervous System Neoplasms/secondary , Central Nervous System Neoplasms/therapy , Melanoma/secondary , Melanoma/therapy , Vitiligo/etiology , Adolescent , Adult , Aged , Antibodies/blood , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Central Nervous System Neoplasms/immunology , Central Nervous System Neoplasms/mortality , Female , Granulocyte-Macrophage Colony-Stimulating Factor/administration & dosage , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , Infusion Pumps , Injections, Subcutaneous , Interleukin-2/administration & dosage , Interleukin-2/therapeutic use , Male , Melanoma/immunology , Melanoma/mortality , Membrane Proteins/immunology , Middle Aged , Peptide Fragments/immunology , Survival Analysis
11.
J Neurosurg ; 102 Suppl: 207-13, 2005 Jan.
Article in English | MEDLINE | ID: mdl-15662812

ABSTRACT

OBJECT: The authors conducted a study to record more detailed information about the natural course and factors predictive of outcome following gamma knife surgery (GKS) for cavernous hemangiomas. METHODS: One hundred twelve patients with brain cavernous hemangiomas underwent GKS between 1993 and 2000. The median prescription dose was 16 Gy. One hundred seven patients were followed for a median of 48 months (range 6-114 months). The rebleeding rate was 1.6%, which is not significantly different with that prior to radiosurgery (2%). An increase in volume was observed in 1.8% of cases and a decrease in 45%. Perilesional edema was detected in 27% of patients, which, together with the rebleeding, caused a transient morbidity rate of 20.5% and permanent morbidity rate of 4.5%. Before radiosurgery 39% of patients suffered from epilepsy and this improved in 45% of them. Two patients with brainstem cavernous hemangiomas died due to rebleeding. Rebleeding was more frequent in female middle-aged patients with a history of bleeding, a larger lesion volume, and a prescription dose below 13 Gy. Edema after GKS occurred more frequently in patients who had surgery, a larger lesion volume, and in those in whom the prescription dose was more than 13 Gy. CONCLUSIONS: Gamma knife surgery of cavernous hemangiomas can produce an acceptable rate of morbidity, which can be reduced by using a lower margin dose. Lesion regression was observed in many patients. Radiosurgery seems to remain a suitable treatment modality in carefully selected patients.


Subject(s)
Central Nervous System Neoplasms/surgery , Hemangioma, Cavernous, Central Nervous System/surgery , Adolescent , Adult , Aged , Aged, 80 and over , Basal Ganglia/pathology , Basal Ganglia/surgery , Brain Stem/pathology , Brain Stem/surgery , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/pathology , Cerebellum/pathology , Cerebellum/surgery , Female , Follow-Up Studies , Frontal Lobe/pathology , Frontal Lobe/surgery , Hemangioma, Cavernous, Central Nervous System/mortality , Hemangioma, Cavernous, Central Nervous System/pathology , Humans , Magnetic Resonance Imaging , Male , Middle Aged , Occipital Lobe/pathology , Occipital Lobe/surgery , Parietal Lobe/pathology , Parietal Lobe/surgery , Postoperative Complications/mortality , Radiation Dosage , Survival Rate , Temporal Lobe/pathology , Temporal Lobe/surgery , Thalamus/pathology , Thalamus/surgery
12.
Semin Oncol Nurs ; 20(4): 253-9, 2004 Nov.
Article in English | MEDLINE | ID: mdl-15612601

ABSTRACT

OBJECTIVES: To provide an overview of the management of central nervous system tumors with radiation therapy. DATA SOURCES: Book chapters, research articles, and review articles. CONCLUSION: Radiation therapy plays a primary role in the treatment and management of primary and metastatic central nervous system tumors. Radiation therapy may be administered in several modalities with either curative or palliative intent. IMPLICATIONS FOR NURSING PRACTICE: A general understanding of the treatment of central nervous system tumors with radiation, and the management of potential side effects can help to provide optimal care and improved quality of life for the patient.


Subject(s)
Central Nervous System Neoplasms/radiotherapy , Brachytherapy , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/nursing , Combined Modality Therapy , Humans , Hyperthermia, Induced , Nurse's Role , Oncology Nursing , Palliative Care , Prognosis , Radiation Oncology/methods , Radiosurgery , Survival Rate , Treatment Outcome
13.
J Neurosurg ; 98(6): 1170-4, 2003 Jun.
Article in English | MEDLINE | ID: mdl-12816259

ABSTRACT

OBJECT: The incidence of pilocytic astrocytomas and the rate of patient survival were analyzed in a population-based study in the canton of Zürich, Switzerland. METHODS: Between 1980 and 1994, 987 astrocytic and oligodendroglial tumors were diagnosed, of which 55 (5.5%) were pilocytic astrocytomas. The incidence rate, adjusted to the World Standard Population, was 4.8 per 1 million per year. The mean age at clinical diagnosis was 19.6 +/- 12.7 years, and the male/female ratio was 1.12. The most frequent tumor sites were the cerebellum (40%), followed by supratentorial locations (35%), the optic pathway and hypothalamus (11%), and the brainstem (9%). The mean follow-up period was 12 years. Observed survival rates were 100% at 5 years and 95.8% at 10 years after diagnosis (relative survival rate at 10 years: 96.8%). Seven patients (13%) received postoperative radiotherapy, but this did not significantly affect survival. In all patients the tumors were histologically classified as WHO Grade I, except in two patients who had anaplastic pilocytic astrocytoma (Grade III), one of whom died after 7 years, whereas the other was still alive after 10 years. CONCLUSIONS: This population-based study shows that, because of the benign biological behavior of pilocytic astrocytomas and advances in microneurosurgery, the survival rates for patients with these tumors are excellent, regardless of postoperative radiotherapy.


Subject(s)
Astrocytoma/epidemiology , Central Nervous System Neoplasms/epidemiology , Adult , Astrocytoma/mortality , Astrocytoma/surgery , Catchment Area, Health , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/surgery , Cerebellum/surgery , Female , Follow-Up Studies , Humans , Hypothalamus/surgery , Incidence , Male , Neoplasm Staging , Population Surveillance , Registries , Retrospective Studies , Survival Rate , Switzerland/epidemiology
14.
Clin Cancer Res ; 9(3): 1063-9, 2003 Mar.
Article in English | MEDLINE | ID: mdl-12631608

ABSTRACT

PURPOSE: The purpose of this study was to investigate the histogenetic origin of primary central nervous system lymphoma (PCNSL) with respect to stage of B-cell differentiation and to identify prognostic markers in a cohort of patients with PCNSL treated with i.v. high-dose methotrexate therapy. EXPERIMENTAL DESIGN: This study included 33 patients with PCNSL treated with high-dose i.v. methotrexate at the Massachusetts General Hospital for whom archival tumor tissue was available. All 33 patients tested negative for HIV. The lymphomas were morphologically subclassified according to the Kiel system, as modified in the WHO classification. Immunohistochemistry for the following antigens was performed: BCL-6; BCL-2; MUM1; CD10; vs38c; CD138; CD44; p16; and p53. Fluorescence in situ hybridization and multiplex PCR for CDKN2A/p16 were also performed. RESULTS: There were 17 women and 16 men enrolled, with a median age of 60 years. All tumors were diffuse large B-cell lymphomas. Of the 23 cases that could be subclassified, 22 were centroblastic, and 1 was immunoblastic. Twenty-six of 33 tumors were BCL-6+, 6 of 32 tumors were CD10+, 27 of 29 tumors were BCL-2+, 31 of 32 tumors were MUM1+, 11 of 31 tumors were CD44+, 4 of 33 tumors were vs38c+, and 0 of 32 tumors were CD138+. There were 18 of 32 (56%) complete responses and 8 of 32 (25%) partial responses to methotrexate, whereas 6 of 33 (18%) progressed during treatment. Ten patients died of disease. Expression of BCL-6 was significantly associated with longer overall survival (P = 0.002; median survival, 101 versus 14.7 months, with approximately 95% lower confidence limits of 41.7 and 8.8 months, respectively). CONCLUSIONS: In this group of 33 patients with PCNSL, expression of BCL-6 was significantly associated with longer overall survival. BCL-6 warrants further investigation as a potentially important prognostic marker in this disease.


Subject(s)
Central Nervous System Neoplasms/metabolism , DNA-Binding Proteins/biosynthesis , Lymphoma/metabolism , Proto-Oncogene Proteins/biosynthesis , Transcription Factors/biosynthesis , Adult , Aged , Aged, 80 and over , Algorithms , Cell Differentiation , Central Nervous System Neoplasms/drug therapy , Central Nervous System Neoplasms/genetics , Central Nervous System Neoplasms/mortality , Cohort Studies , Cyclin-Dependent Kinase Inhibitor p16/biosynthesis , DNA-Binding Proteins/genetics , Female , Humans , Hyaluronan Receptors/biosynthesis , Immunohistochemistry , In Situ Hybridization, Fluorescence , Interferon Regulatory Factors , Lymphoma/drug therapy , Lymphoma/genetics , Lymphoma/mortality , Male , Membrane Glycoproteins/biosynthesis , Methotrexate/therapeutic use , Middle Aged , Neprilysin/biosynthesis , Polymerase Chain Reaction , Prognosis , Proteoglycans/biosynthesis , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins c-bcl-2/biosynthesis , Proto-Oncogene Proteins c-bcl-6 , Syndecan-1 , Syndecans , Transcription Factors/genetics , Treatment Outcome , Tumor Suppressor Protein p53/biosynthesis
15.
Am J Ind Med ; 33(3): 247-55, 1998 Mar.
Article in English | MEDLINE | ID: mdl-9481423

ABSTRACT

The risk of cancer of the central nervous system (CNS) by industry and occupation was investigated with a case-control analysis of the death certificates of 28,416 cases and 113,664 controls, selected from over 4.5 million deaths in 24 U.S. states between 1984 and 1992. Industries showing consistent increases in risk by gender and race included textile mills, paper mills, printing and publishing industries, petroleum refining, motor vehicles manufacturing, telephone and electric utilities, department stores, health care services, elementary and secondary schools, and colleges and universities. CNS cancer risk was increased for administrators in education and related fields, secondary school teachers, and other education- and health-related occupations. The application of job-exposure matrices to the industry/occupation combinations revealed a modest increase in risk for potential contact with the public at work and exposure to solvents. Occupational exposure to electromagnetic fields (EMF) was not associated with CNS cancer, although an association was observed with a few EMF-related occupations and industries. Agricultural exposures were associated with significant risk increases among white women and white men. Further work is required to investigate in more detail specific occupational exposures or possible confounders responsible for the observed associations.


Subject(s)
Central Nervous System Neoplasms/mortality , Occupational Diseases/mortality , Administrative Personnel/statistics & numerical data , Agriculture/statistics & numerical data , Case-Control Studies , Central Nervous System Neoplasms/epidemiology , Confounding Factors, Epidemiologic , Death Certificates , Electricity/adverse effects , Electromagnetic Fields/adverse effects , Extraction and Processing Industry/statistics & numerical data , Female , Health Care Sector/statistics & numerical data , Humans , Male , Middle Aged , Motor Vehicles/statistics & numerical data , Occupational Diseases/epidemiology , Occupational Exposure , Paper , Petroleum/statistics & numerical data , Printing/statistics & numerical data , Publishing/statistics & numerical data , Racial Groups , Risk Factors , Schools/statistics & numerical data , Sex Factors , Solvents/adverse effects , Teaching/statistics & numerical data , Telephone/statistics & numerical data , Textile Industry/statistics & numerical data , United States/epidemiology , Universities/statistics & numerical data , White People
16.
Buenos Aires; s.n; 1978. 171 p. ilus.
Monography in Spanish | BINACIS | ID: biblio-1205500

ABSTRACT

1) Pensamos que nuestra experiencia reafirma una vez más la importancia de difundir a todo nivel la existencia de esta patología. 2) Consideramos fundamental que la asistencia de los niños con tumores sea encarada precozmente y por un equipo que agrupe a diversos especialistas, con medios, experiencia y planes preestablecidos, superando todo individualismo. 3) Incluímos en esta casuística muchos tumores histológicamente benignos, pero que por su localización y/o evolución pueden comportarse como malignos. 4) Con respecto a los tumores del SNC, la presentación en uno y otro sexo no mostró diferencias significativas. 5) La edad de los pacientes, revela un franco predominio en la segunda infancia. 6) Como es habitual en estos casos, la localización de los tumores mostró un ligero predominio de los infratentoriales sobre los supratentoriales. 7) Con respecto al diagnóstico histológico, se observó una mayor frecuencia de astroblastomas, craneofaringiomas y meduloblastomas. 8) Dado que este tipo de lesiones suele tener localizaciones inabordables, es importante contar con planes de estudio adecuados, dentro de los cuales, en la actualidad la tomografía computada ocupa un destacadísimo lugar. 9) Considerando el importante papel que juega la competencia inmune en esta patología, consideramos que todo centro oncológico debe contar con un laboratorio de inmunología que permita el estudio y seguimiento adecuado de estos enfermos. 10) La oncología pediátrica debe ser una realidad y el manejo, planes, personal, terapeutas, equipos y medios deben ser pediátricos y no diseñados para adultos y luego adaptados a los niños, hecho que significaría negar a la pediatría como entidad... (TRUNCADO)


Subject(s)
Male , Female , Humans , Infant, Newborn , Infant , Child , Biopsy , Cyclophosphamide/administration & dosage , Cyclophosphamide/adverse effects , Cyclophosphamide/therapeutic use , Cobalt/therapeutic use , Diagnostic Imaging , Clinical Evolution , Physical Examination , Neurologic Examination , Family/psychology , Antibody Formation , Immunity, Cellular , Immunotherapy , Methotrexate/administration & dosage , Methotrexate/adverse effects , Methotrexate/therapeutic use , Central Nervous System Neoplasms/surgery , Central Nervous System Neoplasms/classification , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/psychology , Central Nervous System Neoplasms/radiotherapy , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/drug therapy , Patients/psychology , Prednisone/administration & dosage , Prednisone/adverse effects , Prednisone/therapeutic use , Drug Therapy, Combination , Graft vs Host Reaction , Follow-Up Studies , Immune System , Survivorship , Immunologic Tests , Psychological Tests , Vincristine/administration & dosage , Vincristine/adverse effects , Vincristine/therapeutic use
17.
Buenos Aires; s.n; 1978. 171 p. ilus. (83544).
Monography in Spanish | BINACIS | ID: bin-83544

ABSTRACT

1) Pensamos que nuestra experiencia reafirma una vez más la importancia de difundir a todo nivel la existencia de esta patología. 2) Consideramos fundamental que la asistencia de los niños con tumores sea encarada precozmente y por un equipo que agrupe a diversos especialistas, con medios, experiencia y planes preestablecidos, superando todo individualismo. 3) Incluímos en esta casuística muchos tumores histológicamente benignos, pero que por su localización y/o evolución pueden comportarse como malignos. 4) Con respecto a los tumores del SNC, la presentación en uno y otro sexo no mostró diferencias significativas. 5) La edad de los pacientes, revela un franco predominio en la segunda infancia. 6) Como es habitual en estos casos, la localización de los tumores mostró un ligero predominio de los infratentoriales sobre los supratentoriales. 7) Con respecto al diagnóstico histológico, se observó una mayor frecuencia de astroblastomas, craneofaringiomas y meduloblastomas. 8) Dado que este tipo de lesiones suele tener localizaciones inabordables, es importante contar con planes de estudio adecuados, dentro de los cuales, en la actualidad la tomografía computada ocupa un destacadísimo lugar. 9) Considerando el importante papel que juega la competencia inmune en esta patología, consideramos que todo centro oncológico debe contar con un laboratorio de inmunología que permita el estudio y seguimiento adecuado de estos enfermos. 10) La oncología pediátrica debe ser una realidad y el manejo, planes, personal, terapeutas, equipos y medios deben ser pediátricos y no diseñados para adultos y luego adaptados a los niños, hecho que significaría negar a la pediatría como entidad... (TRUNCADO)(AU)


Subject(s)
Humans , Male , Female , Infant, Newborn , Infant , Child, Preschool , Child , Adolescent , Central Nervous System Neoplasms/classification , Central Nervous System Neoplasms/diagnosis , Central Nervous System Neoplasms/pathology , Central Nervous System Neoplasms/mortality , Central Nervous System Neoplasms/psychology , Central Nervous System Neoplasms/therapy , Central Nervous System Neoplasms/surgery , Central Nervous System Neoplasms/radiotherapy , Central Nervous System Neoplasms/drug therapy , Physical Examination , Neurologic Examination , Diagnostic Imaging , Biopsy , Immunologic Tests , Immunity, Cellular , Antibody Formation , Immune System , Graft vs Host Reaction , Immunotherapy , Cobalt/therapeutic use , Drug Therapy, Combination , Cyclophosphamide/administration & dosage , Cyclophosphamide/therapeutic use , Cyclophosphamide/adverse effects , Vincristine/administration & dosage , Vincristine/therapeutic use , Vincristine/adverse effects , Methotrexate/administration & dosage , Methotrexate/therapeutic use , Methotrexate/adverse effects , Prednisone/administration & dosage , Prednisone/therapeutic use , Prednisone/adverse effects , Patients/psychology , Family/psychology , Psychological Tests , Follow-Up Studies , Clinical Evolution , Survivorship
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