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1.
Cell Rep ; 42(8): 112816, 2023 08 29.
Article in English | MEDLINE | ID: mdl-37505981

ABSTRACT

Glioblastoma (GBM) is known as an intractable, highly heterogeneous tumor encompassing multiple subclones, each supported by a distinct glioblastoma stem cell (GSC). The contribution of GSC genetic and transcriptional heterogeneity to tumor subclonal properties is debated. In this study, we describe the systematic derivation, propagation, and characterization of multiple distinct GSCs from single, treatment-naive GBMs (GSC families). The tumorigenic potential of each GSC better correlates with its transcriptional profile than its genetic make-up, with classical GSCs being inherently more aggressive and mesenchymal more dependent on exogenous growth factors across multiple GBMs. These GSCs can segregate and recapitulate different histopathological aspects of the same GBM, as shown in a paradigmatic tumor with two histopathologically distinct components, including a conventional GBM and a more aggressive primitive neuronal component. This study provides a resource for investigating how GSCs with distinct genetic and/or phenotypic features contribute to individual GBM heterogeneity and malignant escalation.


Subject(s)
Brain Neoplasms , Glioblastoma , Humans , Glioblastoma/pathology , Brain Neoplasms/metabolism , Gene Amplification , Neoplastic Stem Cells/metabolism , Carcinogenesis/pathology , Cell Line, Tumor
2.
Mol Oncol ; 17(7): 1280-1301, 2023 07.
Article in English | MEDLINE | ID: mdl-36862005

ABSTRACT

In colorectal cancer, the mechanisms underlying tumor aggressiveness require further elucidation. Taking advantage of a large panel of human metastatic colorectal cancer xenografts and matched stem-like cell cultures (m-colospheres), here we show that the overexpression of microRNA 483-3p (miRNA-483-3p; also known as MIR-483-3p), encoded by a frequently amplified gene locus, confers an aggressive phenotype. In m-colospheres, endogenous or ectopic miRNA-483-3p overexpression increased proliferative response, invasiveness, stem cell frequency, and resistance to differentiation. Transcriptomic analyses and functional validation found that miRNA-483-3p directly targets NDRG1, known as a metastasis suppressor involved in EGFR family downregulation. Mechanistically, miRNA-483-3p overexpression induced the signaling pathway triggered by ERBB3, including AKT and GSK3ß, and led to the activation of transcription factors regulating epithelial-mesenchymal transition (EMT). Consistently, treatment with selective anti-ERBB3 antibodies counteracted the invasive growth of miRNA-483-3p-overexpressing m-colospheres. In human colorectal tumors, miRNA-483-3p expression inversely correlated with NDRG1 and directly correlated with EMT transcription factor expression and poor prognosis. These results unveil a previously unrecognized link between miRNA-483-3p, NDRG1, and ERBB3-AKT signaling that can directly support colorectal cancer invasion and is amenable to therapeutic targeting.


Subject(s)
Colonic Neoplasms , Colorectal Neoplasms , MicroRNAs , Rectal Neoplasms , Humans , Proto-Oncogene Proteins c-akt/metabolism , Down-Regulation/genetics , Cell Line, Tumor , MicroRNAs/genetics , MicroRNAs/metabolism , Colorectal Neoplasms/pathology , Colonic Neoplasms/genetics , Transcription Factors/metabolism , Rectal Neoplasms/genetics , Epithelial-Mesenchymal Transition/genetics , Gene Expression Regulation, Neoplastic , Cell Movement/genetics , Neoplasm Invasiveness/genetics
3.
Cell Rep ; 36(4): 109455, 2021 07 27.
Article in English | MEDLINE | ID: mdl-34320350

ABSTRACT

In glioblastoma (GBM), the most frequent and lethal brain tumor, therapies suppressing recurrently altered signaling pathways failed to extend survival. However, in patient subsets, specific genetic lesions can confer sensitivity to targeted agents. By exploiting an integrated model based on patient-derived stem-like cells, faithfully recapitulating the original GBMs in vitro and in vivo, here, we identify a human GBM subset (∼9% of all GBMs) characterized by ERBB3 overexpression and nuclear accumulation. ERBB3 overexpression is driven by inheritable promoter methylation or post-transcriptional silencing of the oncosuppressor miR-205 and sustains the malignant phenotype. Overexpressed ERBB3 behaves as a specific signaling platform for fibroblast growth factor receptor (FGFR), driving PI3K/AKT/mTOR pathway hyperactivation, and overall metabolic upregulation. As a result, ERBB3 inhibition by specific antibodies is lethal for GBM stem-like cells and xenotransplants. These findings highlight a subset of patients eligible for ERBB3-targeted therapy.


Subject(s)
Glioblastoma/genetics , MicroRNAs/metabolism , Receptor, ErbB-3/metabolism , Antibodies/metabolism , Apoptosis , Cell Line, Tumor , Fibroblast Growth Factor 2 , Gene Expression Regulation, Neoplastic , Genes, Tumor Suppressor , Humans , MicroRNAs/genetics , Oligodendroglia/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Prognosis , Protein Kinases/metabolism , Proto-Oncogene Proteins c-akt/metabolism , Receptor, ErbB-3/antagonists & inhibitors , Receptors, Fibroblast Growth Factor/metabolism , Signal Transduction , Spheroids, Cellular/pathology , TOR Serine-Threonine Kinases/metabolism
4.
Clin Cancer Res ; 24(4): 807-820, 2018 02 15.
Article in English | MEDLINE | ID: mdl-28974546

ABSTRACT

Purpose: Patient-derived xenografts ("xenopatients") of colorectal cancer metastases have been essential to identify genetic determinants of resistance to the anti-EGFR antibody cetuximab and to explore new therapeutic strategies. From xenopatients, a genetically annotated collection of stem-like cultures ("xenospheres") was generated and characterized for response to targeted therapies.Experimental Design: Xenospheres underwent exome-sequencing analysis, gene expression profile, and in vitro targeted treatments to assess genetic, biological, and pharmacologic correspondence with xenopatients, and to investigate nongenetic biomarkers of therapeutic resistance. The outcome of EGFR family inhibition was tested in an NRG1-expressing in vivo model.Results: Xenospheres faithfully retained the genetic make-up of their matched xenopatients over in vitro and in vivo passages. Frequent and rare genetic lesions triggering primary resistance to cetuximab through constitutive activation of the RAS signaling pathway were conserved, as well as the vulnerability to their respective targeted treatments. Xenospheres lacking such alterations (RASwt) were highly sensitive to cetuximab, but were protected by ligands activating the EGFR family, mostly NRG1. Upon reconstitution of NRG1 expression, xenospheres displayed increased tumorigenic potential in vivo and generated tumors completely resistant to cetuximab, and sensitive only to comprehensive EGFR family inhibition.Conclusions: Xenospheres are a reliable model to identify both genetic and nongenetic mechanisms of response and resistance to targeted therapies in colorectal cancer. In the absence of RAS pathway mutations, NRG1 and other EGFR ligands can play a major role in conferring primary cetuximab resistance, indicating that comprehensive inhibition of the EGFR family is required to achieve a significant therapeutic response. Clin Cancer Res; 24(4); 807-20. ©2017 AACRSee related commentary by Napolitano and Ciardiello, p. 727.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Colonic Neoplasms/drug therapy , Drug Resistance, Neoplasm/genetics , ErbB Receptors/antagonists & inhibitors , Neoplastic Stem Cells/drug effects , Xenograft Model Antitumor Assays/methods , Animals , Cetuximab/administration & dosage , Colonic Neoplasms/genetics , Colonic Neoplasms/pathology , ErbB Receptors/genetics , ErbB Receptors/metabolism , Gene Expression Profiling/methods , Humans , Mice, Inbred NOD , Mice, SCID , Molecular Targeted Therapy/methods , Neoplastic Stem Cells/metabolism , Tumor Burden/drug effects , Tumor Burden/genetics , Tumor Cells, Cultured , Exome Sequencing/methods
5.
EMBO Mol Med ; 8(5): 550-68, 2016 05.
Article in English | MEDLINE | ID: mdl-27138567

ABSTRACT

Glioblastoma (GBM) contains stem-like cells (GSCs) known to be resistant to ionizing radiation and thus responsible for therapeutic failure and rapidly lethal tumor recurrence. It is known that GSC radioresistance relies on efficient activation of the DNA damage response, but the mechanisms linking this response with the stem status are still unclear. Here, we show that the MET receptor kinase, a functional marker of GSCs, is specifically expressed in a subset of radioresistant GSCs and overexpressed in human GBM recurring after radiotherapy. We elucidate that MET promotes GSC radioresistance through a novel mechanism, relying on AKT activity and leading to (i) sustained activation of Aurora kinase A, ATM kinase, and the downstream effectors of DNA repair, and (ii) phosphorylation and cytoplasmic retention of p21, which is associated with anti-apoptotic functions. We show that MET pharmacological inhibition causes DNA damage accumulation in irradiated GSCs and their depletion in vitro and in GBMs generated by GSC xenotransplantation. Preclinical evidence is thus provided that MET inhibitors can radiosensitize tumors and convert GSC-positive selection, induced by radiotherapy, into GSC eradication.


Subject(s)
Glioblastoma/radiotherapy , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Stem Cells/physiology , Stem Cells/radiation effects , Animals , Ataxia Telangiectasia Mutated Proteins/metabolism , Aurora Kinase A/metabolism , Cell Survival , Cyclin-Dependent Kinase Inhibitor p21/metabolism , DNA Repair , Heterografts , Humans , Mice , Oncogene Protein v-akt/metabolism
6.
Mol Oncol ; 9(2): 377-88, 2015 Feb.
Article in English | MEDLINE | ID: mdl-25306394

ABSTRACT

The inflammatory cytokine Tumor Necrosis Factor Alpha (TNF-α) is known to trigger invasive growth, a physiological property for tissue healing, turning into a hallmark of progression in cancer. However, the invasive response to TNF-α relies on poorly understood molecular mechanisms. We thus investigated whether it involves the MET oncogene, which regulates the invasive growth program by encoding the tyrosine kinase receptor for Hepatocyte Growth Factor (HGF). Here we show that the TNF-α pro-invasive activity requires MET function, as it is fully inhibited by MET-specific inhibitors (small-molecules, antibodies, and siRNAs). Mechanistically, we show that TNF-α induces MET transcription via NF-κB, and exploits MET to sustain MEK/ERK activation and Snail accumulation, leading to E-cadherin downregulation. We then show that TNF-α not only induces MET expression in cancer cells, but also HGF secretion by fibroblasts. Consistently, we found that, in human colorectal cancer tissues, high levels of TNF-α correlates with increased expression of both MET and HGF. These findings suggest that TNF-α fosters a HGF/MET pro-invasive paracrine loop in tumors. Targeting this ligand/receptor pair would contribute to prevent cancer progression associated with inflammation.


Subject(s)
Colorectal Neoplasms/metabolism , Gene Expression Regulation, Neoplastic , MAP Kinase Signaling System , Proto-Oncogene Proteins c-met/biosynthesis , Tumor Necrosis Factor-alpha/metabolism , Cell Line, Tumor , Colorectal Neoplasms/genetics , Hepatocyte Growth Factor/genetics , Hepatocyte Growth Factor/metabolism , Humans , Neoplasm Invasiveness/genetics , Paracrine Communication/genetics , Proto-Oncogene Proteins c-met/genetics , Snail Family Transcription Factors , Transcription Factors/genetics , Transcription Factors/metabolism , Tumor Necrosis Factor-alpha/genetics
7.
Cancer Res ; 74(6): 1857-69, 2014 Mar 15.
Article in English | MEDLINE | ID: mdl-24448239

ABSTRACT

Metastatic colorectal cancer remains largely incurable, although in a subset of patients, survival is prolonged by new targeting agents such as anti-EGF receptor (anti-EGFR) antibodies. This disease is believed to be supported by a subpopulation of stem-like cells termed colon cancer-initiating cell (CCIC), which may also confer therapeutic resistance. However, how CCICs respond to EGFR inhibition has not been fully characterized. To explore this question, we systematically generated CCICs through spheroid cultures of patient-derived xenografts of metastatic colorectal cancer. These cultures, termed "xenospheres," were capable of long-term self-propagation in vitro and phenocopied the original patient tumors in vivo, thus operationally defining CCICs. Xenosphere CCICs retained the genetic determinants for EGFR therapeutic response in vitro and in xenografts; like the original tumors, xenospheres harboring a mutated KRAS gene were resistant to EGFR therapy, whereas those harboring wild-type RAS pathway genes (RAS(wt)) were sensitive. Notably, the effects of EGFR inhibition in sensitive CCICs could be counteracted by cytokines secreted by cancer-associated fibroblasts. In particular, we found that the MET receptor ligand hepatocyte growth factor (HGF) was especially active in supporting in vitro CCIC proliferation and resistance to EGFR inhibition. Ectopic production of human HGF in CCIC xenografts rendered the xenografts susceptible to MET inhibition, which sensitized the response to EGFR therapy. By showing that RAS(wt) CCICs rely on both EGFR and MET signaling, our results offer a strong preclinical proof-of-concept for concurrent targeting of these two pathways in the clinical setting.


Subject(s)
Antibodies, Monoclonal, Humanized/pharmacology , Antineoplastic Agents/pharmacology , Colonic Neoplasms/enzymology , ErbB Receptors/antagonists & inhibitors , Neoplastic Stem Cells/enzymology , Proto-Oncogene Proteins c-met/metabolism , Animals , Cell Proliferation , Cell Survival , Cetuximab , Colonic Neoplasms/drug therapy , Colonic Neoplasms/pathology , Drug Resistance, Neoplasm , Drug Synergism , ErbB Receptors/metabolism , Female , Hepatocyte Growth Factor/physiology , Humans , Mice , Mice, Inbred NOD , Mice, SCID , Mice, Transgenic , Neoplastic Stem Cells/drug effects , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Signal Transduction , Spheroids, Cellular/enzymology , Tumor Burden/drug effects , Tumor Cells, Cultured , Xenograft Model Antitumor Assays
8.
Cancer Res ; 72(17): 4537-50, 2012 Sep 01.
Article in English | MEDLINE | ID: mdl-22738909

ABSTRACT

The existence of treatment-resistant cancer stem cells contributes to the aggressive phenotype of glioblastoma. However, the molecular alterations that drive stem cell proliferation in these tumors remain unknown. In this study, we found that expression of the MET oncogene was associated with neurospheres expressing the gene signature of mesenchymal and proneural subtypes of glioblastoma. Met expression was almost absent from neurospheres expressing the signature of the classical subtype and was mutually exclusive with amplification and expression of the EGF receptor (EGFR) gene. Met-positive and Met-negative neurospheres displayed distinct growth factor requirements, differentiated along divergent pathways, and generated tumors with distinctive features. The Met(high) subpopulation within Met-pos neurospheres displayed clonogenic potential and long-term self-renewal ability in vitro and enhanced growth kinetics in vivo. In Met(high) cells, the Met ligand HGF further sustained proliferation, clonogenicity, expression of self-renewal markers, migration, and invasion in vitro. Together, our findings suggest that Met is a functional marker of glioblastoma stem cells and a candidate target for identification and therapy of a subset of glioblastomas.


Subject(s)
Glioblastoma/genetics , Glioblastoma/metabolism , Neoplastic Stem Cells/metabolism , Proto-Oncogene Proteins c-met/genetics , Adolescent , Adult , Aged , Animals , Biomarkers, Tumor/genetics , Biomarkers, Tumor/metabolism , Cell Proliferation , Cell Transformation, Neoplastic/genetics , ErbB Receptors/genetics , ErbB Receptors/metabolism , Female , Gene Expression Profiling , Glioblastoma/mortality , Glioblastoma/pathology , Humans , Ligands , Male , Mice , Mice, Inbred NOD , Mice, SCID , Middle Aged , Neoplastic Stem Cells/pathology , Proto-Oncogene Proteins c-met/metabolism , Transcription, Genetic , Young Adult
9.
J Natl Cancer Inst ; 103(8): 645-61, 2011 Apr 20.
Article in English | MEDLINE | ID: mdl-21464397

ABSTRACT

BACKGROUND: Ionizing radiation (IR) is effectively used in cancer therapy. However, in subsets of patients, a few radioresistant cancer cells survive and cause disease relapse with metastatic progression. The MET oncogene encodes the hepatocyte growth factor (HGF) receptor and is known to drive "invasive growth", a regenerative and prosurvival program unduly activated in metastasis. METHODS: Human tumor cell lines (MDA-MB-231, MDA-MB-435S, U251) were subjected to therapeutic doses of IR. MET mRNA, and protein expression and signal transduction were compared in treated and untreated cells, and the involvement of the DNA-damage sensor ataxia telangiectasia mutated (ATM) and the transcription factor nuclear factor kappa B (NF-κB) in activating MET transcription were analyzed by immunoblotting, chromatin immunoprecipitation, and use of NF-κB silencing RNA (siRNA). Cell invasiveness was measured in wound healing and transwell assays, and cell survival was measured in viability and clonogenic assays. MET was inhibited by siRNA or small-molecule kinase inhibitors (PHA665752 or JNJ-38877605). Combinations of MET-targeted therapy and radiotherapy were assessed in MDA-MB-231 and U251 xenografts (n = 5-6 mice per group). All P values were from two-sided tests. RESULTS: After irradiation, MET expression in cell lines was increased up to fivefold via activation of ATM and NF-κB. MET overexpression increased ligand-independent MET phosphorylation and signal transduction, and rendered cells more sensitive to HGF. Irradiated cells became more invasive via a MET-dependent mechanism that was further enhanced in the presence of HGF. MET silencing by siRNA or inhibition of its kinase activity by treatment with PHA665752 or JNJ-38877605 counteracted radiation-induced invasiveness, promoted apoptosis, and prevented cells from resuming proliferation after irradiation in vitro. Treatment with MET inhibitors enhanced the efficacy of IR to stop the growth of or to induce the regression of xenografts (eg, at day 13, U251 xenografts, mean volume increase relative to mean tumor volume at day 0: vehicle = 438%, 5 Gy IR = 151%, 5 Gy IR + JNJ-38877605 = 76%; difference, IR vs JNJ-38877604 + IR = 75%, 95% CI = 59% to 91%, P = .01). CONCLUSION: IR induces overexpression and activity of the MET oncogene through the ATM-NF-κB signaling pathway; MET, in turn, promotes cell invasion and protects cells from apoptosis, thus supporting radioresistance. Drugs targeting MET increase tumor cell radiosensitivity and prevent radiation-induced invasiveness.


Subject(s)
Cell Cycle Proteins/metabolism , DNA Damage/radiation effects , DNA-Binding Proteins/metabolism , NF-kappa B/metabolism , Neoplasms/metabolism , Protein Serine-Threonine Kinases/metabolism , Proto-Oncogene Proteins c-met/metabolism , Receptors, Growth Factor/antagonists & inhibitors , Receptors, Growth Factor/metabolism , Signal Transduction/radiation effects , Tumor Suppressor Proteins/metabolism , Animals , Apoptosis/radiation effects , Ataxia Telangiectasia Mutated Proteins , Blotting, Northern , Cell Cycle Proteins/genetics , Cell Cycle Proteins/radiation effects , Cell Line, Tumor , Cell Movement/radiation effects , Cell Survival/radiation effects , Chromatin Immunoprecipitation , DNA-Binding Proteins/genetics , DNA-Binding Proteins/radiation effects , Enzyme-Linked Immunosorbent Assay , Gene Expression Regulation, Neoplastic/drug effects , Gene Silencing , Humans , In Situ Nick-End Labeling , Indoles/pharmacology , Mice , Mitogen-Activated Protein Kinases/metabolism , NF-kappa B/genetics , NF-kappa B/radiation effects , Neoplasm Invasiveness/prevention & control , Neoplasms/pathology , Neoplasms/radiotherapy , Phosphorylation/radiation effects , Polymerase Chain Reaction , Protein Kinase Inhibitors/pharmacology , Protein Serine-Threonine Kinases/genetics , Protein Serine-Threonine Kinases/radiation effects , Proto-Oncogene Proteins c-met/antagonists & inhibitors , Proto-Oncogene Proteins c-met/drug effects , Proto-Oncogene Proteins c-met/genetics , Proto-Oncogene Proteins c-met/radiation effects , RNA, Messenger/metabolism , RNA, Small Interfering , Radiation Tolerance , Radiation, Ionizing , Radiation-Sensitizing Agents/pharmacology , Receptors, Growth Factor/drug effects , Receptors, Growth Factor/genetics , Receptors, Growth Factor/radiation effects , Sulfones/pharmacology , Transcription, Genetic/radiation effects , Transplantation, Heterologous , Tumor Suppressor Proteins/genetics , Tumor Suppressor Proteins/radiation effects , Up-Regulation/radiation effects
10.
Nature ; 434(7031): 396-400, 2005 Mar 17.
Article in English | MEDLINE | ID: mdl-15772665

ABSTRACT

The close relationship between activation of blood coagulation and cancer is an old enigma. In 1865, migrans trombophlebitis ('a condition of the blood that predisposes it to spontaneous coagulation') was described as a forewarning of occult malignancy (Trousseau's sign). This pioneering observation emphasized the existence of haemostasis disorders associated with cancer onset; this phenomenon has since been extensively reported in clinical and epidemiological studies, but has so far resisted a mechanistic explanation. Here we report a mouse model of sporadic tumorigenesis based on genetic manipulation of somatic cells. Targeting the activated, human MET oncogene to adult liver caused slowly progressing hepatocarcinogenesis. This was preceded and accompanied by a syndrome manifesting first with blood hypercoagulation (venous thromboses), and then evolving towards fatal internal haemorrhages. The pathogenesis of this syndrome is driven by the transcriptional response to the oncogene, including prominent upregulation of plasminogen activator inhibitor type 1 (PAI-1) and cyclooxygenase-2 (COX-2) genes. In vivo analysis showed that both proteins support the thrombohaemorrhagic phenotype, thus providing direct genetic evidence for the long-sought-after link between oncogene activation and haemostasis.


Subject(s)
Blood Coagulation , Cell Transformation, Neoplastic/genetics , Hemostasis/physiology , Liver Neoplasms/genetics , Oncogenes/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Receptors, Growth Factor/genetics , Receptors, Growth Factor/metabolism , Animals , Cyclooxygenase 2 , Dimerization , Hematologic Diseases/genetics , Hematologic Diseases/pathology , Hemostasis/genetics , Hepatocytes/metabolism , Hepatocytes/pathology , Humans , Liver Neoplasms/pathology , Membrane Proteins , Mice , Mice, SCID , Plasminogen Activator Inhibitor 1/metabolism , Prostaglandin-Endoperoxide Synthases/metabolism , Proto-Oncogene Proteins c-met , Transcription, Genetic/genetics , Up-Regulation/genetics
11.
Int J Antimicrob Agents ; 23(2): 150-4, 2004 Feb.
Article in English | MEDLINE | ID: mdl-15013040

ABSTRACT

It has been previously demonstrated that some antimicrobial agents enhance activities of human polymorphonuclear neutrophils (PMNs). The effect on the release of cytokines in an inflammatory context from PMNs by these antibiotics was evaluated. We studied the effect of the release of some cytokines by human PMNs RT-PCR analysis on a clinical strain of Klebsiella pneumoniae by comparing the effect with that observed in the presence of co-amoxiclav, sanfetrinem, clarithromycin, prulifloxacin and tobramycin. All the drugs tested were capable of modulating PMN synthesis in vitro of pro-inflammatory cytokines IL-8, IL-1beta, TNF-alpha and IL-6, but not that of anti-inflammatory cytokine IL-10. The degree of their stimulatory or inhibitory potency varied with the cytokine examined.


Subject(s)
Anti-Bacterial Agents/immunology , Cytokines/biosynthesis , Klebsiella pneumoniae/immunology , Neutrophils/metabolism , Anti-Bacterial Agents/pharmacology , Cytokines/genetics , Humans , Inflammation/immunology , Klebsiella pneumoniae/drug effects , Lipopolysaccharides/pharmacology , Microbial Sensitivity Tests , Neutrophil Activation/drug effects , Neutrophils/immunology , Polymerase Chain Reaction
12.
Blood ; 99(3): 856-62, 2002 Feb 01.
Article in English | MEDLINE | ID: mdl-11806987

ABSTRACT

Minimal residual disease (MRD) following sequential administration of CHOP and rituximab was studied in previously untreated patients with follicular lymphoma. At diagnosis, the presence of Bcl-2/IgH-positive cells in the peripheral blood (PB) and/or bone marrow (BM) was demonstrated in all patients (n = 128) by polymerase chain reaction (PCR) analysis. Patients who achieved a clinical response following CHOP but remained PCR-positive were eligible for rituximab (375 mg/m(2) intravenously, weekly for 4 weeks). After CHOP, 57% achieved a complete response (CR), 37% a partial response (PR), and 6% were nonresponders (NR). At this stage, patients proving PCR-negative (n = 41) or failing to achieve a clinical response (n = 8) were excluded from rituximab treatment. Seventy-seven patients received rituximab and entered a scheduled MRD follow-up program. At the first molecular follow-up (+12 weeks), 59% had converted to PCR negativity in the BM and PB, with a further increase documented at the second control (+28 weeks) with 74% PCR negative. At the last molecular follow-up (+44 weeks), 63% of the patients remained PCR negative. At 3 years, the estimated overall survival of all patients is 95% (95% confidence interval [CI], 86-98). For patients achieving PCR-negative status following CHOP and therefore excluded from rituximab treatment, freedom from recurrence (FFR) was 52% (95% CI, 28-71). For patients treated with rituximab, a durable PCR-negative status was associated with a better clinical outcome since FFR was 57% (95% CI, 23-81) compared with 20% (95% CI, 4-46) in patients who never achieved or lost the molecular negativity (P <.001).


Subject(s)
Antibodies, Monoclonal/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Lymphoma, Follicular/drug therapy , Neoplasm, Residual/diagnosis , Adult , Aged , Antibodies, Monoclonal/toxicity , Antibodies, Monoclonal, Murine-Derived , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Blood Cells , Bone Marrow , Cyclophosphamide/administration & dosage , Doxorubicin/administration & dosage , Female , Genes, Immunoglobulin , Genes, bcl-2 , Humans , Lymphoma, Follicular/diagnosis , Lymphoma, Follicular/mortality , Male , Middle Aged , Neoplasm, Residual/drug therapy , Polymerase Chain Reaction , Prednisone/administration & dosage , Prognosis , Rituximab , Survival Analysis , Vincristine/administration & dosage
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