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1.
Infection ; 52(3): 1171-1174, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38512642

RESUMO

BACKGROUND: HIV testing services are a key component of the 95-95-95-0 goals. In many parts of the Democratic Republic of the Congo the availability of test kits is limited for multiple reasons. Targeted testing of patients with HIV indicator conditions is therefore the only feasible option in these settings. METHODS: We introduced an indicator condition-guided HIV testing project in the Emergency Room of the Hôpital Géneral de Référence de Kikwit, DRC. RESULTS: We screened 1274 patients for indicator condition. In 94 (7.4%) patients, the treating physician diagnosed at least one HIV indicator. 34 (36.2%) tested HIV-positive (2.7% of screened patients). 52% of the newly diagnosed patients were lost to follow-up two months after the first diagnosis of HIV. CONCLUSION: In a resource-limited setting with insufficient availability of HIV-Tests, indicator-triggered testing is a useful tool to find a high number of HIV-positive patients. Loss to follow-up is one of the major challenges.


Assuntos
Infecções por HIV , Teste de HIV , População Rural , Humanos , República Democrática do Congo/epidemiologia , Infecções por HIV/diagnóstico , Masculino , Feminino , Adulto , Teste de HIV/métodos , Teste de HIV/estatística & dados numéricos , Pessoa de Meia-Idade , Adulto Jovem , Adolescente , Programas de Rastreamento/métodos
2.
Ann Surg Oncol ; 29(13): 8523-8533, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36094690

RESUMO

BACKGROUND: Pancreatic adenocarcinoma (PDAC) patients with preoperative carbohydrate antigen 19-9 (CA19-9) serum levels higher than 500 U/ml are classified as biologically borderline resectable (BR-B). To date, the impact of cholestasis on preoperative CA19-9 serum levels in these patients has remained unquantified. METHODS: Data on 3079 oncologic pancreatic resections due to PDAC that were prospectively acquired by the German Study, Documentation and Quality (StuDoQ) registry were analyzed in relation to preoperative CA19-9 and bilirubin serum values. Preoperative CA19-9 values were adjusted according to the results of a multivariable linear regression analysis of pathologic parameters, bilirubin, and CA19-9 values. RESULTS: Of 1703 PDAC patients with tumor located in the pancreatic head, 420 (24.5 %) presented with a preoperative CA19-9 level higher than 500 U/ml. Although receiver operating characteristics (ROC) analysis failed to determine exact CA19-9 cut-off values for prognostic indicators (R and N status), the T, N, and G status; the UICC stage; and the number of simultaneous vein resections increased with the level of preoperative CA19-9, independently of concurrent cholestasis. After adjustment of preoperative CA19-9 values, 18.5 % of patients initially staged as BR-B showed CA19-9 values below 500 U/ml. However, the postoperative pathologic results for these patients did not change compared with the patients who had CA19-9 levels higher than 500 U/ml after bilirubin adjustment. CONCLUSIONS: In this multicenter dataset of PDAC patients, elevation of preoperative CA19-9 correlated with well-defined prognostic pathologic parameters. Bilirubin adjustment of CA19-9 is feasible but does not affect the prognostic value of CA19-9 in jaundiced patients.


Assuntos
Adenocarcinoma , Carcinoma Ductal Pancreático , Colestase , Neoplasias Pancreáticas , Humanos , Antígeno CA-19-9 , Neoplasias Pancreáticas/complicações , Neoplasias Pancreáticas/cirurgia , Prognóstico , Adenocarcinoma/complicações , Adenocarcinoma/cirurgia , Bilirrubina , Carcinoma Ductal Pancreático/complicações , Carcinoma Ductal Pancreático/cirurgia , Estudos Retrospectivos , Biomarcadores Tumorais , Neoplasias Pancreáticas
4.
Onkologie ; 36(3): 123-5, 2013.
Artigo em Inglês | MEDLINE | ID: mdl-23486001

RESUMO

BACKGROUND: Unresectable locally advanced pancreatic cancer (LAPC) has an extremely poor prognosis. Results of neoadjuvant (radio-)chemotherapy approaches aiming at achieving resectability are currently not satisfactory. CASE REPORT: We report the case of a 67-year-old woman with histologically confirmed pancreas carcinoma that was not resectable on first surgical exploration who achieved a well-documented complete pathological remission (pCR). The carcinoma became resectable after consecutive neoadjuvant treatment with nanoparticle albumin-bound (nab)-paclitaxel/gemcitabine and FOLFIRINOX chemotherapy regimens. CONCLUSION: This is the first reported LAPC case in which neoadjuvant chemotherapy alone has been shown to lead to demonstrated pCR. CA19-9 levels, but not imaging criteria, were useful for response prediction and timing of the Whipple's procedure. The findings in this case suggest possible conceptual changes in the treatment approach for LAPC, and indicate that the new effective chemotherapy regimens should be integrated into clinical trials for LAPC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias Pancreáticas/tratamento farmacológico , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Quimioterapia Adjuvante/métodos , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Feminino , Fluoruracila/administração & dosagem , Humanos , Irinotecano , Terapia Neoadjuvante/métodos , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Paclitaxel/administração & dosagem , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Indução de Remissão , Resultado do Tratamento , Gencitabina
5.
J Nucl Med ; 64(9): 1424-1430, 2023 09.
Artigo em Inglês | MEDLINE | ID: mdl-37348915

RESUMO

Desmoplastic small round cell tumor (DSRCT) is a rare, radiosensitive, yet difficult-to-treat sarcoma subtype affecting predominantly male adolescents. Extensive intraperitoneal seeding is common and requires multimodal management. With no standard therapy established, the prognosis remains poor, and new treatment options are needed. We demonstrate the clinical potential of C-X-C motif chemokine receptor 4 (CXCR4)-directed imaging and endoradiotherapy in DSRCT. Methods: Eight male patients underwent dual-tracer imaging with [18F]FDG and CXCR4-directed [68Ga]pentixafor PET/CT. A visual comparison of both tracers, along with uptake quantification in active DSRCT lesions, was performed. [68Ga]pentixafor uptake was correlated with immunohistochemical CXCR4 expression on tumor cells. Four patients with end-stage progressive disease underwent CXCR4-based endoradiotherapy. We report the safety, response by RECIST 1.1, and survival after endoradiotherapy. Results: Uptake of [68Ga]pentixafor in tumor lesions was demonstrated in all patients with DSRCT, providing diagnostic power comparable to [18F]FDG PET. Corresponding CXCR4 expression was confirmed by immunohistochemistry in all DSRCT biopsies. Finally, 4 patients were treated with CXCR4-directed [90Y]endoradiotherapy, 3 in a myeloablative dose range with subsequent autologous stem cell transplantation. All 3 required transfusions, and febrile neutropenia occurred in 2 patients (resulting in 1 death). Notably, severe nonhematologic adverse events were absent. We observed signs of response in all 3 patients, translating into disease stabilization in 2 patients for 143 and 176 d, respectively. In the third patient, postmortem autopsy confirmed a partial pathologic response. Conclusion: We validated CXCR4 as a diagnostic biomarker and a promising target for endoradiotherapy in DSRCT, demonstrated its feasibility, and provided the first evidence of its clinical efficacy.


Assuntos
Complexos de Coordenação , Tumor Desmoplásico de Pequenas Células Redondas , Transplante de Células-Tronco Hematopoéticas , Adolescente , Humanos , Masculino , Feminino , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Fluordesoxiglucose F18 , Radioisótopos de Gálio , Tumor Desmoplásico de Pequenas Células Redondas/diagnóstico por imagem , Tumor Desmoplásico de Pequenas Células Redondas/terapia , Transplante Autólogo , Peptídeos Cíclicos , Receptores CXCR4/metabolismo
6.
Lancet Gastroenterol Hepatol ; 6(2): 128-138, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33338442

RESUMO

BACKGROUND: The optimal preoperative treatment for locally advanced pancreatic cancer is unknown. We aimed to compare the efficacy and safety of nab-paclitaxel plus gemcitabine with nab-paclitaxel plus gemcitabine followed by fluorouracil, leucovorin, irinotecan, and oxaliplatin (FOLFIRINOX) as multidrug induction chemotherapy regimens in locally advanced pancreatic cancer. METHODS: In this open-label, multicentre, randomised phase 2 study, done at 28 centres in Germany, eligible patients were adults (aged 18-75 years) with an Eastern Cooperative Oncology Group performance status of 0 or 1 and histologically or cytologically confirmed, treatment-naive locally advanced pancreatic adenocarcinoma, as determined by local multidisciplinary team review. After two cycles of nab-paclitaxel 125 mg/m2 plus gemcitabine 1000 mg/m2 (administered intravenously on days 1, 8, and 15 of each 28-day cycle), patients without progressive disease or unacceptable adverse events were randomly assigned (1:1) to receive either two additional cycles of nab-paclitaxel plus gemcitabine (nab-paclitaxel plus gemcitabine group) or four cycles of sequential FOLFIRINOX (oxaliplatin 85 mg/m2, leucovorin 400 mg/m2, irinotecan 180 mg/m2, fluorouracil 400 mg/m2 by intravenous bolus followed by a continuous intravenous infusion of 2400 mg/m2 for 46 h on day 1 of each 14-day cycle; sequential FOLFIRINOX group). Randomisation was done by the clinical research organisation on request of the trial centre using a permuted block design (block size 2 and 4). Patients, investigators, and study team members were not masked to treatment allocation. The primary endpoint was surgical conversion rate (complete macroscopic tumour resection) in the randomised population by intention-to-treat analysis, which was assessed by surgical exploration in all patients with at least stable disease after completion of induction chemotherapy. This trial is registered with ClinicalTrials.gov, NCT02125136. FINDINGS: Between Nov 18, 2014, and April 27, 2018, 168 patients were registered and 130 were randomly assigned to either the nab-paclitaxel plus gemcitabine group (64 patients) or the sequential FOLFIRINOX group (66 patients). Surgical exploration after completed induction chemotherapy was done in 40 (63%) of 64 patients in the nab-paclitaxel plus gemcitabine group and 42 (64%) of 66 patients in the sequential FOLFIRINOX group. 23 patients in the nab-paclitaxel plus gemcitabine group and 29 in the sequential FOLFIRINOX group had complete macroscopic tumour resection, yielding a surgical conversion rate of 35·9% (95% CI 24·3-48·9) in the nab-paclitaxel plus gemcitabine group and 43·9% (31·7-56·7) in the sequential FOLFIRINOX group (odds ratio 0·72 [95% CI 0·35-1·45]; p=0·38). At a median follow-up of 24·9 months (95% CI 21·8-27·6), median overall survival was 18·5 months (95% CI 14·4-21·5) in the nab-paclitaxel plus gemcitabine group and 20·7 months (13·9-28·7) in the sequential FOLFIRINOX group (hazard ratio 0·86 [95% CI 0·55-1·36]; p=0·53). All other secondary efficacy endpoints, such as investigator-assessed progression-free survival, radiographic response rate, CA 19-9 response rate, and R0 resection rate, were not significantly different between the two treatment groups except for improved histopathological downstaging in evaluable resection specimens from the sequential FOLFIRINOX group (ypT1/2 stage: 20 [69%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·0003; ypN0 stage: 15 [52%] of 29 patients in the sequential FOLFIRINOX group vs four [17%] of 23 patients in the nab-paclitaxel plus gemcitabine group, p=0·02). Grade 3 or higher treatment-emergent adverse events during induction chemotherapy occurred in 35 (55%) of 64 patients in nab-paclitaxel plus gemcitabine group and in 35 (53%) of 66 patients in the sequential FOLFIRINOX group. The most common of which were neutropenia (18 [28%] in nab-paclitaxel plus gemcitabine group, 16 [24%] in the sequential FOLFIRINOX group), nausea and vomiting (two [3%] in nab-paclitaxel plus gemcitabine group, eight [12%] in the sequential FOLFIRINOX group), and bile duct obstruction with cholangitis (six [9%] in nab-paclitaxel plus gemcitabine group, seven [11%] in the sequential FOLFIRINOX group). No deaths were caused by treatment-related adverse events during the induction chemotherapy phase. INTERPRETATION: Our findings suggest that nab-paclitaxel plus gemcitabine is similarly active and safe as nab-paclitaxel plus gemcitabine followed by FOLFIRINOX as multidrug induction chemotherapy regimens for locally advanced pancreatic cancer. Although conversion to resectability was achieved in about a third of patients, additional evidence is required to determine whether this translates into improved overall survival. FUNDING: Celgene.


Assuntos
Adenocarcinoma/tratamento farmacológico , Albuminas/uso terapêutico , Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Paclitaxel/uso terapêutico , Neoplasias Pancreáticas/tratamento farmacológico , Adenocarcinoma/patologia , Adenocarcinoma/cirurgia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Fluoruracila/uso terapêutico , Seguimentos , Humanos , Quimioterapia de Indução , Irinotecano/uso terapêutico , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Estadiamento de Neoplasias , Oxaliplatina/uso terapêutico , Pancreatectomia , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/cirurgia , Resultado do Tratamento , Adulto Jovem , Gencitabina
7.
Case Rep Oncol ; 7(3): 648-55, 2014 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-25408659

RESUMO

The prognosis of patients with locally advanced pancreatic cancer can be improved if secondary complete (R0) resection is possible. In patients initially staged as unresectable this may be achieved with neoadjuvant treatment which is usually chemoradiotherapy based. We report the case of a 46-year-old patient with an unresectable, locally advanced pancreatic cancer (pT4 Nx cM0 G2) who was treated with a sequential neoadjuvant chemotherapy regimen consisting of 2 cycles of nab-paclitaxel plus gemcitabine followed by 4 cycles of FOLFIRINOX. Neoadjuvant chemotherapy resulted in secondary resectability (R0 resection). After 2 cycles of nab-paclitaxel plus gemcitabine, the patient already had a complete metabolic remission as measured by integrated fludeoxyglucose ((18)F) positron emission tomography and computerized tomography. After a follow-up of 18 months the patient is alive without progression of disease. We propose to assess the clinical benefit of sequencing the combinations nab-paclitaxel plus gemcitabine and FOLFIRINOX as neoadjuvant therapy for patients with locally advanced and initially unresectable pancreatic cancer in a controlled clinical trial.

8.
Leuk Res ; 33(7): 929-36, 2009 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-19233470

RESUMO

A variety of genetic and epigenetic abnormalities were characterized over the last years in Hodgkin and Reed-Sternberg (H-RS) cells of classic Hodgkin Lymphoma (cHL). It was speculated that simultaneous inhibition of multiple signalling pathways might be a promising strategy to target this tumor entity. In the present study we tested the effect of histone deacetylase (HDAC) inhibition using depsipeptide (also known as romidepsin, FK228, FR901228 or NSC-630176) in cHL cell lines in vitro. Molecular mechanisms of toxicity were analyzed using RNA expression analysis and functional assays. It is shown that depsipeptide is effective at submicromolar concentrations and acts mainly by apoptosis induction, upregulation of p21 and cell cycle inhibition in G2/M. Of special note, HDAC mediated toxicity in H-RS cells does not require RelA/p65 downregulation, which was previously shown to drive the malignant phenotype of H-RS cells. In summary, depsipeptide induced protein acetylation results in transcriptional changes of a large number of pathogenetically relevant genes and increased RelA/p65 binding activity in cHL cell lines. Our preclinical data suggest that HDAC inhibition using depsipeptide might be a promising approach for the treatment of cHL patients.


Assuntos
Antibióticos Antineoplásicos/uso terapêutico , Apoptose/efeitos dos fármacos , Depsipeptídeos/uso terapêutico , Inibidores Enzimáticos/farmacologia , Inibidores de Histona Desacetilases , Doença de Hodgkin/patologia , Acetilação , Western Blotting , Ciclo Celular/efeitos dos fármacos , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Proliferação de Células/efeitos dos fármacos , Inibidor de Quinase Dependente de Ciclina p21/genética , Inibidor de Quinase Dependente de Ciclina p21/metabolismo , Perfilação da Expressão Gênica , Regulação Leucêmica da Expressão Gênica , Humanos , NF-kappa B/genética , NF-kappa B/metabolismo , Análise de Sequência com Séries de Oligonucleotídeos , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Tumorais Cultivadas
9.
Eur J Immunol ; 33(5): 1334-40, 2003 May.
Artigo em Inglês | MEDLINE | ID: mdl-12731059

RESUMO

Endowing tumor cells with costimulatory signals for T cell activation has emerged as a promising strategy for tumor immunotherapy. Costimulatory molecules were either transfected into tumor cells to generate vaccines or were fused, e.g. to antibodies against tumor-associated antigens, to achieve targeted T cell costimulation in vivo. Here we report the production and purification of rM28, a recombinant bispecific single-chain antibody directed to a melanoma-associated proteoglycan and to the costimulatory CD28 molecule on human T cells. We found that a dimer of the recombinant molecule, bound to tumor target cells, induced pronounced T cell activation in peripheral blood mononuclear cell preparations without additional TCR/CD3 stimulation being required. The lytic activity generated after 3 days of stimulation effectively prevented tumor cell growth. However, it was unspecific and predominantly mediated by non T cells. Our findings demonstrate that presentation of a CD28 antibody within a suitable recombinant, bispecific format may result in a "targeted supra-agonistic stimulation" of the CD28 molecule, which leads to effective tumor cell killing after induction of unspecifically lytic cells.


Assuntos
Anticorpos Biespecíficos/imunologia , Antígenos CD28/imunologia , Melanoma/imunologia , Melanoma/terapia , Proteoglicanas/imunologia , Anticorpos Biespecíficos/uso terapêutico , Citotoxicidade Imunológica , Humanos , Ativação Linfocitária , Proteínas Recombinantes/imunologia , Linfócitos T/imunologia , Células Tumorais Cultivadas
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