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1.
Gastroenterology ; 155(2): 479-489.e7, 2018 08.
Artigo em Inglês | MEDLINE | ID: mdl-29655834

RESUMO

BACKGROUND & AIMS: Metformin seems to have anticancer effects. However, it is not clear whether use of glycemia and metformin affect outcomes of patients with advanced pancreatic neuroendocrine tumors (pNETs). We investigated the association between glycemia and progression-free survival (PFS) of patients with pNETs treated with everolimus and/or somatostatin analogues, as well as the association between metformin use and PFS time. METHODS: We performed a retrospective analysis of 445 patients with advanced pNET treated at 24 medical centers in Italy from 1999 through 2015. Data on levels of glycemia were collected at time of diagnosis of pNET, before treatment initiation, and during treatment with everolimus (with or without somatostatin analogues), octreotide, or lanreotide. Diabetes was defined as prior or current use of glycemia control medication and/or fasting plasma glucose level ≥ 126 mg/dL, hemoglobin A1c ≥ 6.5% (48 mmol/L), or a random sample of plasma glucose ≥ 200 mg/dL (11.1 mmol/L), with reported classic symptoms of hyperglycemia or hyperglycemic crisis. Patients were assigned to groups based on diagnosis of diabetes before or during antitumor therapy. PFS was compared between patients with vs without diabetes. Among patients with diabetes, the association between metformin use and PFS was assessed. We performed sensitivity and landmark analyses to exclude patients who developed diabetes while receiving cancer treatment and to exclude a potential immortal time bias related to metformin intake. RESULTS: PFS was significantly longer in patients with diabetes (median, 32.0 months) than without diabetes (median, 15.1 months) (hazard ratio for patients with vs without diabetes, 0.63; 95% confidence interval, 0.50-0.80; P = .0002). PFS of patients treated with metformin was significantly longer (median PFS, 44.2 months) than for patients without diabetes (hazard ratio for survival of patients with diabetes receiving metformin vs without diabetes, 0.45; 95% confidence interval, 0.32-0.62; P < .00001) and longer than for patients with diabetes receiving other treatments (median PFS, 20.8 months; hazard ratio, 0.49; 95% confidence interval, 0.34-0.69; P < .0001). In multivariable analysis, adjusted for other factors associated with outcomes, metformin was associated with longer PFS but level of glycemia was not. Metformin was associated with increased PFS of patients receiving somatostatin analogues and in those receiving everolimus, with or without somatostatin analogues. Sensitivity and landmark analyses produced similar results. CONCLUSIONS: In a retrospective study of patients with pNETs, we found a significant association between metformin use and longer PFS.


Assuntos
Antineoplásicos/uso terapêutico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Everolimo/uso terapêutico , Metformina/uso terapêutico , Tumores Neuroendócrinos/tratamento farmacológico , Neoplasias Pancreáticas/tratamento farmacológico , Somatostatina/análogos & derivados , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Diabetes Mellitus Tipo 2/mortalidade , Intervalo Livre de Doença , Feminino , Humanos , Hipoglicemiantes/uso terapêutico , Itália/epidemiologia , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/patologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto Jovem
2.
Clin Gastroenterol Hepatol ; 14(8): 1216-20, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27033429

RESUMO

Refractory celiac disease is characterized by mucosal damage in patients with celiac disease despite a gluten-free diet. Little is known about the mechanisms that cause persistent intestinal inflammation in these patients. We performed a case-control study of 17 consecutive patients diagnosed with refractory celiac disease from 2001 through 2014 (median age, 51 y; 10 women) and 24 patients with uncomplicated celiac disease (controls) to determine whether refractory disease is associated with infection by lymphotropic oncogenic viruses. We performed real-time PCR analyses of duodenal biopsy samples from all patients to detect Epstein-Barr virus (EBV), human herpesvirus-8, and human T-cell lymphotropic virus-I, -II, or -III. We used in situ hybridization and immunohistochemical analyses to identify infected cells and viral proteins. We did not detect human herpesvirus-8 or human T-cell lymphotropic viruses in any of the biopsy specimens. However, 12 of 17 (70.5%) biopsy specimens from patients with refractory celiac disease were positive for EBV, compared with 4 of 24 (16.6%) biopsy specimens from controls (P < .001). EBV was detected in inflammatory cells and enterocytes. An analysis of latency- and replication-associated proteins confirmed active infection. Further studies are needed to determine whether EBV infection contributes to the pathogenesis of refractory celiac disease and enteropathy-associated T-cell lymphoma.


Assuntos
Doença Celíaca/complicações , Duodeno/patologia , Infecções por Vírus Epstein-Barr/diagnóstico , Infecções por Vírus Epstein-Barr/patologia , Herpesvirus Humano 4/isolamento & purificação , Mucosa Intestinal/patologia , Adulto , Idoso , Biópsia , Estudos de Casos e Controles , Doença Celíaca/etiologia , DNA Viral/análise , DNA Viral/genética , Infecções por Vírus Epstein-Barr/complicações , Feminino , Herpesvirus Humano 4/genética , Herpesvirus Humano 8/genética , Herpesvirus Humano 8/isolamento & purificação , Vírus Linfotrópico T Tipo 1 Humano/genética , Vírus Linfotrópico T Tipo 1 Humano/isolamento & purificação , Humanos , Imuno-Histoquímica , Hibridização In Situ , Masculino , Pessoa de Meia-Idade , RNA Viral/análise , RNA Viral/genética , Reação em Cadeia da Polimerase em Tempo Real
3.
Blood ; 123(23): 3543-52, 2014 Jun 05.
Artigo em Inglês | MEDLINE | ID: mdl-24665135

RESUMO

Poor prognosis and limited therapeutic options characterize immunoglobulin light-chain (AL) amyloidosis with major heart involvement. Reliable experimental models are needed to study light-chain (LC)/heart interactions and to explore strategies for prevention of cardiac damage. We have exploited the nematode Caenorhabditis elegans as a novel tool, because its pharynx is evolutionarily related to the vertebrate heart. Our data demonstrate that the pharyngeal pumping of C elegans is significantly and selectively reduced by LCs from AL patients suffering from cardiomyopathy, but not by amyloid LCs with different organ tropism or nonamyloidogenic LCs from multiple myeloma. This functional alteration is dependent on the LC concentration and results in persistent pharyngeal dysfunction and in a significant reduction of the worms' lifespan. These manifestations are paralleled by an increase of mitochondrial reactive oxygen species and can be prevented by treatment with antioxidant agents. In conclusion, these data indicate that this nematode-based assay is a promising surrogate model for investigating the heart-specific toxicity of amyloidogenic LCs and for a rapid screening of new therapeutic strategies.


Assuntos
Amiloidose/diagnóstico , Caenorhabditis elegans , Cardiopatias/diagnóstico , Cadeias Leves de Imunoglobulina/imunologia , Adulto , Idoso , Amiloidose/imunologia , Animais , Bioensaio , Cardiotoxinas/isolamento & purificação , Cardiotoxinas/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Feminino , Cardiopatias/imunologia , Humanos , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/imunologia , Faringe/citologia , Faringe/efeitos dos fármacos , Faringe/fisiologia
4.
Blood ; 119(1): 144-50, 2012 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-22067386

RESUMO

Monoclonal Ig light chains (LC) can be responsible for pathologic conditions in humans, as in systemic amyloid light amyloidosis. Protean clinical manifestations characterize this disorder with the most varied combination of symptoms generated by different degrees of diverse organ involvement. Kidney and heart are most frequently interested, with major heart involvement as the most relevant prognostic factor. The identification of the underlying mechanism involved in organ targeting is of major relevance for the pathobiology of this disorder. To this aim, we characterized the repertoire of variable region germline genes of λ LC preferentially targeting the heart and compared it with the repertoire of LC that do not in a case-control study. We found that the repertoires were highly restricted, showing preferential use of the same few germline genes but with a different frequency pattern. A single gene, IGVL1-44, was found associated with a 5-fold increase in the odds of dominant heart involvement (after adjusting for confounders in a multivariable logistic model). These results support an involvement of LC genetics in the determination of organ targeting. Study of the characteristics of IGVL1-44-LC with, and of the minority without, heart involvement might lead to identification of LC/tissue interactions.


Assuntos
Amiloide/genética , Amiloidose/etiologia , Genes de Imunoglobulinas/genética , Cardiopatias/etiologia , Cadeias Leves de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Cadeias lambda de Imunoglobulina/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Sequência de Aminoácidos , Amiloidose/mortalidade , Amiloidose/patologia , Estudos de Casos e Controles , Feminino , Células Germinativas , Cardiopatias/mortalidade , Cardiopatias/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Prognóstico , Homologia de Sequência de Aminoácidos , Taxa de Sobrevida
5.
Biochim Biophys Acta ; 1814(3): 409-19, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21215335

RESUMO

An excess of circulating monoclonal free immunoglobulin light chains (FLC) is common in plasma cell disorders. A subset of FLC, as amyloidogenic ones, possess intrinsic pathogenicity. Because of their complex purification, little is known on the biochemical features of serum FLC, possibly related to their pathogenic spectrum. We developed an immunopurification approach to isolate serum FLC from patients with monoclonal gammopathies, followed by proteomic characterization. Serum monoclonal FLC were detected and quantified by immunofixation and immunonephelometry. Immunoprecipitation was performed by serum incubation with agarose beads covalently linked to polyclonal anti-κ or λ FLC antibodies. Isolated FLC were analyzed by SDS-PAGE, 2D-PAGE, immunoblotting, mass spectrometry (MS). Serum FLC were immunoprecipitated from 15 patients with ALλ amyloidosis (serum λ FLC range: 98-2350mg/L), 5 with ALκ amyloidosis and 1 with κ light chain (LC) myeloma (κ FLC range: 266-2660mg/L), and 3 controls. Monoclonal FLC were the prevalent eluted species in patients. On 2D-PAGE, both λ and κ FLC originated discrete spots with multiple pI isoforms. The nature of eluted FLC and coincidence with the LC sequence from the bone marrow clone was confirmed by MS, which also detected post-translational modifications, including truncation, tryptophan oxidation, cysteinylation, peptide dimerization. Serum FLC were purified in soluble form and adequate amounts for proteomics, which allowed studying primary sequence and detecting post-translational modifications. This method is a novel instrument for studying the molecular bases of FLC pathogenicity, allowing for the first time the punctual biochemical description of the circulating forms.


Assuntos
Cadeias Leves de Imunoglobulina/sangue , Cadeias kappa de Imunoglobulina/isolamento & purificação , Cadeias lambda de Imunoglobulina/isolamento & purificação , Proteômica/métodos , Adulto , Idoso , Sequência de Aminoácidos , Amiloidose/sangue , Anticorpos Monoclonais/isolamento & purificação , Cromatografia Líquida , Feminino , Humanos , Cadeias Leves de Imunoglobulina/isolamento & purificação , Imunoprecipitação/métodos , Masculino , Espectrometria de Massas , Pessoa de Meia-Idade , Dados de Sequência Molecular , Processamento de Proteína Pós-Traducional , Alinhamento de Sequência
6.
J Clin Gastroenterol ; 46(8): 675-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22298086

RESUMO

BACKGROUND: Refractory celiac disease (RCD) is a preneoplastic condition as many patients develop an enteropathy-type T-cell lymphoma, a mature T-cell receptor α-ß lymphoma arising in the gut with an ominous outcome. Recently, research focused on a population of intraepithelial intestinal lymphocytes expressing the same lymphoma T-cell receptor variable region (V)γ, as shown by polymerase chain reaction (PCR) analysis and sequencing. Meanwhile, the Biomedicine and Health-2 Concerted Action has made available standardized, highly specific, and sensitive PCR assays not only for Vγ but also for Vß. GOALS: We verified whether analyzing both rearrangements in duodenal biopsies from RCD patients increases the diagnostic accuracy of this method. STUDY: Duodenal biopsies were analyzed from 15 RCD patients, 21 negative controls, and 2 positive controls (enteropathy-type T-cell lymphoma complicating celiac disease). Multiplex clonality analyses were performed according to the Biomedicine and Health-2 protocols. PCR products were cloned and sequenced. RESULTS: Monoclonal rearrangements were found in 5/15 samples from patients with RCD (both rearrangements in 2 cases, Vß only in 2, and only 1 solitary Vγ clonality). Monoclonality was found in 4/8 of the RCD patients who subsequently died, whereas only 1/7 of the patients still alive presented a monoclonal rearrangement. Positive controls revealed both monoclonal rearrangements; rearrangements were not detected in 20 of 21 negative controls. Sequencing of the amplified fragments confirmed the results. CONCLUSIONS: The combined analysis of both rearrangements allowed recognition of monoclonal populations in otherwise negative patients, with detection rates from 20% (Vγ only) to 33% (Vγ and Vß), thus raising the likelihood of early identification of RCD patients at high risk of death.


Assuntos
Doença Celíaca/complicações , Doença Celíaca/diagnóstico , Duodeno/imunologia , Rearranjo Gênico da Cadeia beta dos Receptores de Antígenos dos Linfócitos T/genética , Rearranjo Gênico da Cadeia gama dos Receptores de Antígenos dos Linfócitos T/genética , Linfoma de Células T/complicações , Linfoma de Células T/diagnóstico , Adolescente , Adulto , Biópsia , Doença Celíaca/imunologia , Doença Celíaca/patologia , Duodeno/metabolismo , Duodeno/patologia , Feminino , Humanos , Linfoma de Células T/imunologia , Linfoma de Células T/patologia , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Valor Preditivo dos Testes , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Receptores de Antígenos de Linfócitos T gama-delta/genética , Receptores de Antígenos de Linfócitos T gama-delta/metabolismo , Análise de Sequência de DNA , Adulto Jovem
7.
JAMA Netw Open ; 5(2): e220290, 2022 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-35201309

RESUMO

Importance: Data about the optimal timing for the initiation of peptide receptor radionuclide therapy (PRRT) for advanced, well-differentiated enteropancreatic neuroendocrine tumors are lacking. Objective: To evaluate the association of upfront PRRT vs upfront chemotherapy or targeted therapy with progression-free survival (PFS) among patients with advanced enteropancreatic neuroendocrine tumors who experienced disease progression after treatment with somatostatin analogues (SSAs). Design, Setting, and Participants: This retrospective, multicenter cohort study analyzed the clinical records from 25 Italian oncology centers for patients aged 18 years or older who had unresectable, locally advanced or metastatic, well-differentiated, grades 1 to 3 enteropancreatic neuroendocrine tumors and received either PRRT or chemotherapy or targeted therapy after experiencing disease progression after treatment with SSAs between January 24, 2000, and July 1, 2020. Propensity score matching was done to minimize the selection bias. Exposures: Upfront PRRT or upfront chemotherapy or targeted therapy. Main Outcomes and Measures: The main outcome was the difference in PFS among patients who received upfront PRRT vs among those who received upfront chemotherapy or targeted therapy. A secondary outcome was the difference in overall survival between these groups. Hazard ratios (HRs) were fitted in a multivariable Cox proportional hazards regression model to adjust for relevant factors associated with PFS and were corrected for interaction with these factors. Results: Of 508 evaluated patients (mean ([SD] age, 55.7 [0.5] years; 278 [54.7%] were male), 329 (64.8%) received upfront PRRT and 179 (35.2%) received upfront chemotherapy or targeted therapy. The matched group included 222 patients (124 [55.9%] male; mean [SD] age, 56.1 [0.8] years), with 111 in each treatment group. Median PFS was longer in the PRRT group than in the chemotherapy or targeted therapy group in the unmatched (2.5 years [95% CI, 2.3-3.0 years] vs 0.7 years [95% CI, 0.5-1.0 years]; HR, 0.35 [95% CI, 0.28-0.44; P < .001]) and matched (2.2 years [95% CI, 1.8-2.8 years] vs 0.6 years [95% CI, 0.4-1.0 years]; HR, 0.37 [95% CI, 0.27-0.51; P < .001]) populations. No significant differences were shown in median overall survival between the PRRT and chemotherapy or targeted therapy groups in the unmatched (12.0 years [95% CI, 10.7-14.1 years] vs 11.6 years [95% CI, 9.1-13.4 years]; HR, 0.81 [95% CI, 0.62-1.06; P = .11]) and matched (12.2 years [95% CI, 9.1-14.2 years] vs 11.5 years [95% CI, 9.2-17.9 years]; HR, 0.83 [95% CI, 0.56-1.24; P = .36]) populations. The use of upfront PRRT was independently associated with improved PFS (HR, 0.37; 95% CI, 0.26-0.51; P < .001) in multivariable analysis. After adjustment of values for interaction, upfront PRRT was associated with longer PFS regardless of tumor functional status (functioning: adjusted HR [aHR], 0.39 [95% CI, 0.27-0.57]; nonfunctioning: aHR, 0.29 [95% CI, 0.16-0.56]), grade of 1 to 2 (grade 1: aHR, 0.21 [95% CI, 0.12-0.34]; grade 2: aHR, 0.52 [95% CI, 0.29-0.73]), and site of tumor origin (pancreatic: aHR, 0.41 [95% CI, 0.24-0.61]; intestinal: aHR, 0.19 [95% CI, 0.11-0.43]) (P < .001 for all). Conversely, the advantage was not retained in grade 3 tumors (aHR, 0.31; 95% CI, 0.12-1.37; P = .13) or in tumors with a Ki-67 proliferation index greater than 10% (aHR, 0.73; 95% CI, 0.29-1.43; P = .31). Conclusions and Relevance: In this cohort study, treatment with upfront PRRT in patients with enteropancreatic neuroendocrine tumors who had experienced disease progression with SSA treatment was associated with significantly improved survival outcomes compared with upfront chemotherapy or targeted therapy. Further research is needed to investigate the correct strategy, timing, and optimal specific sequence of these therapeutic options.


Assuntos
Tumores Neuroendócrinos , Neoplasias Pancreáticas , Radioterapia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/epidemiologia , Tumores Neuroendócrinos/mortalidade , Tumores Neuroendócrinos/radioterapia , Neoplasias Pancreáticas/tratamento farmacológico , Neoplasias Pancreáticas/epidemiologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/radioterapia , Intervalo Livre de Progressão , Radioterapia/efeitos adversos , Radioterapia/métodos , Radioterapia/estatística & dados numéricos , Receptores de Peptídeos , Estudos Retrospectivos
8.
World J Surg Oncol ; 9: 105, 2011 Sep 16.
Artigo em Inglês | MEDLINE | ID: mdl-21923918

RESUMO

The spleen is an infrequent site for metastatic lesions, and solitary splenic metastases from squamous cell carcinoma of the esophagus are very rare: only 4 cases have been reported thus far. These lesions are whitish nodules that are macroscopically and radiologically similar to primary splenic lymphomas. We report a case of metachronous splenic metastases from esophageal cancer and multiple splenic abscesses, which developed nine months after apparently curative esophagectomy without adjuvant chemotherapy. The patient underwent splenectomy dissection followed by adjuvant chemotherapy, but liver and skin metastases developed, and the patient died 9 months later.


Assuntos
Carcinoma de Células Escamosas/secundário , Neoplasias Esofágicas/patologia , Neoplasias Esplênicas/secundário , Biópsia , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/cirurgia , Diagnóstico Diferencial , Endoscopia Gastrointestinal , Neoplasias Esofágicas/cirurgia , Esofagectomia , Evolução Fatal , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , Esplenectomia , Neoplasias Esplênicas/diagnóstico , Neoplasias Esplênicas/cirurgia , Tomografia Computadorizada por Raios X
9.
Thorac Cancer ; 12(17): 2415-2419, 2021 09.
Artigo em Inglês | MEDLINE | ID: mdl-34346158

RESUMO

Neuroendocrine tumors (NETs) are epithelial neoplasms with predominant neuroendocrine differentiation that arise in most organs of the body. Mediastinal NETs are very rare, and account for no more than 5% of all mediastinal tumors. R0 surgery represents the milestone of treatment. Here, we describe a case of a locally advanced primary atypical carcinoid of the mediastinum. This was initially considered inoperable due to infiltration of a great vessel and was successfully resected after neoadjuvant treatment as a result of very extensive surgery. Only through an accurate preoperative diagnosis and good radiological planning is it possible to obtain satisfactory oncological results.


Assuntos
Antineoplásicos/uso terapêutico , Tumor Carcinoide/tratamento farmacológico , Tumor Carcinoide/cirurgia , Neoplasias do Mediastino/tratamento farmacológico , Neoplasias do Mediastino/cirurgia , Terapia Neoadjuvante/métodos , Idoso , Terapia Combinada , Humanos , Masculino , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/cirurgia
10.
Blood ; 112(3): 750-9, 2008 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-18474725

RESUMO

The interleukin-12 (IL-12) receptor (R) B2 gene acts as tumor suppressor in human acute and chronic B-cell leukemias/lymphomas and IL-12rb2-deficient mice develop spontaneously localized plasmacytomas. With this background, we investigated the role of IL-12R beta 2 in multiple myeloma (MM) pathogenesis. Here we show the following: (1) IL-12R beta 2 was expressed in primary MM cells but down-regulated compared with normal polyclonal plasmablastic cells and plasma cells (PCs). IL-6 dampened IL-12R beta 2 expression on polyclonal plasmablastic cells and MM cells. (2) IL-12 reduced the proangiogenic activity of primary MM cells in vitro and decreased significantly (P = .001) the tumorigenicity of the NCI-H929 cell line in SCID/NOD mice by inhibiting cell proliferation and angiogenesis. The latter phenomenon was found to depend on abolished expression of a wide panel of proangiogenic genes and up-regulated expression of the antiangiogenic genes IFN-gamma, IFN-alpha, platelet factor-4, and TIMP-2. Inhibition of the angiogenic potential of primary MM cells was related to down-regulated expression of the proangiogenic genes CCL11, vascular endothelial-cadherin, CD13, and AKT and to up-regulation of an IFN-gamma-related antiangiogenic pathway. Thus, IL-12R beta 2 directly restrains MM cell growth, and targeting of IL-12 to tumor cells holds promise as new therapeutic strategy.


Assuntos
Regulação Neoplásica da Expressão Gênica , Mieloma Múltiplo/química , Receptores de Interleucina-12/análise , Idoso , Idoso de 80 Anos ou mais , Animais , Proliferação de Células/efeitos dos fármacos , Humanos , Interleucina-12/farmacologia , Camundongos , Camundongos SCID , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Mieloma Múltiplo/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/genética , Receptores de Interleucina-12/genética , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
11.
Endocr Pathol ; 31(4): 411-417, 2020 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-32388775

RESUMO

Pancreatic neuroendocrine carcinomas (NECs) are rare and very aggressive neoplasms with dismal prognosis, especially when metastatic or with negative prognostic factors, such as vascular invasion. To the best of our knowledge, no case of pancreatic NEC with mismatch repair deficiency has been reported to date. We describe a 62-year-old patient who underwent pancreaticoduodenectomy for a NEC located in the pancreatic head, with peripancreatic lymph node metastases. Tumor necrosis was prominent and the Ki67 proliferative index was 60%. One year after the diagnosis, the patient experienced recurrence with a left supraclavicular lymph node metastasis, which was surgically removed, followed by standard cisplatin-etoposide chemotherapy. Neoplastic cells showed combined loss of expression of MLH1 and PMS2 in both primary tumor and lymph node metastasis. Microsatellite instability (MSI) test using a mononucleotide repeats pentaplex PCR (BAT-25, BAT-26, NR-21, NR-22, and NR-24) revealed minimal mononucleotide shifts showing deletion of less than 3 bp at NR-21, BAT-26, NR-24, and NR-22 loci. MLH1 methylation analysis revealed absence of the gene promoter methylation. BRAF and KRAS mutations were not detected. In gut, NECs' mismatch repair deficiency phenotype has been reported in about 10% of cases, and it represents an independent factor of more favorable outcome. Likewise, our patient is currently alive with a follow-up of more than 12 years after pancreaticoduodenectomy, by itself an unexpected finding for such an aggressive neoplasm.


Assuntos
Carcinoma Neuroendócrino , Endonuclease PMS2 de Reparo de Erro de Pareamento/deficiência , Proteína 1 Homóloga a MutL/deficiência , Neoplasias Pancreáticas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Neuroendócrino/metabolismo , Carcinoma Neuroendócrino/terapia , Cisplatino/uso terapêutico , Terapia Combinada , Reparo de Erro de Pareamento de DNA/fisiologia , Etoposídeo/uso terapêutico , Humanos , Masculino , Instabilidade de Microssatélites , Pessoa de Meia-Idade , Recidiva Local de Neoplasia/tratamento farmacológico , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/terapia , Pancreaticoduodenectomia/métodos , Indução de Remissão , Neoplasias Pancreáticas
12.
Clin Lung Cancer ; 21(6): e567-e571, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32591311

RESUMO

INTRODUCTION: Non-small-cell lung cancer (NSCLC) is predominantly a disease of the elderly population. Over the past few years, immunotherapy with monoclonal antibodies named checkpoint inhibitors (ICIs) greatly improved the clinical management of a significant proportion of patients with metastatic NSCLC. However, pivotal trials excluded older patients, although, given the favorable clinical profile of ICIs, this treatment may be revealed to be a most valuable option also for these patients. To this aim, a multicenter retrospective analysis was performed on patients aged ≥ 75 years with NSCLC treated with anti-programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) immunotherapy. MATERIAL AND METHODS: Inclusion criteria were: diagnosis of locally advanced or metastatic NSCLC (stage IIIB or IV, according to the American Joint Committee on Cancer (AJCC) classification system, version 8.0); age ≥ 75 years; treatment with anti-PD-1/PD-L1 monoclonal antibodies in first or subsequent lines of treatment; absence of epidermal growth factor receptor-activating mutations or anaplastic lymphoma kinase and ROS-1 rearrangements. The primary endpoints of the study were the efficacy, in terms of overall response rate, progression-free survival, and overall survival, and safety, by means of evaluations of the incidence of immune-related adverse events. RESULTS: Eighty-six patients were considered for the final analysis; 71 (82.6%) were male. The mean age was 78.5 years (range, 75-86 years; SD, 3.12 years). Of the 86 patients, 69 (80.2%) of patients had a performance status of 0 or 1. The overall median progression-free survival was 5.6 months (range 1-36 months; SD, 7.5 months,) whereas the median overall survival was 10.1 months (range, 1.7-34.8 months; SD, 8 months). At the Cox regression analysis, the only parameter significantly associated with survival was the smoking status (P = .008). No difference in survival was found between patients younger and older than 80 years. CONCLUSIONS: In the present real-world retrospective cohort, efficacy and toxicity profiles of ICIs in older patients with advanced NSCLC were comparable with those observed in younger patients enrolled in clinical trials.


Assuntos
Adenocarcinoma de Pulmão/tratamento farmacológico , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma de Células Escamosas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Itália , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Ann Hematol ; 88(4): 347-50, 2009 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-18779964

RESUMO

Patients with primary (AL) amyloidosis and heart failure have a very poor prognosis and cannot tolerate aggressive therapy, such as autologous stem cell transplantation and high-dose dexamethasone-based regimens. We prospectively treated 22 patients with advanced cardiac amyloidosis combining oral melphalan, thalidomide, and reduced intensity dexamethasone (MTD). Six patients died due to cardiac amyloidosis before completing cycle 3. Early death was associated with reduced ejection fraction. Eight patients achieved a hematological response and four achieved a durable improvement of cardiac dysfunction. Treatment with MTD is feasible in patients with advanced cardiac AL amyloidosis and effective in subjects with preserved systolic function.


Assuntos
Amiloidose/tratamento farmacológico , Cardiopatias/tratamento farmacológico , Idoso , Dexametasona/administração & dosagem , Quimioterapia Combinada , Feminino , Insuficiência Cardíaca/tratamento farmacológico , Humanos , Masculino , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Volume Sistólico , Taxa de Sobrevida , Talidomida , Resultado do Tratamento
14.
Clin Lymphoma Myeloma ; 9(1): 80-3, 2009 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-19362981

RESUMO

IgM-associated AL amyloidosis is rare and may represent a distinct entity. Sixty (7%) of 868 consecutive AL patients referred to our center had an IgM monoclonal protein. They were significantly older than non-IgM patients (median, 67 years vs. 62 years), had a higher frequency of lymph-node involvement (25% vs. 2%) and significantly lower median proteinuria (1.2 g/24h vs. 3.4 g/24h), N-terminal pro-natriuretic peptide type-B (1177 ng/L vs. 2135 ng/L) and troponin I (0.02 ng/mL vs. 0.05 ng/mL). In IgM patients, kappa light-chains were more frequent (42% vs. 23%) and the involved free light-chain concentration was lower (median 63 mg/L vs. 182 mg/L). Serum albumin and NT-proBNP were independent prognostic determinants. Response to treatment improved survival. The 14 patients who received melphalan/dexamethasone showed a 64% hematologic (complete remissions, 29%) and a 43% organ response rate. IgM-associated AL amyloidosis is a distinct entity, with less advanced organ dysfunction. Treatment with melphalan/ dexamethasone might be effective in these patients.


Assuntos
Amiloidose/sangue , Imunoglobulina M/sangue , Adulto , Idoso , Amiloidose/tratamento farmacológico , Feminino , Humanos , Cadeias Leves de Imunoglobulina/sangue , Masculino , Pessoa de Meia-Idade , Resultado do Tratamento
15.
Mol Immunol ; 45(5): 1519-24, 2008 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-17949814

RESUMO

Cold-precipitating monoclonal immunoglobulins can rarely aggregate in form of crystals (cryocrystalglobulins) and cause serious clinical manifestations. The structural basis underlying this phenomenon remains to be defined. This study was undertaken to provide the first characterization of the heavy (VH) and light chain (VL) variable regions of two human pathogenic cryocrystalglobulins. The immunoglobulins used different heavy and light chain constant regions and germline gene fragments, underwent high degrees of somatic hypermutation, and showed distributions of replacement and silent nucleotide changes suggestive of antigenic selection. Primary sequences analyses and computer-generated modeling identified a positive charge and the introduction of unusual hydrophobic residues in exposed areas of VH and VL. In particular, a rare replacement of a polar residue with proline is shared at the beginning of the VH complementarity-determining region 2, and this residue might be involved in intermolecular contacts.


Assuntos
Anticorpos Monoclonais/genética , Temperatura Baixa , Cadeias Pesadas de Imunoglobulinas/genética , Cadeias Leves de Imunoglobulina/genética , Região Variável de Imunoglobulina/genética , Sequência de Aminoácidos , Anticorpos Monoclonais/química , Cristalização , Humanos , Interações Hidrofóbicas e Hidrofílicas , Cadeias Pesadas de Imunoglobulinas/química , Cadeias Leves de Imunoglobulina/química , Região Variável de Imunoglobulina/química , Modelos Moleculares
17.
Haematologica ; 92(9): 1291-2, 2007 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-17768134

RESUMO

We assessed the percentage of endothelial progenitor cells (EPCs) in the peripheral blood of a patient with POEMS with elevated VEGF plasma levels. High VEGF plasma levels were associated with increased EPC concentration and treatment with an anti-VEGF antibody induced a consensual decrease of both parameters. In vitro cultures of the patient BM cells suggested that the stromal compartment could be responsible for VEGF overproduction.


Assuntos
Movimento Celular , Endotélio Vascular/citologia , Síndrome POEMS/sangue , Células-Tronco/citologia , Fator A de Crescimento do Endotélio Vascular/farmacologia , Inibidores da Angiogênese/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Anticorpos Monoclonais Humanizados , Bevacizumab , Células Cultivadas , Endotélio Vascular/metabolismo , Humanos , Neovascularização Patológica , Síndrome POEMS/tratamento farmacológico , Síndrome POEMS/patologia , Células-Tronco/metabolismo
18.
Eur J Gastroenterol Hepatol ; 19(7): 599-601, 2007 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-17556909

RESUMO

Bortezomib is the first anticancer proteasome inhibitor introduced into clinical practice. It has been recently approved for the treatment of multiple myeloma, an incurable plasma cell tumour that accounts for 10-15% of all haematologic malignancies and for approximately 20% of deaths. Gastrointestinal toxicity associated with the use of this drug is common but generally mild to moderate. Paralytic ileus in patients undergoing bortezomib treatment has been reported, although a definite attribution to bortezomib administration has not been established. We report a myeloma patient who developed severe paralytic ileus during bortezomib therapy, which presented in the context of progressive constipation without other known causes and which regressed promptly with medical management after drug cessation, suggesting a direct causal relationship. Awareness of the various potential gastrointestinal toxic effects of bortezomib is of relevance given the growing number of patients undergoing treatment with this important and effective new cancer drug.


Assuntos
Antineoplásicos/efeitos adversos , Ácidos Borônicos/efeitos adversos , Pseudo-Obstrução Intestinal/induzido quimicamente , Inibidores de Proteases/efeitos adversos , Pirazinas/efeitos adversos , Antineoplásicos/uso terapêutico , Ácidos Borônicos/uso terapêutico , Bortezomib , Humanos , Pseudo-Obstrução Intestinal/diagnóstico por imagem , Masculino , Pessoa de Meia-Idade , Mieloma Múltiplo/tratamento farmacológico , Inibidores de Proteases/uso terapêutico , Pirazinas/uso terapêutico , Radiografia
19.
Oncotarget ; 8(34): 56158-56167, 2017 Aug 22.
Artigo em Inglês | MEDLINE | ID: mdl-28915580

RESUMO

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. GISTs express the receptor tyrosine kinase KIT, and the majority of GISTs present KIT gain-of-function mutations that cluster in the 5' end of the receptor juxtamembrane domain. On the other hand, little information is known about GISTs carrying mutations in the 3' end of the KIT juxtamembrane domain. Here we report and discuss a clinical case of localized duodenal GIST whose molecular characterization revealed the presence of a new 21 nucleotide/7 amino acid deletion in the 3' end of KIT juxtamembrane domain (Δ574-580). The patient was treated with Imatinib at standard regimen dose (400 mg/day), and responded well as the original tumor mass reduced, ultimately allowing conservative surgery. In line with these clinical evidences computer simulations, biophysical techniques and in vitro experiments demonstrated that the receptor tyrosine kinase KIT carrying the Δ574-580 mutation displays constitutive phosphorylation, which can be switched-off upon Imatinib treatment. In addition, results from this study showed that a clinical useful procedure, neoadjuvant treatment, can occasionally be of value for the understanding of the molecular pathogenesis of GIST.

20.
Antioxid Redox Signal ; 27(9): 567-582, 2017 Sep 20.
Artigo em Inglês | MEDLINE | ID: mdl-28132512

RESUMO

AIMS: The knowledge of the mechanism underlying the cardiac damage in immunoglobulin light chain (LC) amyloidosis (AL) is essential to develop novel therapies and improve patients' outcome. Although an active role of reactive oxygen species (ROS) in LC-induced cardiotoxicity has already been envisaged, the actual mechanisms behind their generation remain elusive. This study was aimed at further dissecting the action of ROS generated by cardiotoxic LC in vivo and investigating whether transition metal ions are involved in this process. In the absence of reliable vertebrate model of AL, we used the nematode Caenorhabditis elegans, whose pharynx is an "ancestral heart." RESULTS: LC purified from patients with severe cardiac involvement intrinsically generated high levels of ROS and when administered to C. elegans induced ROS production, activation of the DAF-16/forkhead transcription factor (FOXO) pathway, and expression of proteins involved in stress resistance and survival. Profound functional and structural ROS-mediated mitochondrial damage, similar to that observed in amyloid-affected hearts from AL patients, was observed. All these effects were entirely dependent on the presence of metal ions since addition of metal chelator or metal-binding 8-hydroxyquinoline compounds (chelex, PBT2, and clioquinol) permanently blocked the ROS production and prevented the cardiotoxic effects of amyloid LC. Innovation and Conclusion: Our findings identify the key role of metal ions in driving the ROS-mediated toxic effects of LC. This is a novel conceptual advance that paves the way for new pharmacological strategies aimed at not only counteracting but also totally inhibiting the vicious cycle of redox damage. Antioxid. Redox Signal. 27, 567-582.


Assuntos
Amiloidose de Cadeia Leve de Imunoglobulina/metabolismo , Metais/metabolismo , Mitocôndrias/metabolismo , Espécies Reativas de Oxigênio/metabolismo , Animais , Caenorhabditis elegans , Proteínas de Caenorhabditis elegans/metabolismo , Modelos Animais de Doenças , Fatores de Transcrição Forkhead/metabolismo , Humanos , Estresse Oxidativo , Oxiquinolina , Transdução de Sinais
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