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Roberto Iacovelli - One of the best experts on this subject based on the ideXlab platform.
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evidence and clinical relevance of Tumor Flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma
European Urology, 2015Co-Authors: Roberto Iacovelli, Francesco Massari, Laurence Albiges, Yohann Loriot, Christophe Massard, Karim Fizazi, Bernard EscudierAbstract:Abstract Background Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a Tumor Flare (TF) but its clinical relevance is still questionable. Objective This analysis investigates the occurrence of Tumor Flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC. Design, setting, and participants Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of Tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2. Outcome measurements and statistical analysis Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 – GR1). Cox proportional hazards regression was used to assess the prognostic role. Results and limitations Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] –0.07 to 0.53) and 0.70cm/mo (IQR 0.21–1.46), respectively ( p =0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08–1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001–1.225; p =0.048). Conclusions This study reports clinical evidence that TKI discontinuation results in acceleration of Tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients. Patient summary In this report, we looked at the outcomes for patients affected by metastatic kidney Tumors who discontinued treatment with antiangiogenic agents. We found that Tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in Tumor growth rate, which is related to patient survival.
Bernard Escudier - One of the best experts on this subject based on the ideXlab platform.
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evidence and clinical relevance of Tumor Flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma
European Urology, 2015Co-Authors: Roberto Iacovelli, Francesco Massari, Laurence Albiges, Yohann Loriot, Christophe Massard, Karim Fizazi, Bernard EscudierAbstract:Abstract Background Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a Tumor Flare (TF) but its clinical relevance is still questionable. Objective This analysis investigates the occurrence of Tumor Flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC. Design, setting, and participants Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of Tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2. Outcome measurements and statistical analysis Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 – GR1). Cox proportional hazards regression was used to assess the prognostic role. Results and limitations Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] –0.07 to 0.53) and 0.70cm/mo (IQR 0.21–1.46), respectively ( p =0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08–1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001–1.225; p =0.048). Conclusions This study reports clinical evidence that TKI discontinuation results in acceleration of Tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients. Patient summary In this report, we looked at the outcomes for patients affected by metastatic kidney Tumors who discontinued treatment with antiangiogenic agents. We found that Tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in Tumor growth rate, which is related to patient survival.
Nuket Bayram Kayar - One of the best experts on this subject based on the ideXlab platform.
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Tumor Flare reaction in a patient with mantle cell lymphoma
Blood Research, 2014Co-Authors: Yusuf Kayar, Nuket Bayram KayarAbstract:TO THE EDITOR: Tumor Flare reaction (TFR) is a syndrome that clinically presents with painful lymph nodes and/or spleen enlargement, and it can be accompanied by fever, rash, and clear lymphocytosis [1]. Medical literature frequently points out its association with chronic lymphocytic leukemia (CLL) and lenalidomide treatment. In a study by Chanan-Khan et al. [2], it was observed that of 26 (58% of 45 patients) CLL patients who were administered 25 mg/day oral lenalidomide treatment for 21 days in 28-day cycles developed TFR reactions (50% developed grade 1-2 reactions, and 8% developed grade 3-4 reactions). In another study by Ferrajoli et al. [3], it was observed that 10 (28% of 35 patients) CLL patients who were first treated with a dose of 10 mg/day of lenalidomide and then with an increased dose of 25 mg/day developed TFR. While TFR cases after lenalidomide treatment have been frequently reported, TFR has not been reported after Hyper-CVAD plus Rituximab (R-HCVAD) treatment. Herein, we report a patient diagnosed with mantle cell lymphoma who developed TFR after use of high dose cyclophosphamide, doxorubicin, adriamycin and dexamethasone plus rituximab. The patient, who was being followed up for relapse of mantle cell lymphoma, developed fever, throat swelling, pain, and difficulty in swallowing after R-HCVAD treatment. Magnetic resonance imaging (MRI) of the patient's throat showed a mass, sized approximately 65×29 mm at its broadest point, with its borders not clearly identified; the mass caused distinct asymmetry in the hypopharynx and oropharynx, displaced the uvula to the right side, and continued to the epiglottis level. Distinct hypertrophy of the lingual and left palatine tonsils as well as of multiple lymph nodes on both sides were observed in the left submandibular area of the cervical chain of the neck, the biggest of which was sized 20×12.5 mm (Fig. 1). These findings suggested TFR after chemotherapy, and dexamethasone (24 mg/day) was initiated. The patient's fever decreased, and his complaints regressed on the 10th day of the treatment; throat MRI revealed edema and inflammation regression when compared to that observed on the previous MRI scan. A thin area of loculation was observed in the left retropharyngeal and parapharyngeal space and a small mass residue, 2.5×8 mm in size, was observed in the parapharyngeal space, with no clear contrast involvement. The patient's complaints abated completely after dexamethasone treatment; therefore, medications were stopped and follow-up was initiated. Fig. 1 The patient's throat magnetic resonance imaging scan showing a heterogeneously dense mass, sized approximately 65×29 mm at its broadest point, with its borders not clearly identified; therefore, the mass caused distinct asymmetry in the hypopharynx ... Until recently, it was thought that TFR associated with lenalidomide was a condition specific only in CLL patients. However, in 2010, Corazzelli et al. [4], reported three patients with relapsing or refractory Hodgkin lymphoma who developed TFR, and thus, showed that it was not so. Similarly, Eve and Rule [5], showed that three of 25 patients with mantle cell lymphoma who were treated with lenalidomide developed TFR. It was observed that two of the mantle cell lymphoma patients who developed TFR had a mild condition and recovered without any treatment. However, the other patient died of cerebrovascular complications although he was hospitalized owing to the severity of his condition (he had a prolonged reaction and his pain could not be controlled) [5]. While the etiology of TFR is not clearly known, it is thought that some mechanisms may be because of secondary production of cytokines. Studies have shown that lenalidomide does not directly induce apoptosis of or cytokine production by Tumor cells, but depending on the dose, it does increase CD40, CD80, CD86, HLA-DR, and CD95 expression by activating B cells [1]. It has been shown that there is distinctive CD40 and CD86 expression in CLL cells on ex vivo lenalidomide administration, and that the expression is associated with TFR [1]. Andritsos et al. [1] have shown that, on pre- and post-treatment evaluation of the lymph nodes, infiltration of Ki67- and CD3-positive, CD8-positive, granzyme B-positive T cells increases. It has been observed that, in patients with Hodgkin lymphoma who are treated with lenalidomide and who develop TFR, cytokines (particularly interleukin [IL]-6, IL7, APRIL, BAFF/BLyS) are released because of B cell activation, and levels of free light chains increase distinctively; these changes are reflected in the clinical properties. Likewise, it has been shown that when the TFR subsides, cytokines and light chain levels decrease to normal levels [5]. Therefore, for patients who develop TFR, it is suggested that dexamethasone be used, as it provides distinctive improvement by especially inhibiting CD40 regulation [1]. The mechanism through which the R-HCVAD treatment leads to TFR is not known, but one of the above-listed mechanisms may play a role.
Francesco Massari - One of the best experts on this subject based on the ideXlab platform.
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evidence and clinical relevance of Tumor Flare in patients who discontinue tyrosine kinase inhibitors for treatment of metastatic renal cell carcinoma
European Urology, 2015Co-Authors: Roberto Iacovelli, Francesco Massari, Laurence Albiges, Yohann Loriot, Christophe Massard, Karim Fizazi, Bernard EscudierAbstract:Abstract Background Several tyrosine kinase inhibitors (TKIs) and one monoclonal antibody targeting the vascular endothelial growth factor (VEGF)/VEGF receptor (VEGFR) axis have been approved for the treatment of metastatic renal cell carcinoma (mRCC). Preclinical data suggest that cessation of anti-VEGF therapy may generate a Tumor Flare (TF) but its clinical relevance is still questionable. Objective This analysis investigates the occurrence of Tumor Flare and its prognostic role after discontinuation of anti-VEGFR TKIs in patients affected by mRCC. Design, setting, and participants Patients with mRCC treated with first-line sunitinib or pazopanib at standard dosages were screened. Patients included in the analysis were required to have: (1) discontinued treatment because of progression of disease or intolerable toxicity or sustained response; (2) evaluation of Tumor growth rates immediately before (GR1) and after discontinuation (GR2); and (3) no treatment during evaluation of GR2. Outcome measurements and statistical analysis Overall survival (OS) was the main outcome. TF was calculated as the difference between the GR values (TF=GR2 – GR1). Cox proportional hazards regression was used to assess the prognostic role. Results and limitations Sixty-three consecutive patients were analyzed; the median duration of treatment was 9.3 mo, the median progression-free survival (PFS) was 11.1 mo, and the median OS was 41.5 mo. The reasons for treatment discontinuation were sustained response (partial response/stable disease) in 15.9%, toxicity in 22.2%, and progression of disease in 61.9% of cases. The median GR1 and GR2 were 0.16cm/mo (interquartile range [IQR] –0.07 to 0.53) and 0.70cm/mo (IQR 0.21–1.46), respectively ( p =0.001). In the overall population, the median TF was 0.55cm/mo (IQR 0.08–1.22) and differed according to the reason for discontinuation: 0.15cm/mo for response, 0.95cm/mo for toxicity, and 1.66cm/mo for progression. When TF was compared to other prognostic variables, Cox analysis confirmed its prognostic role (hazard ratio 1.11, 95% confidence interval 1.001–1.225; p =0.048). Conclusions This study reports clinical evidence that TKI discontinuation results in acceleration of Tumor GR and induces TF, which can negatively affect the prognosis of mRCC patients. Patient summary In this report, we looked at the outcomes for patients affected by metastatic kidney Tumors who discontinued treatment with antiangiogenic agents. We found that Tumor regrowth after discontinuation of therapy was related to the reason for discontinuation: regrowth was higher in patients who discontinued treatment because of disease progression, and lower in patients who discontinued treatment because of a sustained response. Moreover, we found that the higher the growth rate, the shorter the survival. We conclude that discontinuation of antiangiogenic agents may cause an increase in Tumor growth rate, which is related to patient survival.
Naoki Miyao - One of the best experts on this subject based on the ideXlab platform.
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transient atelectasis due to hilar lymph node swelling affected by lenalidomide induced Tumor Flare reaction
Journal of Clinical and Experimental Hematopathology, 2021Co-Authors: Takahiro Suyama, Terue Yui, Atsuo Horiuchi, Rie Irie, Yoshiyuki Osamura, Naoki MiyaoAbstract:Tumor Flare reaction (TFR) is a unique immune-mediated Tumor recognition phenomenon presenting as rapid enlargement of the Tumor, which mimics disease progression, developing in the early stage of treatment using immunomodulatory drugs or immune checkpoint inhibitors. A 59-year-old man with follicular lymphoma had residual Tumor burden in the left hilar lymph nodes after R-CHOP therapy, and received lenalidomide and rituximab (R2) therapy. He developed respiratory distress on day 11 of R2 therapy. Chest X-ray and CT demonstrated left lung atelectasis due to left hilar lymph node swelling. We performed transbronchial lung biopsy on day 20 of R2 therapy. The biopsied left bronchus tissue exhibited extensive necrosis, which had a B-cell phenotype consistent with that of follicular lymphoma. Neither NK cells nor cytotoxic T cells were detected. It was unclear whether the immune effector cells disappeared at the time of transbronchial lung biopsy. Atelectasis in our patient improved by continuing R2 therapy beyond TFR.
