Treatment Of Other Tumors Research Articles

Tamoxifen non-estrogen receptor mediated molecular targets

Recent experimental studies revealing new biological effects of tamoxifen on tumor cells both expressing and not expressing different types of estrogen receptors (ERα and ERβ) show new aspects of a seemingly well known agent. This review describes tamoxifen targets, the blocking of which leads to inhibition of tumor cell growth and angiogenesis, stimulation of programmed cell death (apoptosis, autophagia and necrosis), inhibition of multidrug resistance, invasion and metastasis. Since outcomes of tamoxifen action on cells are prognostically good from the point of view of both tumor growth/metastasis inhibition and tumor response to drug therapy, the authors believe this is an extremely important addition to tamoxifen antiestrogenic effect. Arguments are provided to consider the strategy of long-term tamoxifen treatment proposed by Professor Craig V. Jordan in the 1970s that is also applicable to the treatment of other tumors. This is, first of all, the fact that expression of estrogen receptor-beta that can also be targeted by tamoxifen therapy in solid tumors of practically all known sites and histologies. The authors believe that molecular biological screening of patients with respect to expression of tamoxifen cellular targets other than ERα and ERβ is needed to use to the full all tamoxifen biological activities other than modulation of estrogen receptors during long-term adjuvant therapy for cancers of various sites.

Tamoxifen non-estrogen receptor mediated molecular targets

Recent experimental studies revealing new biological effects of tamoxifen on tumor cells both expressing and not expressing different types of estrogen receptors (ERα and ERβ) show new aspects of a seemingly well known agent. This review describes tamoxifen targets, the blocking of which leads to inhibition of tumor cell growth and angiogenesis, stimulation of programmed cell death (apoptosis, autophagia and necrosis), inhibition of multidrug resistance, invasion and metastasis. Since outcomes of tamoxifen action on cells are prognostically good from the point of view of both tumor growth/metastasis inhibition and tumor response to drug therapy, the authors believe this is an extremely important addition to tamoxifen antiestrogenic effect. Arguments are provided to consider the strategy of long-term tamoxifen treatment proposed by Professor Craig V. Jordan in the 1970s that is also applicable to the treatment of other tumors. This is, first of all, the fact that expression of estrogen receptor-beta that can also be targeted by tamoxifen therapy in solid tumors of practically all known sites and histologies. The authors believe that molecular biological screening of patients with respect to expression of tamoxifen cellular targets other than ERα and ERβ is needed to use to the full all tamoxifen biological activities other than modulation of estrogen receptors during long-term adjuvant therapy for cancers of various sites.

Le traitement médical des GIST : du palliatif au curatif

Since the discovery of the remarkable efficacy of Imatinib in metastatic GIST at the end of the last century, dozens of studies have further advanced the management of this disease. Considerable progress has been made in the last dozen years thanks to this tyrosine kinase inhibitor, not only in terms of the definition and classification of these tumors, but also in our knowledge of their molecular mechanisms and in the therapeutic management of patients with this rare disease. Treatment of GIST now serves as a model--or even the model--for targeted therapy in oncology. Over 90% of relapsing patients benefit from first-line Imatinib therapy, with a median survival time of 60 months compared to only 18 months before the Imatinib era. This revolution has transformed the outlook of patients with metastatic disease. It has also led to a review of medical and surgical attitudes and prolonged the management of these patients, most of whom will live normally with dormant residual disease. Imatinib should not be interrupted but continued until the tumor progresses or intolerable adverse effects occur. Early studies showed that adjuvant Imatinib therapy given for one year after resection of localized GIST reduced the recurrence rate by 70% in patients with a significant risk of relapse. Administered for three consecutive years, Imatinib even had a significant impact on survival. Despite these results, the optimal duration of Imatinib therapy in the adjuvant setting remains to be defined, as patients who relapse after Imatinib discontinuation remain remarkably sensitive to the same drug In addition to Imatinib (and sunitinib, that has also proven effective in metastatic disease), several other tyrosine kinase inhibitors are in the pipeline. Coupling of these drugs with the GIST molecular profile opens up promising perspectives for the future. Successive advances in GIST therapy have created significant opportunities for the treatment of other tumors.

Reversible Cardiomyopathy Associated with Sunitinib and Sorafenib

To the Editor: Tyrosine kinase inhibitors with potent properties against vascular endothelial growth factor (VEGF) signaling pathway (VSP inhibitors) are effective antitumor agents in metastatic renal-cell carcinoma and are now increasingly used in the treatment of other tumors.1 Although VSP inhibitors have been associated with cardiomyopathy, the nature of this side effect is unclear. We report two cases of severe symptomatic, yet reversible, cardiomyopathy after VSP inhibitor therapy. A 46-year-old woman with metastatic gastrointestinal stromal tumor was started on sunitinib therapy after unsuccessful treatment with imatinib. She tolerated sunitinib well for 2 years at a dose of 25 mg once . . .

Management of Chest Wall Reconstruction After Resection for Cancer

In this study, we report our experience on immediate reconstruction after resection of primary or metastatic chest wall tumors, to restore protective function and elasticity of chest or sternum. Between 2005 and 2009, 22 patients underwent reconstruction using a free or pedicled flap combined, or not, to alloplastic materials (Goretex®) in order to cover full-thickness defects of the chest wall after cancer surgery. Reconstruction was immediate in all cases. Mean follow-up was 27 months. Of these, 18 patients were alive at the end of the study (81.5%). Eighteen patients had malignant tumors (82%); within these patients, 12 were alive without recurrence at the end of the study (67%). The average size of the chest wall defect was 255 cm². Goretex® Mesh was used in 8 patients. All patients benefited from reconstruction with a flap: pedicled or free latissimus dorsi flap (n = 15), pedicled great omentum (n=3), deep inferior epigastric perforator free flap (n = 3), and parascapular pedicled flap (n=1). In this series, we were able to achieve long-term palliation and even cure in some patients by resecting full-thickness chest wall in local primary or recurrence of breast cancer without increasing morbidity. The same process was used successfully in association with adjuvant treatment in other tumors like skin sarcoma. We have followed a surgical algorithm according to the tumor localization and etiology.

Radiation-induced olfactory neuroblastoma: a new etiology is possible

Radiation-induced olfactory neuroblastoma (ONB) is an uncommon neoplasm that is generally associated with a poor prognosis. We describe a new case of olfactory neuroblastoma in a patient previously treated for astrocytoma with holocranial radiotherapy 9years ago. We reviewed the medical records of four patients with radiation-induced olfactory neuroblastoma between 2001 and 2009. This work supports the idea that ONB can be induced by radiation. As radiotherapy is a standard treatment in other tumors, clinicians must be aware of the possibility of a second tumor induced by radiation.

(−)-Epigallocatechin-3-Gallate (EGCG), Green Tea Component, Antagonize the Anti-Myeloma Activity of Proteasome Inhibitor PS-341 by Direct Chemical Interaction.

PS-341 (also known as bortezomib, Velcade®) has a remarkable anti-myeloma acitivity and is also potential candidate for the treatment of other tumors either alone or in combination with other chemotherapeutic agents. Investigations on the effectiveness of PS-341 in combination with other anti-neoplastic agents are currently under clinical trial. Since (−)-epigallocatechin-3-gallate (EGCG) has been reported its anti-cancer activity in various cancer types, we tried a co-treatment of PS-341 with EGCG on myeloma cells, expecting a synergistic effect. However, the anti-cancer activity of PS-341 was blocked by EGCG without any synergistic effect. At the early stage of our research, we suspected antioxidant function of EGCG is the main cause of antagonistic effect on PS-341-induced cell death. Thus we selected polyphenols showing strong antioxidant function including vitamin C. But, we did not obtain any consistant data that support the significant correlation of antioxidant function of polyphenols with antagonistic effects. Instead, the structural features of polyphenols showed striking correlations with antagonistic effect; especially the presence or absence of vicinal diol moiety on polyphenol was the key elements for the effective blocking on anti-cancer function of PS-341. We infer that vicinal diols on polyphenols interact with boronic acid of PS-341, which convert active triangular boronic acid (sp2 character) of PS-341 to inactive tetrahedral boronate (sp3 character) through direct chemical interaction. The equilibrium of this conversion is controlled by structures and concentration of polyphenols, and this conversion abolished the anti-myeloma activity of PS-341. We confirmed our hypothesis on direct chemical interaction of PS-341 with EGCG through 11B NMR experiment and cell viability assay data clearly support the antagonistic interaction between PS-341 and polyphenols in multiple myeloma cell lines and primary myeloma cells from patients. Based on our researches, restriction of the intake of natural polyphenols by food or vitamin supplements should be considered during the treatment with PS-341 in MM patients. [Display omitted]

Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate

AbstractPhyllodes tumor of the prostate is a rare neoplasm with an unpredictable clinical behavior. It may undergo early recurrence with sarcomatous transformation or may even metastasize. Because targeted therapies have shown great success against several malignancies, there is hope that these same therapies may show similar promise in the treatment of other neoplasms. This study was undertaken to investigate both amplification of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridization and the overexpression of EGFR, Her-2/neu, CD117 (c-kit), and androgen receptor by immunohistochemical staining in a series of 11 phyllodes tumors of the prostate. In the stromal elements, EGFR gene amplification was present in four of 11 tumors and polysomy chromosome 7 was present in two of 11 tumors. No amplification was present in the epithelial components. Only one of 11 tumors had polysomy of chromosome 7 in the epithelial components. Immunohistochemically, in the stromal components, EGFR expression was demonstrable in four of 11 tumors and androgen receptor was demonstrated in six of 10 tumors. Neither Her-2/neu nor c-kit expression was seen in the stromal components of any of the 11 tumors. In the epithelial components, EGFR expression was present in all 11 tumors with strong staining in the basal cell layers and weak or no staining in luminal epithelium; androgen receptor expression was seen in seven of 10 tumors; Her-2/neu was weakly positive in four of 11 tumors; and c-kit expression was present focally and weakly in two of 11 cases with only 2–5% of cells staining. The highest staining intensity and the highest percentage of positively staining cells were seen with EGFR immunostaining in both the stromal and epithelial (mainly basal cells) components. Androgen receptor staining showed the next highest staining intensity and percentage of positive cells in both components. Her-2/neu and c-kit were only weakly or infrequently expressed in the epithelial components of prostatic phyllodes tumors. Our data indicate that EGFR and androgen receptor are frequently and strongly expressed in both epithelial and stromal components of prostatic phyllodes tumors. EGFR gene amplification is frequently present in prostatic phyllodes tumors and may account for one of the mechanisms leading to protein overexpression in some but not all cases. Anti-EGFR and/or antiandrogen agents may be potentially useful for management of patients with tumors expressing EGFR and/or androgen receptor.

Clinical and histopathologic observations of the action of imiquimod in an epithelioid hemangioendothelioma and Paget's mammary disease

An epithelioid hemangioendothelioma and Paget's disease of the breast were treated with topical imiquimod 5% cream with very impressive results. In both of the tumors complete disappearance of the lesions occurred. In this article, in addition to describing the treatment approach, the findings in biopsy specimens of the epithelioid hemangioendothelioma and the Paget's disease before, during, and after therapy will be described. The histologic findings show ample evidence that there is both a lymphocytic T helper 1-like and T helper 2-like response from imiquimod. Direct evidence of lymphocytotoxicity was found. Furthermore, mast cells appear to be involved in the development of regression in the vascular tumor. Although the study is very limited and reports only two cases, the results are striking. We considered it important to describe these findings because of their possible use in developing strategies for the application of imiquimod in the treatment of other tumors in human beings.

The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab

Radioimmunotherapy (RIT) is a promising emerging therapy for non-Hodgkin's lymphoma and may ultimately prove useful in the treatment of other tumors. The most extensively investigated RIT agent is tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA, and GlaxoSmithKline, Philadelphia, PA) which has been administered to over 1,000 patients during the past 9 years. As with most drugs, there is considerable interpatient variability in the clearance rate (or total body residence time) of radioimmunoconjugates. The clearance rate of iodine I 131 tositumomab in clinical trials has varied by as much as five-fold. The advantage of RIT with iodine-131, which emits both gamma photons and beta particles, is that by scanning it allows for the determination of the patient-specific total body residence time by the administration of a trace-labeled dose of the radionuclide (ie, dosimetric dose). By administration of the dosimetric (trace-labeled) dose, and determination of the patient's residence time (a measure of how long the radionuclide is retained in the body), the therapeutic dose can be precisely adjusted to maximize the therapeutic effect and minimize toxicity. Tositumomab and iodine I 131 tositumomab is a specific therapeutic at two levels: first, it specifically targets the tumor, delivering a log or more radiation to tumor compared with the rest of the body; and second, the administered dose of radioactivity is patient-specific. The paradigm of a targeted drug with a patient-specific dose may become more routine as targeted therapies are further developed along with better assays to directly measure drug levels. For the present, whole-body dosimetry is routinely applied for RIT with tositumomab and iodine I 131 tositumomab and has proven to be a reliable method to determine the patient-specific maximally tolerated therapeutic radiation dose to maximize efficacy while minimizing organ and bone marrow toxicity. Semin Oncol 30 (suppl 4):31-38. © 2003 Elsevier Inc. All rights reserved.

The clinical importance of dosimetry in radioimmunotherapy with tositumomab and iodine I 131 tositumomab.

Radioimmunotherapy (RIT) is a promising emerging therapy for non-Hodgkin's lymphoma and may ultimately prove useful in the treatment of other tumors. The most extensively investigated RIT agent is tositumomab and iodine I 131 tositumomab (Bexxar; Corixa Corp, South San Francisco, CA, and GlaxoSmithKline, Philadelphia, PA) which has been administered to over 1,000 patients during the past 9 years. As with most drugs, there is considerable interpatient variability in the clearance rate (or total body residence time) of radioimmunoconjugates. The clearance rate of iodine I 131 tositumomab in clinical trials has varied by as much as five-fold. The advantage of RIT with iodine-131, which emits both gamma photons and beta particles, is that by scanning it allows for the determination of the patient-specific total body residence time by the administration of a trace-labeled dose of the radionuclide (ie, dosimetric dose). By administration of the dosimetric (trace-labeled) dose, and determination of the patient's residence time (a measure of how long the radionuclide is retained in the body), the therapeutic dose can be precisely adjusted to maximize the therapeutic effect and minimize toxicity. Tositumomab and iodine I 131 tositumomab is a specific therapeutic at two levels: first, it specifically targets the tumor, delivering a log or more radiation to tumor compared with the rest of the body; and second, the administered dose of radioactivity is patient-specific. The paradigm of a targeted drug with a patient-specific dose may become more routine as targeted therapies are further developed along with better assays to directly measure drug levels. For the present, whole-body dosimetry is routinely applied for RIT with tositumomab and iodine I 131 tositumomab and has proven to be a reliable method to determine the patient-specific maximally tolerated therapeutic radiation dose to maximize efficacy while minimizing organ and bone marrow toxicity.

Imatinib mesylate--a new oral targeted therapy.

This review discusses the development and uses of imatinib mesylate, a protein tyrosine kinase inhibitor useful in the treatment of chronic myelogenous leukemia and gastrointestinal stromal tumors that was recently approved by the Food and Drug Administration. Imatinib targets platelet-derived growth factor receptor, inhibits the fusion product of the Philadelphia chromosome, and targets c-kit, a protein tyrosine kinase. The drug may also be effective in the treatment of other tumors that express platelet-derived growth factor receptor or c-kit.

Effect of breathing a hyperoxic hypercapnic gas mixture on the oxygenation of meningiomas; preliminary results.

For meningiomas in which complete resection is impossible stereotactic radiosurgery and radiotherapy are increasingly important therapeutical options. The radiosensitivity of meningiomas may be improved by increasing tumor oxygen levels. Hyperoxygenating agents, like breathing a hyperoxic hypercapnic gas mixture, have already been applied successfully in the treatment of other tumors. The aim of this study was to explore the effect of breathing a hyperoxic hypercapnic gas mixture on tumor blood oxygenation of meningiomas using magnetic resonance imaging (MRI) methods. Three patients with convexity meningiomas were each measured twice; with and without breathing the hyperoxic hypercapnic gas mixture. Tumor blood oxygenation changes were measured using blood oxygen level dependent MR imaging. Dynamic contrast enhanced MRI was used to assess functional changes of tumor vasculature. A significant increase in tumor blood oxygenation was observed under hypercapnic hyperoxic conditions in all patients, exceeding the increase in normal brain tissue. It was concluded that the oxygenation status of meningiomas can be improved by breathing a hyperoxic hypercapnic gas mixture.

Efficient Transfer of a Tumor Antigen-Reactive TCR to Human Peripheral Blood Lymphocytes Confers Anti-Tumor Reactivity

The tumor-associated-Ag MART-1 is expressed by most human melanomas. The genes encoding an alphabeta TCR from a MART-1-specific, HLA-A2-restricted, human T cell clone have been efficiently transferred and expressed in human PBL. These retrovirally transduced PBL cultures were MART-1 peptide reactive, and most cultures recognized HLA-A2+ melanoma lines. Limiting dilution clones were generated from three bulk transduced PBL cultures to investigate the function of individual clones within the transduced cultures. Twenty-nine of 29 CD8+ clones specifically secreted IFN-gamma in response to T2 cells pulsed with MART-1(27-35) peptide, and 23 of 29 specifically secreted IFN-gamma in response to HLA-A2+ melanoma lines. Additionally, 23 of 29 CD8+ clones lysed T2 cells pulsed with the MART-1(27-35) peptide and 15 of 29 lysed the HLA-A2+ melanoma line 888. CD4+ clones specifically secreted IFN-gamma in response to T2 cells pulsed with the MART-1(27-35) peptide. TCR gene transfer to patient PBL can produce CTL with anti-tumor reactivity in vitro and could potentially offer a treatment for patients with metastatic melanoma. This approach could also be applied to the treatment of other tumors and viral infections. Additionally, TCR gene transfer offers unique opportunities to study the fate of adoptively transferred T cells in vivo.

The role of gemcitabine in the treatment of other tumours.

Gemcitabine (GEMZAR) is a novel nucleoside analogue with activity in a range of preclinical models both in vitro and in vivo. It is highly schedule dependent, with weekly x3 every 4 weeks being the recommended schedule for phase II/III studies. Early phase II trials identified activity against non-small-cell lung cancer and pancreatic cancers, tumour types for which gemcitabine has a licence for treatment in many countries. However, the preclinical models indicated that gemcitabine may be active against many other human solid tumours. In phase II studies, activity has been identified against breast cancer, both as a single agent and in combination. In bladder cancer, impressive single-agent activity of gemcitabine has also been seen, as well as in combination with cisplatin, initially in MVAC and platinum failures but more recently as first-line therapy both as a single agent and combined with cisplatin. Anti-tumour activity has also been seen in patients with ovarian cancer, head and neck cancer, small-cell lung cancer and cervical cancer, with minimal activity in renal carcinoma, prostate and colon cancer. In view of the excellent side-effect profile and the potential for gemcitabine to inhibit DNA repair after exposure to DNA-damaging agents, further developments of gemcitabine will include its use in combination chemotherapy and combined modality schedules.

Dendritic cells: potential role in cancer therapy.

Dendritic cells (DC) are extremely potent antigen presenting cells, uniquely capable of sensitizing naive T cells to protein antigens and eliciting antigen specific immune responses. Studies of human DC isolated from peripheral blood indicate that these cells can be used to stimulate and expand antigen specific CD4+ and CD8+ T cells, in vitro. On the basis of these findings we have initiated pilot clinical studies to investigate the ability of DC pulsed ex vivo with tumor associated proteins to stimulate host anti-tumor immunity when re-infused as a vaccine. In the first such study DC pulsed with tumor derived idiotype protein were infused into patients with low grade malignant B cell lymphoma who had failed conventional chemotherapy. The majority of treated patients developed T cell mediated anti-idiotype immune responses and some of the patients experienced tumor regression. These results suggest that DC based immunotherapy is a potentially useful approach to B cell lymphoma and raises the possibility that the approach may prove useful in the treatment of other tumors as well.

Immunology and immunotherapy of melanoma.

The successes achieved in the treatment of melanomas through immunotherapy suggest what may be possible in the treatment of other tumors. Although immunotherapy had to prove itself at first in patients with widespread tumors late in the course of the disease, melanoma patients have more recently been referred for treatment with adjunctive immunotherapy shortly after removal of their primary tumor and/or involved lymph nodes. Even patients with disseminated disease have been seen earlier than in the past, often before any chemotherapy has been administered, because chemotherapy for melanoma has been notably unsuccessful in prolonging useful survival despite increases in the rates of response.

Abolished production of interferon by leucocytes of patients with the acquired cytogenetic abnormalities 5q -- or -- 5 in secondary and de-novo acute non-lymphocytic leukaemia.

Interferon production by leucocytes on stimulation with inactivated antigens from herpes simplex virus, varicella zoster virus and cytomegalovirus was determined in 19 patients with preleukaemia or acute non-lymphocytic leukaemia, in 15 following treatment for other tumours. Production of interferon was abolished in 10 patients and preserved in nine cases after stimulation with herpes simplex antigen. Cytogenetic studies of bone marrow demonstrated an abnormal karyotype in 13/15 patients with secondary preleukaemia or leukaemia. Characteristics were (a) hypodiploid cell lines demonstrated in eight cases, (b) a B-chromosome defect found in five cases and verified as 5q -- in four, and (c) defects in C-group chromosomes in 10, verified as monosomy 7 in nine. All four patients with de-novo preleukaemia or leukaemia had abnormal cytogenetic findings, two B-chromosome abnormalities verified as monosomy 5. A relationship between abnormalities in chromosome no. 5 and abolished production of interferon was demonstrated, as only one of seven patients with 5q --, --5 or --B produced interferon by the leucocytes, compared with eight of a total of 12 patients with other cytogenetic defects or a normal karyotype (P=0.04). The results are remarkable, as chromosome no. 5 has recently been discovered to contain a gene for interferon production. Furthermore abolished production of interferon by leucocytes seemed correlated to previous irradiation and to disease-related fever.