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1.
ESMO Open ; 7(5): 100574, 2022 10.
Article in English | MEDLINE | ID: mdl-36029652

ABSTRACT

BACKGROUND: The role and the durability of the immunogenicity of the third dose of vaccine against COVID-19 variants of concern in cancer patients have to be elucidated. PATIENTS AND METHODS: We have prospectively evaluated the immunogenicity of the third dose of the SARS-CoV-2 BNT162b2 messenger RNA vaccine in triggering both humoral and cell-mediated immune response in patients with solid tumors undergoing active treatment 6 months after the booster. Neutralizing antibody (NT Ab) titers and total anti-spike immunoglobulin G concentrations were measured in serum. Heparinized whole blood samples were used for the SARS-CoV-2 interferon-γ release assay (IGRA). RESULTS: Six months after the third dose only two patients (2.4%) showed negative spike-specific immunoglobulin G antibody levels (<33.8 BAU/ml). The median level of SARS-CoV-2 NT Abs decreased and only 39/83 (47%) subjects showed maximum levels of NT Abs. T-cellular positive response was observed in 38/61 (62.3%) patients; the highest median level of response was observed 21 days after the third dose (354 mIU/ml, interquartile range 83.3-846.3 mIU/ml). The lowest median level of NT Ab response was observed against the Omicron variant (1 : 10, interquartile range 1 : 10-1 : 40) with a significant reduced rate of responder subjects with respect to the wild-type strain (77.5% versus 95%; P = 0.0022) and Delta variant (77.5% versus 93.7%; P = 0.0053). During the follow-up period, seven patients (8%) had a confirmed post-vaccination infection, but none of them required hospitalization or oxygen therapy. CONCLUSIONS: Our work highlights a significant humoral and cellular immune response among patients with solid tumors 6 months after the third BNT162b2 vaccine dose, although a reduction in neutralizing activity against Omicron was observed.


Subject(s)
COVID-19 , Neoplasms , Viral Vaccines , Humans , COVID-19 Vaccines/pharmacology , BNT162 Vaccine , Longitudinal Studies , Antibodies, Viral , Viral Vaccines/genetics , SARS-CoV-2 , COVID-19/prevention & control , Antibodies, Neutralizing , Immunoglobulin G , Immunity, Cellular , Neoplasms/drug therapy , Oxygen , mRNA Vaccines
3.
ESMO Open ; 7(2): 100458, 2022 04.
Article in English | MEDLINE | ID: mdl-35427842

ABSTRACT

BACKGROUND: Although a full course of coronavirus disease 2019 (COVID-19) vaccine is effective in cancer patients, the duration of the protection and the efficacy of a booster dose against the new variants remain unknown. We prospectively evaluated the immunogenicity of the third dose of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) BNT162b2 messenger RNA vaccine in cancer patients undergoing active treatment. PATIENTS AND METHODS: Patients with solid cancer, vaccinated with a booster dose during active treatment, were enrolled in this study. Patients were classified into SARS-CoV-2 naïve (without previous COVID-19 infection) and SARS-CoV-2 experienced (with previous COVID-19 infection). Neutralizing antibody (NT Ab) titer and total anti-Spike immunoglobulin G (IgG) concentration were quantified in serum. Heparinized whole blood samples were used for SARS-CoV-2 Interferon Gamma Release Assay (IGRA). The primary endpoint was to assess the increase of IgG antibody level between baseline and 3 weeks after the booster. RESULTS: One hundred and forty-two consecutive patients were recruited. In SARS-CoV-2-naïve subjects, the median level of IgG was 157 BAU/ml [interquartile range (IQR) 62-423 BAU/ml] at T0 and reached a median of 2080 BAU/ml (IQR 2080-2080 BAU/ml) at 3 weeks after booster administration (T1; P < 0.0001). A median 16-fold increase of SARS-CoV-2 NT Ab titer (IQR 4-32) was observed in naïve subjects (from median 20, IQR 10-40, to median 640, IQR 160-640; P < 0.0001). Median interferon-γ level at T1 was significantly higher than that measured at T0 in SARS-CoV-2-naïve subjects (P = 0.0049) but not in SARS-CoV-2-experienced patients. The median level of SARS-CoV-2 NT Abs was 32-fold lower against Omicron compared to the wild-type strain (P = 0.0004) and 12-fold lower compared to the Delta strain (P = 0.0110). CONCLUSIONS: The third dose is able to trigger both the humoral and the cell-mediated immune response in cancer patients on active treatment. Our preliminary data about the neutralization of the SARS-CoV-2 vaccine against variants of concern seem to confirm the lower vaccine activity.


Subject(s)
COVID-19 , Neoplasms , Antibodies, Viral , BNT162 Vaccine , COVID-19/prevention & control , COVID-19 Vaccines/adverse effects , Humans , Immunoglobulin G/therapeutic use , Neoplasms/drug therapy , Prospective Studies , SARS-CoV-2 , Vaccines, Synthetic , mRNA Vaccines
4.
ESMO Open ; 7(1): 100359, 2022 02.
Article in English | MEDLINE | ID: mdl-34973510

ABSTRACT

BACKGROUND: The durability of immunogenicity of SARS-CoV-2 vaccination in cancer patients remains to be elucidated. We prospectively evaluated the immunogenicity of the vaccine in triggering both the humoral and the cell-mediated immune response in cancer patients treated with anti-programmed cell death protein 1/programmed death-ligand 1 with or without chemotherapy 6 months after BNT162b2 vaccine. PATIENTS AND METHODS: In the previous study, 88 patients were enrolled, whereas the analyses below refer to the 60 patients still on immunotherapy at the time of the follow-up. According to previous SARS-CoV-2 exposure, patients were classified as SARS-CoV-2-naive (without previous SARS-CoV-2 exposure) and SARS-CoV-2-experienced (with previous SARS-CoV-2 infection). Neutralizing antibody (NT Ab) titer against the B.1.1 strain and total anti-spike immunoglobulin G concentration were quantified in serum samples. The enzyme-linked immunosorbent spot assay was used for quantification of anti-spike interferon-γ (IFN-γ)-producing cells/106 peripheral blood mononuclear cells. Fifty patients (83.0%) were on immunotherapy alone, whereas 10 patients (7%) were on chemo-immunotherapy. We analyzed separately patients on immunotherapy and patients on chemo-immunotherapy. RESULTS: The median T-cell response at 6 months was significantly lower than that measured at 3 weeks after vaccination [50 interquartile range (IQR) 20-118.8 versus 175 IQR 67.5-371.3 IFN-γ-producing cells/106 peripheral blood mononuclear cells; P < 0.0001]. The median reduction of immunoglobulin G concentration was 88% in SARS-CoV-2-naive subjects and 2.1% in SARS-CoV-2-experienced subjects. SARS-CoV-2 NT Ab titer was maintained in SARS-CoV-2-experienced subjects, whereas a significant decrease was observed in SARS-CoV-2-naive subjects (from median 1 : 160, IQR 1 : 40-1 : 640 to median 1 : 20, IQR 1 : 10-1 : 40; P < 0.0001). A weak correlation was observed between SARS-CoV-2 NT Ab titer and spike-specific IFN-γ-producing cells at both 6 months and 3 weeks after vaccination (r = 0.467; P = 0.0002 and r = 0.428; P = 0.0006, respectively). CONCLUSIONS: Our work highlights a reduction in the immune response in cancer patients, particularly in SARS-CoV-2-naive subjects. Our data support administering a third dose of COVID-19 vaccine to cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors.


Subject(s)
B7-H1 Antigen , BNT162 Vaccine , COVID-19 , Immune Checkpoint Inhibitors , Neoplasms , Programmed Cell Death 1 Receptor , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , BNT162 Vaccine/administration & dosage , BNT162 Vaccine/immunology , COVID-19/immunology , COVID-19/prevention & control , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/immunology , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology
5.
ESMO Open ; 6(5): 100272, 2021 10.
Article in English | MEDLINE | ID: mdl-34543863

ABSTRACT

BACKGROUND: Very few cancer patients were enrolled in coronavirus disease-2019 vaccine studies. In order to address this gap of knowledge, real-world studies are mandatory. The aim of this study was to assess both humoral and cellular response after a messenger RNA vaccination schedule. PATIENTS AND METHODS: Eighty-eight consecutive cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors were enrolled from the beginning of the vaccination campaign for frail patients. Blood samples for humoral and cell-mediated immune response evaluation were obtained before vaccination (T0), before the second administration (T1) and 21 days after the second dose (T2). The primary endpoint was the evaluation of the percentage of participants showing a significant increase in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells, measured by an enzyme-linked immunospot assay, after the second dose of BNT162b2 vaccine. The proportion of patients who reached the primary endpoint is computed together with its exact binomial 95% confidence interval. RESULTS: In SARS-CoV-2-naïve subjects, spike-specific T-cell response was almost undetectable at T0 [median 0.0 interferon-γ (IFN-γ) spot forming units (SFU)/million peripheral blood mononuclear cell (PBMC) interquartile range (IQR) 0-7.5] and significantly increased at T1 and T2 (median 15.0 IFN-γ SFU/million PBMC, 25th-75th 0-40 versus 90 IFN-γ SFU/million PBMC, 25th-75th 32.5-224, respectively) (P < 0.001). Focusing on naïve and experienced SARS-CoV-2 subjects, no differences were reported both in terms of CD4- and CD8-specific T-cell response, suggesting that BNT162b2 is able to elicit both adaptive responses after complete vaccination schedule, regardless of previous SARS-CoV-2 exposure. The level of SARS-CoV-2 neutralizing antibodies was low at T1 in SARS-CoV-2-naïve subjects [median 1 : 5 (IQR 1 : 5-1 : 20)] but reached a significantly higher median of 1 : 80 (25th-75th 1 : 20-1 : 160) at T2 (P < 0.0001). Moreover, no COVID-19 cases were documented throughout the period of study. CONCLUSIONS: Our data have demonstrated that the administration of a full course of BNT162b2 vaccine elicited a sustained immune response against SARS-CoV-2 regardless of the type of cancer and/or the type of immune checkpoint inhibitors.


Subject(s)
COVID-19 , Neoplasms , Antibodies, Viral , BNT162 Vaccine , COVID-19 Vaccines , Cohort Studies , Humans , Immune Checkpoint Inhibitors , Leukocytes, Mononuclear , Longitudinal Studies , Neoplasms/drug therapy , Programmed Cell Death 1 Receptor , SARS-CoV-2
6.
EJNMMI Radiopharm Chem ; 2(1): 12, 2017.
Article in English | MEDLINE | ID: mdl-29503853

ABSTRACT

The EU regulation 536/2014 aims to facilitate the experimental use of diagnostic radiopharmaceuticals in particular for GMP requirements and needs to be applied in EU countries. As definitely clarified by this survey, the application is still far from being completed due to national restrictions that are conflicting with the content of the above EU regulation. Although the nuclear medicine centers are obliged to be compliant with national regulatory, national authorities have to be required to work towards full application of the regulation. On the other hand, an update of 536/2014 that includes therapeutic radiopharmaceuticals would also be beneficial to a rational and safe advance of nuclear medicine.

7.
Bone Marrow Transplant ; 48(3): 414-8, 2013 Mar.
Article in English | MEDLINE | ID: mdl-22863724

ABSTRACT

The median survival of women with metastatic breast cancer (MBC) is 18-24 months, and fewer than 5% are alive and disease free at 5 years. We report toxicity and survival in a cohort of MBC patients receiving high-dose chemotherapy (HDC) with autologous hematopoietic SCT (AHSCT) in Italy between 1990 and 2005. Data set for survival analysis has been obtained for 415 patients. Clinical parameters including probability of transplant-related mortality (TRM), PFS and OS. With a median follow-up of 27 months (range 0-172), OS and PFS at 5 and 10 years in the whole population were 47/23 and 32/14%, respectively. A total 239 patients are alive with a median follow-up of 33 months (range 2-174). Survival was significantly more pronounced in patients harboring hormone receptor positive tumors (P=0.028), without visceral metastases (P=0.009) and in women with chemosensitive disease (P<0.0001). Sixty eight patients (20.4%) who received HDC in partial response, stable or progressive disease underwent conversion to CR. TRM was 2.5% overall and 1.3% since 2000. Our findings suggest that could be a role for HDC and AHSCT in delaying disease progression and possibly cure a subset of MBC patient harboring chemosensitive tumors.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Hematopoietic Stem Cell Transplantation/methods , Adolescent , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Combined Modality Therapy , Disease-Free Survival , Female , Humans , Italy , Kaplan-Meier Estimate , Middle Aged , Retrospective Studies , Survival Analysis , Young Adult
8.
Ann Oncol ; 23(2): 435-41, 2012 Feb.
Article in English | MEDLINE | ID: mdl-21586688

ABSTRACT

BACKGROUND: We and others have demonstrated that adoptive cell therapy with Epstein-Barr virus (EBV)-specific autologous cytotoxic T lymphocytes (CTLs) may control disease progression in patients with EBV-associated nasopharyngeal carcinoma (NPC). With the aim of favoring in vivo T-cell expansion, we optimized our cell therapy approach by administering higher doses of EBV-specific CTLs, following lymphodepleting chemotherapy. PATIENTS AND METHODS: Eleven patients with EBV-related NPC in whom conventional treatment failed have been enrolled. Patients received nonmyeloablative lymphodepleting chemotherapy consisting of cyclophosphamide and fludarabine. Two doses of autologous EBV-specific CTLs were subsequently infused, 2 weeks apart. Study end points were feasibility and clinical outcome. RESULTS: All patients enrolled completed the treatment and were assessable for analysis. The median dose of CTLs per infusion was 3.7 × 10(8). Therapy was well tolerated, with no severe adverse events ascribable to either chemotherapy or cell therapy. Disease control (defined as either tumor regression or disease stabilization lasting >4 months) was obtained in 6 of 11 patients, in keeping with previously published results. CONCLUSIONS: Our data confirm that EBV-specific CTL therapy is safe and associated with antitumor activity in patients with advanced NPC. The use of lymphodepleting chemotherapy before high-dose CTL infusion did not enhance the clinical benefit observed in our previous series.


Subject(s)
Cell- and Tissue-Based Therapy , Epstein-Barr Virus Infections/complications , Lymphocyte Depletion , Nasopharyngeal Neoplasms/therapy , Nasopharyngeal Neoplasms/virology , T-Lymphocytes, Cytotoxic/immunology , Adult , Aged , Carcinoma , Disease Progression , Female , Humans , Immunotherapy, Adoptive , Male , Middle Aged , Nasopharyngeal Carcinoma , Nasopharyngeal Neoplasms/immunology , Young Adult
9.
Cancer Treat Rev ; 36 Suppl 3: S1-5, 2010 Nov.
Article in English | MEDLINE | ID: mdl-21129603

ABSTRACT

Metastatic colorectal cancer (mCRC) patients carrying KRAS mutated tumors do not benefit from epidermal growth factor receptor (EGFR)-targeted cetuximab- or panitumumab-based therapies. Indeed, the mutational status of KRAS is currently a validated predictive biomarker employed to select mCRC patients for EGFR targeted drugs. When patients fail standard 5-fluorouracil-, oxaliplatin-, irinotecan- and bevacizumab-based therapies, EGFR-targeted salvage therapy can be prescribed only for those individuals with KRAS wild-type cancer. Thus, clinicians are now facing the urgent issue of better understanding the biology of KRAS mutant disease, in order to devise novel effective therapies in such defined genetic setting. In addition to KRAS, recent data point out that BRAF and PIK3CA exon 20 mutations hamper response to EGFR-targeted treatment in mCRC, potentially excluding from treatment also patients with these molecular alterations in their tumor. This review will focus on current knowledge regarding the molecular landscape of mCRC including and beyond KRAS, and will summarize novel rationally-developed combinatorial regimens that are being evaluated in early clinical trials.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Colorectal Neoplasms/drug therapy , Colorectal Neoplasms/genetics , Drug Resistance, Neoplasm/genetics , ErbB Receptors/drug effects , Proto-Oncogene Proteins/analysis , ras Proteins/analysis , Animals , Antibodies, Monoclonal/therapeutic use , Class I Phosphatidylinositol 3-Kinases , Colorectal Neoplasms/diagnosis , Disease Models, Animal , Humans , Membrane Proteins/metabolism , Mutation , Neoplasm Metastasis/drug therapy , Neoplasm Metastasis/genetics , PTEN Phosphohydrolase/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Proto-Oncogene Proteins p21(ras) , Receptors, Cell Surface/drug effects , Receptors, Cell Surface/metabolism , Salvage Therapy , Xenograft Model Antitumor Assays
10.
Eur Eat Disord Rev ; 16(4): 311-8, 2008 Jul.
Article in English | MEDLINE | ID: mdl-18240121

ABSTRACT

Limited research indicates that public attitudes toward individuals with eating disorders are moderately negative. The present study examined specific forms of stigmatisation attributed to individuals with anorexia nervosa (AN). Eighty female participants recruited from an undergraduate institution completed questionnaires assessing stereotypes, prejudice and discrimination of four target individuals: a woman with AN, depression, schizophrenia and mononucleosis. AN was considered to result more from lack of social support and biological factors than poor living habits. Characteristics attributed to targets were less positive for AN than the targets with schizophrenia and mononucleosis; participants reported greater discomfort interacting with the target with AN compared to the targets with depression and mononucleosis. Having actual contact with an individual with AN related to a positive predicted outcome of and comfort in interacting with the target with AN. Findings support the existence of stigma toward individuals with AN. Future research should examine means of reducing stigma.


Subject(s)
Anorexia Nervosa/psychology , Attitude to Health , Interpersonal Relations , Prejudice , Stereotyping , Adolescent , Adult , Depressive Disorder/psychology , Female , Humans , Infectious Mononucleosis/psychology , Schizophrenia , Social Behavior , Social Isolation/psychology , Students/psychology , Surveys and Questionnaires
11.
Cytotherapy ; 9(5): 499-507, 2007.
Article in English | MEDLINE | ID: mdl-17786611

ABSTRACT

BACKGROUND: The adoptive transfer of ex vivo-induced tumor-specific T-cell lines provides a promising approach for cancer immunotherapy. We have demonstrated previously the feasibility of inducing in vitro long-term anti-tumor cytotoxic T-cell (CTL) lines directed against different types of solid tumors derived from both autologous and allogeneic PBMC. We have now investigated the possibility of producing large amounts of autologous anti-tumor CTL, in compliance with good manufacturing practices, for in vivo use. METHODS: Four patients with advanced solid tumors (two sarcoma, one renal cell cancer and one ovarian cancer), who had received several lines of anticancer therapy, were enrolled. For anti-tumor CTL induction, patient-derived CD8-enriched PBMC were stimulated with DC pulsed with apoptotic autologous tumor cells (TC) as the source of tumor Ag. CTL were then restimulated in the presence of TC and expanded in an Ag-independent way. RESULTS: Large amounts of anti-tumor CTL (range 14-20 x 10(9)), which displayed high levels of cytotoxic activity against autologous TC, were obtained in all patients by means of two-three rounds of tumor-specific stimulation and two rounds of Ag-independent expansion, even when a very low number of viable TC was available. More than 90% of effector cells were CD3(+) CD8(+) T cells, while CD4(+) T lymphocytes and/or NK cells were less than 10%. DISCUSSION: Our results demonstrate the feasibility of obtaining large quantities of anti-tumor specific CTL suitable for adoptive immunotherapy approaches.


Subject(s)
Carcinoma/therapy , Immunotherapy, Adoptive/methods , Neoplasms/therapy , Sarcoma/therapy , T-Lymphocyte Subsets/transplantation , T-Lymphocytes, Cytotoxic/transplantation , Adult , CD8 Antigens/immunology , Carcinoma/immunology , Carcinoma/physiopathology , Cell Culture Techniques/methods , Cell Culture Techniques/standards , Cell Line , Cell Proliferation , Cytotoxicity Tests, Immunologic , HLA Antigens/immunology , Humans , Immunophenotyping , Neoplasms/immunology , Neoplasms/physiopathology , Sarcoma/immunology , Sarcoma/physiopathology , T-Lymphocyte Subsets/immunology , T-Lymphocytes, Cytotoxic/immunology , Treatment Outcome
12.
Int J Eat Disord ; 39(4): 320-5, 2006 May.
Article in English | MEDLINE | ID: mdl-16523470

ABSTRACT

OBJECTIVE: The current study examined the perceptions about an individual with anorexia nervosa (AN) relative to perceptions about a healthy person and a person with another mental or nonmental illness. METHOD: Ninety-one participants recruited from the community completed questionnaires targeting perceptions about 4 individuals: a healthy person, a person with asthma, a person with schizophrenia, and a person with AN. RESULTS: Evaluations of personal characteristics were most negative for persons with AN. Participants believed the person with AN was most to blame for his/her condition, was best able to pull him/herself together if he/she wanted to, and was most acting this way for attention and that biological factors were least relevant in developing the illness. CONCLUSION: Negative perceptions of a person with AN fell into stigma categories of self-attribution and responsibility. These attitudes may contribute to reluctance to seek treatment among individuals with AN.


Subject(s)
Anorexia Nervosa , Attitude , Prejudice , Adult , Aged , Anorexia Nervosa/psychology , Boston , Cross-Sectional Studies , District of Columbia , Female , Humans , Male , Middle Aged
13.
J Psychol ; 139(5): 389-400, 2005 Sep.
Article in English | MEDLINE | ID: mdl-16285210

ABSTRACT

For this study, the authors analyzed the contents of 16 psychology journals for the presence of empirical articles on African Americans, Latinos, Asians, and Native Americans during the period ranging from 1990 to 1999. In 6 APA journals, there was a low percentage (4.7%) of such articles. African Americans were the most studied ethnic group. Data collected for this study also indicated that minority research has been increasing more in non-APA journals than in APA journals. In both APA and non-APA journals, counseling-oriented journals had higher percentages of minority articles than did journals of other subdisciplines. Possible explanations, consequences, and suggestions for future research are discussed.


Subject(s)
Ethnicity/statistics & numerical data , Minority Groups/statistics & numerical data , Periodicals as Topic/statistics & numerical data , Psychology , Publishing/statistics & numerical data , Research Subjects , Counseling/statistics & numerical data , Cultural Diversity , Data Interpretation, Statistical , Humans , Research Subjects/psychology , Societies, Scientific
14.
Ann Oncol ; 15(1): 113-7, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14679129

ABSTRACT

BACKGROUND: The outcome of patients with nasopharyngeal carcinoma (NPC) presenting as advanced-stage disease or failing conventional radio-chemotherapy is poor. Thus, additional forms of effective, low-toxicity treatment are warranted to improve NPC prognosis. Since NPC is almost universally associated with Epstein-Barr virus (EBV), cellular immunotherapy with EBV-specific cytotoxic T lymphocytes (CTLs) may prove a successful treatment strategy. Patient and methods A patient with relapsed NPC, refractory to conventional treatments, received salvage adoptive immunotherapy with EBV-specific CTLs reactivated ex vivo from a human leukocyte antigen-identical sibling. EBV-specific immunity, as well as T-cell repertoire in the tumor, before and after immunotherapy, was evaluated. RESULTS: CTL transfer was well tolerated, and a temporary stabilization of disease was obtained. Moreover, notwithstanding the short in-vivo duration of allogeneic CTLs, immunotherapy induced a marked increase of endogenous tumor-infiltrating CD8+ T lymphocytes, and a long-term increase of latent membrane protein 2-specific immunity. CONCLUSIONS: Preliminary data obtained in this patient indicate that EBV-specific CTLs are safe, may exert specific killing of NPC tumor cells in vitro, and induce antitumor effect in vivo.


Subject(s)
Antigens, Viral/immunology , Herpesvirus 4, Human/immunology , Immunotherapy, Adoptive , Nasopharyngeal Neoplasms/immunology , Nasopharyngeal Neoplasms/therapy , Neoplasms, Glandular and Epithelial/immunology , Neoplasms, Glandular and Epithelial/therapy , T-Lymphocytes, Cytotoxic/immunology , Viral Matrix Proteins/immunology , Adult , Humans , Immunohistochemistry , Male , Nasopharyngeal Neoplasms/pathology , Neoplasms, Glandular and Epithelial/pathology , Neoplasms, Glandular and Epithelial/virology , T-Lymphocytes, Cytotoxic/transplantation , Transplantation, Homologous , Virus Latency
15.
Bone Marrow Transplant ; 32(5): 489-94, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12942095

ABSTRACT

The aim of this study was to identify trends in high-dose chemotherapy (HDC) with autologous hematopoietic stem cell transplantation (ASCT) and to assess survival in a large cohort of breast cancer (BC) patients receiving this therapy in Europe from 1990 to 1999. A total of 7471 patients who received HDC with ASCT between January 1, 1990 and December 31, 1999 were reported to the European Group for Blood and Marrow Transplantation Registry. Data required for demographics and survival analysis were available for 2679 patients with high-risk primary BC; 921 patients with inflammatory BC (IBC), and 2295 patients with metastatic disease. The main evaluation parameters were progression-free survival (PFS) and overall survival (OS). Between 1990 and 1998, autotransplants for BC increased 30-fold. Significant trends included use of blood-derived rather than marrow-derived stem cells, increment of reporting centers and decrease of mortality within 100 days from transplantation. The 5-year PFS and OS probabilities were 53 and 68% for high-risk disease and 42 and 53% for IBC, respectively. For metastatic disease 5-year PFS and OS probabilities in the whole cohort were 18 and 27%, respectively, while for women transplanted in complete remission the 5-year PFS was 29%. In conclusion, HDC with ASCT has been increasingly used until 1998 and the 100-day mortality rate has been constantly less than 2% from 1995 to date. The 5-year survival of high-risk BC is related to the number of axillary nodes involved at surgery. Outcome of patients with IBC is encouraging, suggesting the need for randomized trials. Patients with metastatic disease responding to pretransplant chemotherapy and harboring ER+ tumors have a better outcome.


Subject(s)
Breast Neoplasms/mortality , Breast Neoplasms/therapy , Hematopoietic Stem Cell Transplantation/mortality , Hematopoietic Stem Cell Transplantation/trends , Registries , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/pathology , Europe , Female , Hematopoietic Stem Cell Transplantation/statistics & numerical data , Humans , Survival Analysis , Transplantation, Autologous
16.
Clin Cancer Res ; 7(9): 2770-5, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11555591

ABSTRACT

PURPOSE: The goal of this work was to study the expression of epidermal growth factor receptor (by use of monoclonal antibody EGFR 1) and HER-2/neu (by use of monoclonal antibody EGFR 2), as well as EGFR activation [phosphorylated EGFR (P-EGFR)] and autocrine stimulation [ligand transforming growth factor-alpha (TGF-alpha)] markers in a series of 24 testicular tumors [18 nonseminomatous germ cell tumors (GCTs), 1 Leydig cell tumor, and 5 seminomatous GCTs]. EXPERIMENTAL DESIGN: Paraffin-embedded sections of tumors were studied immunohistochemically for beta-human chorionic gonadotropin (beta-HCG), EGFR 1, HER-2/neu, TGF-alpha, and P-EGFR expression. In one case of pure choriocarcinoma, fresh-frozen tumor sections were also evaluated. The presence of EGFR mRNA was studied in the Jar choriocarcinoma cell line using reverse transcription-PCR. RESULTS: Staining for cell membrane EGFR was detected immunohistochemically in the 16 beta-HCG-positive components of 18 nonseminomatous GCTs as well as in the control Jar choriocarcinoma cell line and normal placenta. In contrast, 1 Leydig cell tumor, 5 seminomatous GCTs, and beta-HCG-negative components of 18 GCTs, as well as control B and T lymphoma cell lines, did not express EGFR. Expression of HER-2/neu, TGF-alpha, and P-EGFR was detected in 25, 36, and 27% of EGFR-positive, nonseminomatous GCTs, respectively. EGFR mRNA was detected in the Jar choriocarcinoma cells. CONCLUSIONS: We report data, for the first time, that document EGFR and HER-2/neu expression and indicate EGFR activation and autocrine stimulation in beta-HCG-positive, nonseminomatous GCTs. These findings may be clinically relevant in relation to the recent availability of active EGFR- and HER-2/neu-targeted pharmaceutical agents and to the extensively described negative prognostic significance of beta-HCG expression in mixed GCTs.


Subject(s)
ErbB Receptors/metabolism , Germinoma/metabolism , Testicular Neoplasms/metabolism , Chorionic Gonadotropin, beta Subunit, Human/analysis , ErbB Receptors/genetics , Gene Expression Regulation, Neoplastic , Germinoma/genetics , Germinoma/pathology , Humans , Immunohistochemistry , Male , Phosphorylation , RNA, Messenger/genetics , RNA, Messenger/metabolism , Receptor, ErbB-2/analysis , Reverse Transcriptase Polymerase Chain Reaction , Testicular Neoplasms/genetics , Testicular Neoplasms/pathology , Transforming Growth Factor alpha/analysis
17.
Blood ; 97(12): 3910-8, 2001 Jun 15.
Article in English | MEDLINE | ID: mdl-11389034

ABSTRACT

The molecular cloning of the t(5;10)(q33;q22) associated with atypical chronic myeloid leukemia (CML) is reported. Fluorescence in situ hybridization (FISH), Southern blot, and reverse transcriptase- polymerase chain reaction analysis demonstrated that the translocation resulted in an H4/platelet-derived growth factor receptor betaR (PDGFbetaR) fusion transcript that incorporated 5' sequences from H4 fused in frame to 3' PDGFbetaR sequences encoding the transmembrane, WW-like, and tyrosine kinase domains. FISH combined with immunophenotype analysis showed that t(5;10)(q33;q22) was present in CD13(+) and CD14(+) cells but was not observed in CD3(+) or CD19(+) cells. H4 has previously been implicated in pathogenesis of papillary thyroid carcinoma as a fusion partner of RET. The H4/RET fusion incorporates 101 amino acids of H4, predicted to encode a leucine zipper dimerization domain, whereas the H4/PDGFbetaR fusion incorporated an additional 267 amino acids of H4. Retroviral transduction of H4/PDGFbetaR, but not a kinase-inactive mutant, conferred factor-independent growth to Ba/F3 cells and caused a T-cell lymphoblastic lymphoma in a murine bone marrow transplantation assay of transformation. Mutational analysis showed that the amino-terminal H4 leucine zipper domain (amino acids 55-93), as well as H4 amino acids 101 to 386, was required for efficient induction of factor-independent growth of Ba/F3 cells. Tryptophan-to-alanine substitutions in the PDGFbetaR WW-like domain at positions 566/593, or tyrosine-to-phenylalanine substitutions at PDGFbetaR positions 579/581 impaired factor-independent growth of Ba/F3 cells. H4/PDGFbetaR is an oncoprotein expressed in t(5;10)(q33;q22) atypical CML and requires dimerization motifs in the H4 moiety, as well as residues implicated in signal transduction by PDGFbetaR, for efficient induction of factor-independent growth of Ba/F3 cells. (Blood. 2001;97:3910-3918)


Subject(s)
Carcinoma, Papillary/genetics , Chromosomes, Human, Pair 10 , Chromosomes, Human, Pair 5 , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/genetics , Proteins/genetics , Receptor, Platelet-Derived Growth Factor beta/genetics , Thyroid Neoplasms/genetics , Translocation, Genetic , Cell Transformation, Neoplastic/genetics , Chromosomes, Human, Pair 10/genetics , Chromosomes, Human, Pair 5/genetics , Cloning, Molecular , Cytogenetic Analysis , Cytoskeletal Proteins , DNA, Neoplasm/genetics , DNA, Neoplasm/isolation & purification , Gene Rearrangement , Humans , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/etiology , Leukemia, Myelogenous, Chronic, BCR-ABL Positive/pathology , Mutagenesis , Myeloid Cells/metabolism , Myeloid Cells/pathology , Oncogene Proteins, Fusion , Protein Structure, Tertiary , Proteins/metabolism , Transfection
18.
Tumori ; 86(4): 312-3, 2000.
Article in English | MEDLINE | ID: mdl-11016712

ABSTRACT

A new phase of breast conserving surgery has started very recently, aimed at eliminating axillary dissection in node-negative patients by using the sentinel lymph node (SN) technique. Between November 1998 and January 2000 we performed 151 operations for breast cancer on 145 patients. We performed axillary lymphoscintigraphy using 99Tc-labeled human serum albumin microcolloidal particles injected subdermally in 50 patients who met our selection criteria. In this series we focused on the success rate of scintigraphic and surgical sentinel node identification. The number of scintigraphic identifications of the SN was 44 (88%). Only forty-three cases were evaluable, as in one case mapping showed an internal mammary hot node. All SNs were located at the first level. After removal of the SN complete axillary dissection was performed. Eighteen patients (41.8%) had metastatic disease in the axilla. There were five (11.6%) false negatives: two in T2 tumors, one in a T4 tumor and two in T1c tumors. We consider this series as our training series. Our results are similar to those reported in the literature. We believe that the most reasonable approach to SN biopsy is a two-step procedure: the ideal candidates are patients with T1 cancer who can undergo the operation in an outpatient setting under local anesthesia and sedation. Complete axillary dissection is performed only if paraffin sections and immunohistochemistry show metastatic disease.


Subject(s)
Breast Neoplasms/diagnostic imaging , Breast Neoplasms/pathology , General Surgery/education , Lymph Nodes/diagnostic imaging , Lymph Nodes/pathology , Sentinel Lymph Node Biopsy , Axilla , Breast Neoplasms/surgery , Breast Neoplasms, Male/diagnostic imaging , Breast Neoplasms, Male/pathology , Education, Medical, Continuing , Female , Humans , Italy , Lymph Nodes/surgery , Male , Patient Selection , Predictive Value of Tests , Radionuclide Imaging , Sentinel Lymph Node Biopsy/methods
20.
Br J Haematol ; 108(3): 653-9, 2000 Mar.
Article in English | MEDLINE | ID: mdl-10759725

ABSTRACT

We have recently reported the possibility of supporting the phase of severe thrombocytopenia after high-dose chemotherapy (HDC) and stem cell transplantation using 5% dimethylsulphoxide (DMSO)-cryopreserved autologous platelet concentrates (PCs). The aim of the present study was to evaluate the therapeutic potential of ThromboSol (a recently developed platelet storage solution) plus PCs cryopreserved in 2% DMSO in patients undergoing myeloablative chemotherapy and autologous transplantation. PCs were collected from 14 women with breast cancer by a single plateletapheresis and cryopreserved in ThromboSol/2% DMSO by either direct insertion in a -80 degrees C freezer or in liquid nitrogen after computer-controlled rate (CR) freezing. When required, PCs were thawed, centrifuged to remove the cryoprotectants and transfused. In vitro studies on thawed platelets showed loss of epitopes of surface glycoproteins and a marked reduction of functional activity compared with fresh platelets. Transfusion of CR-frozen PCs was associated with a mean 1 h corrected count increment (CCI) of 9.2 +/- 5.4 x 109/l and only one allogeneic PC was required in this group. In contrast, six out of seven patients required additional allogeneic transfusions in the -80 degrees C group (CCI = 2.7 +/- 1.4 x 109/l). ThromboSol-treated PCs have the ability to overcome thrombocytopenia if processed by a CR freezing protocol, but appear ineffective when frozen by direct placing at -80 degrees C.


Subject(s)
Breast Neoplasms/therapy , Platelet Transfusion/methods , Thrombocytopenia/therapy , Blood Transfusion, Autologous , Cryopreservation/methods , Cryoprotective Agents , Dimethyl Sulfoxide , Drug Administration Schedule , Female , Flow Cytometry , Humans , Pilot Projects , Platelet Aggregation
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