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PURPOSE: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. PATIENTS AND METHODS: Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. RESULTS: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells ≥ 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. CONCLUSION: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.
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BACKGROUND: To determine if pretreatment quality of life is associated with performance status in patients with pancreatic and periampullary tumors. METHODS: Eighty consecutive patients evaluated for surgical treatment of pancreatic or periampullary tumors completed the social functioning SF-36, a generic quality of life instrument. This instrument measures 8 domains of quality of life: physical functioning (PF), role-physical (RP), role-emotional, bodily pain, vitality, mental health, social functioning, and general health (GH). The best possible score is 100 and the worst possible score is 0. Each patient was then assigned a Karnofsky performance score (KPS), with the best possible score of 100 (normal, no complaints, no evidence of disease) and worst score of 0 (dead). Data recorded included age, gender, pathology, stage, resection, use of chemotherapy, and radiation therapy. Statistical analysis was done using single and multiple linear regression analysis, correlation coefficients (r) and coefficient of determination (r (2)). RESULTS: KPS was significantly associated with all domains of the SF-36 by single linear regression. By multiple linear regression, KPS was significantly associated with the PF domain (p < 0.001, r = 0.74), and nearly significantly associated with the RP (p = 0.07, r = 0.62) and GH (p = 0.06, r = 0.64) domains. This appears to be independent of tumor pathology and stage. CONCLUSION: The results imply that pretreatment quality of life and performance status are related concepts in patients with pancreatic and periampullary tumors. This is primarily true for the physical component of the SF-36. However, despite statistical significance, coefficients of determination (r (2) values) suggest that there are additional factors determining both quality of life and performance status in patients with pancreatic and periampullary tumors.
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Neoplasias Pancreáticas/epidemiologia , Qualidade de Vida , Idoso , Feminino , Nível de Saúde , Humanos , Avaliação de Estado de Karnofsky/estatística & dados numéricos , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Inquéritos e QuestionáriosRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma is a largely incurable cancer. Surgical resection remains the only potential option for cure. Even in surgically resectable patients, only about 10% to 20% are long-term survivors. Emerging data suggest a role for neoadjuvant therapy to target occult micrometastatic disease. AIM: To report our institutional experience with a novel neoadjuvant chemoradiation (CRT) regimen in resectable and borderline resectable pancreatic cancer. MATERIALS AND METHODS: Patients were treated with 2 cycles of induction chemotherapy with FOLFOX and then received CRT with gemcitabine and intensity-modulated radiotherapy (IMRT). RESULTS: From April 2014 to June 2017, 24 patients were enrolled. Eighteen patients were borderline resectable and 6 patients were resectable. All patients received induction chemotherapy with FOLFOX. Thirteen patients underwent pancreatectomy after CRT with a resection rate of 62%. R0 resection achieved in 11 patients (84.6%) and 2 patients had R1 resection (15.4%). For patients who underwent resection, the median progression-free survival (PFS) was 31 months, 1-year PFS rate was 69.2% (95% confidence interval [CI], 0.48-0.99), and 2-year PFS rate was 51.9% (95% CI, 0.3-0.89). Median overall survival (OS) was 34.8 months (95% CI, 1.045 to infinity), 1-year OS rate was 91.7% (95% CI, 0.77-1.0), and 2-year OS rate was 75% (95% CI, 0.54-1.0). Median CA 19-9 at screening for patients who underwent surgery was 659 (range, 18 to 2154), which decreased to 146.9 (range, 18 to 462) after CRT before resection. CONCLUSION: Neoadjuvant therapy for borderline resectable and resectable pancreatic ductal adenocarcinoma with CRT facilitated R0 resection in 84% patients who underwent surgery.
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Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma Ductal Pancreático/terapia , Desoxicitidina/análogos & derivados , Neoplasias Pancreáticas/terapia , Radioterapia de Intensidade Modulada , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Ductal Pancreático/cirurgia , Quimiorradioterapia , Desoxicitidina/uso terapêutico , Feminino , Fluoruracila/uso terapêutico , Humanos , Quimioterapia de Indução , Leucovorina/uso terapêutico , Masculino , Pessoa de Meia-Idade , Terapia Neoadjuvante , Compostos Organoplatínicos/uso terapêutico , Neoplasias Pancreáticas/cirurgia , GencitabinaRESUMO
OBJECTIVE: Communication during racially-discordant interactions is often of poor quality and may contribute to racial treatment disparities. We evaluated an intervention designed to increase patient active participation and other communication-related outcomes during interactions between Black patients and non-Black oncologists. METHODS: Participants were 18 non-Black medical oncologists and 114 Black patients at two cancer hospitals in Detroit, Michigan, USA. Before a clinic visit to discuss treatment, patients were randomly assigned to usual care or to one of two question prompt list (QPL) formats: booklet (QPL-Only), or booklet and communication coach (QPL-plus-Coach). Patient-oncologist interactions were video recorded. Patients reported perceptions of the intervention, oncologist communication, role in treatment decisions, and trust in the oncologist. Observers assessed interaction length, patient active participation, and oncologist communication. RESULTS: The intervention was viewed positively and did not increase interaction length. The QPL-only format increased patient active participation; the QPL-plus-Coach format decreased patient perceptions of oncologist communication. No other significant effects were found. CONCLUSION: This QPL booklet is acceptable and increases patient active participation in racially-discordant oncology interactions. Future research should investigate whether adding physician-focused interventions might improve other outcomes. PRACTICE IMPLICATIONS: This QPL booklet is acceptable and can improve patient active participation in racially-discordant oncology interactions.
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Comunicação , Neoplasias/etnologia , Neoplasias/terapia , Folhetos , Participação do Paciente , Relações Médico-Paciente , Adulto , Idoso , Feminino , Disparidades em Assistência à Saúde , Humanos , Masculino , Michigan , Pessoa de Meia-Idade , Neoplasias/psicologia , Oncologistas , Aceitação pelo Paciente de Cuidados de Saúde , Inquéritos e Questionários , ConfiançaRESUMO
PURPOSE: Results from the first-in-human phase I trial of the anti-programmed death-1 (PD-1) antibody BMS-936558 in patients with treatment-refractory solid tumors, including safety, tolerability, pharmacodynamics, and immunologic correlates, have been previously reported. Here, we provide long-term follow-up on three patients from that trial who sustained objective tumor regressions off therapy, and test the hypothesis that reinduction therapy for late tumor recurrence can be effective. EXPERIMENTAL DESIGN: Three patients with colorectal cancer, renal cell cancer, and melanoma achieved objective responses on an intermittent dosing regimen of BMS-936558. Following cessation of therapy, patients were followed for more than 3 years. A patient with melanoma who experienced a prolonged partial regression followed by tumor recurrence received reinduction therapy. RESULTS: A patient with colorectal cancer experienced a complete response, which is ongoing after 3 years. A patient with renal cell cancer experienced a partial response lasting 3 years off therapy, which converted to a complete response, which is ongoing at 12 months. A patient with melanoma achieved a partial response that was stable for 16 months off therapy; recurrent disease was successfully treated with reinduction anti-PD-1 therapy. CONCLUSION: These data represent the most prolonged observation to date of patients with solid tumors responding to anti-PD-1 immunotherapy and the first report of successful reinduction therapy following delayed tumor progression. They underscore the potential for immune checkpoint blockade with anti-PD-1 to reset the equilibrium between tumor and the host immune system.
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Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias/tratamento farmacológico , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Idoso , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Carcinoma de Células Renais/tratamento farmacológico , Neoplasias Colorretais/tratamento farmacológico , Feminino , Humanos , Masculino , Melanoma/tratamento farmacológico , Pessoa de Meia-Idade , Neoplasias/metabolismo , Nivolumabe , Resultado do TratamentoRESUMO
A 28-year-old man presented with stridor and dyspnoea. Imaging showed a tracheal mass with severe narrowing of the subglottic airway. Histopathology was consistent with non-seminomatous germ cell tumour. The patient underwent cricotracheal resection and reconstruction of the trachea with tracheostomy. Subsequent positron emission tomography demonstrated new right upper lobe nodules. Postoperative chemotherapy was initiated using the VIP regimen (etoposide, ifosfamide and cisplatin). After four cycles of chemotherapy, CT of the thorax showed interval resolution of most of the pulmonary nodules. Thoracoscopy with right upper and lower lobe wedge resections was performed to remove the residual disease. The patient is currently disease-free and undergoing continued surveillance to assess for clinical, biochemical or radiographical evidence of disease recurrence.
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Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/cirurgia , Neoplasias da Traqueia/diagnóstico , Neoplasias da Traqueia/cirurgia , Adulto , Diagnóstico Diferencial , Humanos , Masculino , Neoplasias Testiculares , Toracoscopia , Tomografia Computadorizada por Raios X , TraqueostomiaRESUMO
Radiation recall dermatitis has been documented to occur in previously irradiated skin (within the radiation port) the administration of some chemotherapeutic agents. Clinically, it can occur weeks or months after radiation therapy, and resembles the appearance of acute radiation skin reaction. The patterns of the reaction correspond with radiation fields and skin doses. We report a case of recall dermatitis 8 weeks after of spine radiosurgery initiated by the use of a multi-targeted tyrosine kinase inhibitor, Sorafenib, used for treatment of hepatocellular carcinoma.
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PURPOSE: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This phase I study sought to determine the safety and tolerability of anti-PD-1 blockade in patients with treatment-refractory solid tumors and to preliminarily assess antitumor activity, pharmacodynamics, and immunologic correlates. PATIENTS AND METHODS: Thirty-nine patients with advanced metastatic melanoma, colorectal cancer (CRC), castrate-resistant prostate cancer, non-small-cell lung cancer (NSCLC), or renal cell carcinoma (RCC) received a single intravenous infusion of anti-PD-1 (MDX-1106) in dose-escalating six-patient cohorts at 0.3, 1, 3, or 10 mg/kg, followed by a 15-patient expansion cohort at 10 mg/kg. Patients with evidence of clinical benefit at 3 months were eligible for repeated therapy. RESULTS: Anti-PD-1 was well tolerated: one serious adverse event, inflammatory colitis, was observed in a patient with melanoma who received five doses at 1 mg/kg. One durable complete response (CRC) and two partial responses (PRs; melanoma, RCC) were seen. Two additional patients (melanoma, NSCLC) had significant lesional tumor regressions not meeting PR criteria. The serum half-life of anti-PD-1 was 12 to 20 days. However, pharmacodynamics indicated a sustained mean occupancy of > 70% of PD-1 molecules on circulating T cells > or = 2 months following infusion, regardless of dose. In nine patients examined, tumor cell surface B7-H1 expression appeared to correlate with the likelihood of response to treatment. CONCLUSION: Blocking the PD-1 immune checkpoint with intermittent antibody dosing is well tolerated and associated with evidence of antitumor activity. Exploration of alternative dosing regimens and combinatorial therapies with vaccines, targeted therapies, and/or other checkpoint inhibitors is warranted.
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Anticorpos Monoclonais/uso terapêutico , Antígenos CD/imunologia , Proteínas Reguladoras de Apoptose/imunologia , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/farmacocinética , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Renais/tratamento farmacológico , Carcinoma de Células Renais/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/patologia , Relação Dose-Resposta a Droga , Fadiga/induzido quimicamente , Feminino , Humanos , Neoplasias Renais/tratamento farmacológico , Neoplasias Renais/patologia , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/patologia , Linfopenia/induzido quimicamente , Masculino , Melanoma/tratamento farmacológico , Melanoma/patologia , Pessoa de Meia-Idade , Neoplasias/patologia , Nivolumabe , Receptor de Morte Celular Programada 1 , Neoplasias da Próstata/tratamento farmacológico , Neoplasias da Próstata/patologia , Resultado do TratamentoRESUMO
The importance of tumor angiogenesis in tumor biology is now widely accepted. Hepatocellular carcinoma (HCC) is a highly vascular tumor, and angiogenesis is believed to play a considerable role in its development and progression. The authors reviewed the role of circulating vascular endothelial growth factor (VEGF) in screening for HCC and in risk stratification and treatment monitoring. They searched the world medical literature by accessing MEDLINE and PubMed for articles on: 1) the utility of circulating VEGF for HCC screening in patients with cirrhosis; 2) the role of circulating VEGF as a predictor of the invasive potential of HCC; and 3) monitoring anti-HCC treatment effects by serial measurements of circulating VEGF. They found evidence to support a potential role for VEGF in screening and surveillance of HCC. They also found support for developing the use of VEGF in the monitoring of treatment outcomes. Several studies suggested that the circulating VEGF level may be an independent prognostic marker in HCC. Further studies are needed to determine the utility of circulating VEGF in screening of patients with cirrhosis and to determine its potential role as a prognostic and predictive biomarker in patients with HCC. Cancer 2009. (c) 2009 American Cancer Society.
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Biomarcadores Tumorais/análise , Carcinoma Hepatocelular/diagnóstico , Neoplasias Hepáticas/diagnóstico , Fator A de Crescimento do Endotélio Vascular/análise , Inibidores da Angiogênese/uso terapêutico , Carcinoma Hepatocelular/irrigação sanguínea , Carcinoma Hepatocelular/tratamento farmacológico , Ensaios Clínicos como Assunto , Progressão da Doença , Humanos , Neoplasias Hepáticas/irrigação sanguínea , Neoplasias Hepáticas/tratamento farmacológico , Modelos Biológicos , Neovascularização Patológica , Prognóstico , Resultado do Tratamento , Fator A de Crescimento do Endotélio Vascular/sangueRESUMO
BACKGROUND: There is no standard first-line therapy for advanced gastric and gastroesophageal junction (GEJ) adenocarcinoma and the prognosis remains poor. Our institution conducted a phase I study of oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule. The regimen was tolerated; pharmacodynamic studies revealed no drug interactions, and there was one confirmed response in a gastric cancer patient. We performed a phase II trial in advanced gastric and GEJ adenocarcinoma to determine response rate and response duration. METHODS: This was a multi-center single treatment arm study involving six sites. Only prior adjuvant therapy was allowed. Patients had ECOG performance status of 0-2, adequate organ function, and were able to tolerate oral medications. All patients received oxaliplatin 60 mg/m(2) intravenously (IV) and irinotecan 50 mg/m(2) IV weekly times 4 weeks with a 2-week rest period. Capecitabine 450 mg bid orally was received on days 1 through 5 every week for 4 weeks, followed by a 2-week rest. Patients were assessed for response after the first two cycles; response duration, overall survival, and adverse events were also recorded. We estimated an improvement in historical response rate by 30% would have clinical meaning. RESULTS: A total of 39 patients were accrued and all were assessed for toxicity; 30 patients were evaluable for response. The median age was 57.8 years (31-79 years) and 74% were male. Two patients had a complete response, with nine patients achieving a partial response. The total response rate was 28%, with nine patients not evaluable for response. The median response duration was noted at 5.97 months and median overall survival was 8.98 months. There were no grade 5 treatment related events, with all deaths secondary to disease progression. Only five grade 4 events occurred (neutropenia, hyperkalemia, hypokalemia (2), thrombosis/embolism) without grade 4 diarrhea or sensory neuropathy. CONCLUSIONS: Oxaliplatin, irinotecan, and capecitabine given in a novel, weekly schedule does induce responses in advanced gastric and GEJ adenocarcinoma. However, the total response rate is modest and not an improvement over other regimens.
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Adenocarcinoma/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Junção Esofagogástrica/efeitos dos fármacos , Neoplasias Gástricas/tratamento farmacológico , Adenocarcinoma/secundário , Adolescente , Adulto , Idoso , Camptotecina/administração & dosagem , Camptotecina/análogos & derivados , Capecitabina , Desoxicitidina/administração & dosagem , Desoxicitidina/análogos & derivados , Progressão da Doença , Relação Dose-Resposta a Droga , Junção Esofagogástrica/patologia , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/análogos & derivados , Humanos , Irinotecano , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Cuidados Paliativos , Prognóstico , Neoplasias Gástricas/patologia , Taxa de Sobrevida , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
PURPOSE: A case of a fatal hypersensitivity reaction to gemtuzumab ozogamicin in a patient who received a platelet transfusion on the same day is presented. SUMMARY: A 75-year-old man went to a hematology clinic in April 2005 because of anemia and thrombocytopenia. He was diagnosed with acute myelogenous leukemia (AML). In May 2005, the patient was started on induction chemotherapy with cytarabine and idarubicin. During the induction phase, the patient received platelet transfusions on multiple occasions without any evidence of transfusion reactions. He went into partial remission and received two cycles of cytarabine and idarubicin followed by one cycle of high-dose cytarabine. In March 2006, the patient relapsed, and he received dose number one of the first cycle of gemtuzumab ozogamicin at a dose of 9 mg/m2 on March 28, 2006. He tolerated the infusion. He had received multiple platelet transfusions during the week before gemtuzumab infusion without reaction but received no transfusions on the same day as the gemtuzumab infusion. On April 4, 2006, the patient received an infusion of gemtuzumab at 11 a.m., and he received 6 units of leukocyte-depleted, irradiated platelets at 6:40 p.m. At 1 a.m. the next morning, the patient developed fever and shortness of breath and went into severe distress. Despite treatment, the patient died shortly after. CONCLUSION: A patient with AML developed severe respiratory distress and died after receiving gemtuzumab and 6 units of platelets on the same day. The fact that he had previously received gemtuzumab and platelets safely on separate days suggests that the gemtuzumab-platelet combination contributed to a fatal hypersensitivity reaction.