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Background: Cholangiocarcinoma (CCA) includes cancers arising from the intrahepatic and extrahepatic bile ducts. The etiology and pathogenesis of CCA remain poorly understood. This is the first study investigating both incidence patterns of CCA from 1973 through 2012 and demographic, clinical, and treatment variables affecting survival of patients with CCA. Patients and Methods: Using the SEER database, age-adjusted incidence rates were evaluated from 1973-2012 using SEER*Stat software. A retrospective cohort of 26,994 patients diagnosed with CCA from 1973-2008 was identified for survival analysis. Cox proportional hazards models were used to perform multivariate survival analysis. Results: Overall incidence of CCA increased by 65% from 1973-2012. Extrahepatic CCA (ECC) remained more common than intrahepatic CCA (ICC), whereas the incidence rates for ICC increased by 350% compared with a 20% increase seen with ECC. Men belonging to non-African American and non-Caucasian ethnicities had the highest incidence rates of CCA. This trend persisted throughout the study period, although African Americans and Caucasians saw 50% and 59% increases in incidence rates, respectively, compared with a 9% increase among other races. Median overall survival (OS) was 8 months in patients with ECC compared with 4 months in those with ICC. Our survival analysis found Hispanic women to have the best 5-year survival outcome (P<.0001). OS diminished with age (P<.0001), and ECC had better survival outcomes compared with ICC (P<.0001). Patients who were married, were nonsmokers, belonged to a higher income class, and underwent surgery had better survival outcomes compared with others (P<.0001). Conclusions: This is the most up-to-date study of CCA from the SEER registry that shows temporal patterns of increasing incidence of CCA across different races, sexes, and ethnicities. We identified age, sex, race, marital status, income, smoking status, anatomic location of CCA, tumor grade, tumor stage, radiation, and surgery as independent prognostic factors for OS in patients with CCA.
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Neoplasias dos Ductos Biliares/epidemiologia , Colangiocarcinoma/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias dos Ductos Biliares/história , Neoplasias dos Ductos Biliares/mortalidade , Colangiocarcinoma/história , Colangiocarcinoma/mortalidade , Feminino , História do Século XX , História do Século XXI , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Vigilância em Saúde Pública , Fatores de Risco , Programa de SEER , Taxa de Sobrevida , Estados Unidos/epidemiologia , Adulto JovemRESUMO
BACKGROUND: The causes of death in COVID-19 patients with cardiac injury are uncertain. METHODS: We conducted a case-control study and reviewed the electronic medical record of 109 deceased COVID-19 patients with cardiac injury on admission and 32 deceased COVID-19 patients without cardiac injury at two hospitals in Rhode Island. RESULTS: Among the 109 deceased COVID-19 patients who had cardiac injury on admission, 79 patients (72.5%) died of hypoxic respiratory failure, 21 patients (19.2%) of multi-organ failure and septic shock, 6 patients (5.5%) of cardiac arrhythmia, 3 patients (2.8%) of severe kidney failure as the immediate causes of death. We observed a similar pattern of distribution when compared to deceased patients without cardiac injury on admission (n=32). CONCLUSION: The main causes of death of COVID-19 patients with cardiac injury were non-cardiac, mostly hypoxic respiratory failure. Cardiac-related arrhythmia only accounted for a small proportion of cases.
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COVID-19 , Estudos de Casos e Controles , Causas de Morte , Humanos , Estudos Retrospectivos , SARS-CoV-2RESUMO
Effective chimeric antigen receptor-modified T-cell (CAR-T) therapy for liver metastases (LM) will require innovative solutions to ensure efficient delivery and minimization of systemic toxicity. We previously demonstrated the safety of CAR-T hepatic artery infusions (HAI). We subsequently conducted the phase 1b HITM-SIR trial, in which six patients (pts) with CEA+ LM received anti-CEA CAR-T HAIs and selective internal radiation therapy (SIRT). The primary endpoint was safety with secondary assessments of biologic activity. Enrolled pts had a mean LM size of 6.4 cm, 4 pts had >10 LM, and pts received an average of two lines of prior systemic therapy. No grade 4 or 5 toxicities were observed, and there were no instances of severe cytokine-release syndrome (CRS) or neurotoxicity. The mean transduction efficiency was 60.4%. Following CAR-T HAI, reduced levels of GM-CSF-R, IDO, and PD-L1 were detected in LM, and serum CEA levels were stable or decreased in all subjects. Median survival time was 8 months (mean 11, range 4-31). Anti-CEA CAR-T HAI with subsequent SIRT was well tolerated, and biologic responses were demonstrated following failure of conventional therapy. HAI of CAR-T was once again confirmed not to be associated with severe CRS or neurotoxicity.
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Braquiterapia/métodos , Imunoterapia Adotiva/métodos , Neoplasias Hepáticas/terapia , Adulto , Idoso , Antígeno Carcinoembrionário/metabolismo , Neoplasias do Colo/imunologia , Neoplasias do Colo/mortalidade , Neoplasias do Colo/patologia , Neoplasias do Colo/terapia , Terapia Combinada/métodos , Feminino , Seguimentos , Proteínas Ligadas por GPI/antagonistas & inibidores , Proteínas Ligadas por GPI/metabolismo , Humanos , Infusões Intra-Arteriais , Fígado/irrigação sanguínea , Fígado/imunologia , Fígado/patologia , Fígado/efeitos da radiação , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/mortalidade , Neoplasias Hepáticas/secundário , Masculino , Pessoa de Meia-Idade , Neoplasias Pancreáticas/imunologia , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/patologia , Neoplasias Pancreáticas/terapia , Receptores de Antígenos Quiméricos/imunologia , Neoplasias Retais/imunologia , Neoplasias Retais/mortalidade , Neoplasias Retais/patologia , Neoplasias Retais/terapia , Critérios de Avaliação de Resposta em Tumores SólidosRESUMO
In recent years, cell therapy technologies have resulted in impressive results in hematologic malignancies. Treatment of solid tumors with chimeric antigen receptor T-cells (CAR-T) has been less successful. Solid tumors present challenges not encountered with hematologic cancers, including high intra-tumoral pressure and ineffective CAR-T trafficking to the site of disease. Novel delivery methods may enable CAR-T therapies for solid tumor malignancies. A patient with liver metastases secondary to pancreatic adenocarcinoma received CAR-T targeting carcinoembryonic antigen (CEA). Previously we reported that Pressure-Enabled Drug Delivery (PEDD) enhanced CAR-T delivery to liver metastases 5.2-fold. Three doses of anti-CEA CAR-T were regionally delivered via hepatic artery infusion (HAI) using PEDD technology to optimize the therapeutic index. Interleukin-2 was systemically delivered by continuous intravenous infusion to support CAR-T in vivo. HAI of anti-CEA CAR-T was not associated with any serious adverse events (SAEs) above grade 3 and there were no on-target/off-tumor SAEs. Following CAR-T treatment, positron emission tomography-CT demonstrated a complete metabolic response within the liver, which was durable and sustained for 13 months. The response was accompanied by normalization of serum tumor markers and an abundance of CAR+ cells found within post-treatment tumor specimens. The findings from this report exhibit biologic activity and safety of regionally infused CAR-T for an indication with limited immune-oncology success to date. Further studies will determine how HAI of CAR-T may be included in multidisciplinary treatment plans for patients with liver metastases. ClinicalTrials.gov number, NCT02850536.
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Neoplasias Hepáticas/genética , Sistemas de Liberação de Medicamentos , Humanos , Imunoterapia/métodos , Neoplasias Hepáticas/patologia , Masculino , Pessoa de Meia-Idade , Receptores de Antígenos Quiméricos/metabolismo , Microambiente TumoralRESUMO
The SARS-CoV-2 virus responsible for the COVID-19 pandemic can result in severe or fatal disease in a subset of infected patients. While the pathogenesis of severe COVID-19 disease has yet to be fully elucidated, an overexuberant and harmful immune response to the SARS-CoV-2 virus may be a pivotal aspect of critical illness in this patient population. The inflammatory cytokine, IL-6, has been found to be consistently elevated in severely ill COVID-19 patients, prompting speculation that IL-6 is an important driver of the pathologic process. The inappropriately elevated levels of inflammatory cytokines in COVID-19 patients is similar to cytokine release syndrome (CRS) observed in cell therapy patients. We sought to describe outcomes in a series of severely ill patients with COVID-19 CRS following treatment with anti-IL-6/IL-6-Receptor (anti-IL-6/IL-6-R) therapy, including tocilizumab or siltuximab. At our academic community medical center, we formed a multi-disciplinary committee for selecting severely ill COVID-19 patients for therapy with anti-IL-6 or IL-6-R agents. Key selection criteria included evidence of hyperinflammation, most notably elevated levels of C-reactive protein (CRP) and ferritin, and an increasing oxygen requirement. By the data cutoff point, we treated 31 patients with anti-IL-6/IL-6-R agents including 12 who had already been intubated. Overall, 27 (87%) patients are alive and 24 (77%) have been discharged from the hospital. Clinical responses to anti-IL-6/IL-6-R therapy were accompanied by significant decreases in temperature, oxygen requirement, CRP, IL-6, and IL-10 levels. Based on these data, we believe anti-IL-6/IL-6-R therapy can be effective in managing early CRS related to COVID-19 disease. Further study of anti-IL-6/IL-6-R therapy alone and in combination with other classes of therapeutics is warranted and trials are underway.
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BACKGROUND: There has been a significant improvement in survival of advanced malignancies with the advent of checkpoint inhibitors. These newer treatment modalities come with a wide spectrum of unique side effects, termed immune related adverse events (irAE), ranging from mild skin rash to severe colitis. Included in that spectrum is the rare side effect of autoimmune diabetes mellitus. Despite a few case reports illustrating the incidence of autoimmune diabetes associated with immunotherapy, there has not been much mentioned about exacerbation or acceleration of hyperglycemia in non-autoimmune settings leading to de novo diagnosis of type 2 diabetes mellitus. CASE PRESENTATION: We report the case of a 42 year old man with metastatic melanoma and no prior history of diabetes mellitus, who presented with diabetic ketoacidosis (DKA) after 3 cycles of combination checkpoint inhibitor therapy using nivolumab and ipilimumab. New onset diabetes mellitus was diagnosed on the basis of elevated hemoglobin A1c, in the absence of prior personal or family history. Autoimmune or type 1 diabetes mellitus was ruled out with normal levels of anti-glutamic acid decarboxylase 65 (GAD65) antibody, zinc transporter 8 (ZnT8) antibody, and islet antigen-2 (IA-2) antibody. CONCLUSIONS: This case report highlights the importance of recognizing rare but serious adverse events related to immunotherapy and incorporation of appropriate tools for early identification and management in national cancer treatment guidelines.
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Antineoplásicos Imunológicos/efeitos adversos , Diabetes Mellitus Tipo 2/diagnóstico , Cetoacidose Diabética/induzido quimicamente , Melanoma/tratamento farmacológico , Adulto , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Cetoacidose Diabética/etiologia , Humanos , Ipilimumab/efeitos adversos , Ipilimumab/uso terapêutico , Masculino , Metástase Neoplásica , NivolumabeRESUMO
Multiple myelomas is a neoplastic plasma cell disorder that accounts for one percent of all cancers and 13% of hematologic malignancies. Although primarily known to be a bone marrow disorder, it can metastasize to extramedullary sites or it can present as a solitary extramedullary plasmacytoma. Primary pleural effusion from myeloma is rare, occurring in less than one percent of the patients. The following case report highlights a case of bilateral pleural effusion, directly attributable to multiple myeloma after other causes were ruled out. The diagnosis was made using cytology and immunohistochemical (IHC) staining of the pleural fluid. Myelomatous pleural effusion (MPE) is a poor prognostic feature heralding an aggressive underlying disease state, as represented in this case.
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PURPOSE: Etirinotecan pegol (NKTR-102) is a unique, long-acting topoisomerase-I inhibitor with prolonged systemic exposure to SN38 (7-ethyl-10-hydroxycamptothecin), the active metabolite of irinotecan. This randomized phase II trial investigated two dosing schedules of etirinotecan pegol in patients with platinum-resistant/refractory ovarian carcinoma. PATIENTS AND METHODS: A total of 71 eligible patients were randomly assigned to receive etirinotecan pegol 145 mg/m(2) every 14 or 21 days until progression or unacceptable adverse events (AEs). The primary end point was objective response rate (ORR) by RECIST (version 1.0). Secondary end points included response by Gynecologic Cancer Intergroup criteria, duration of ORR, progression-free survival (PFS), and overall survival (OS). RESULTS: The overall confirmed ORR was 20% (95% CI, 10% to 30%): 20% for once every 14 days, and 19% for once every 21 days. Median response duration was 4.1 months for once every 14 days and 4.0 months for once every 21 days. Median PFS for every 14 and every 21 days was 4.1 and 5.3 months, respectively, and median OS was 10.0 and 11.7 months, respectively. Etirinotecan pegol was well tolerated, with the most common grade 3 to 4 AEs being dehydration (24%) and diarrhea (23%). Diarrhea, dehydration, nausea, and neutropenia were less frequent with the schedule of once every 21 days than with that of once every 14 days. CONCLUSION: Both schedules of etirinotecan pegol showed activity in patients with heavily pretreated ovarian cancer, with encouraging ORR and PFS rates. The schedule of once every 21 days was better tolerated and had slightly longer PFS and OS rates. The treatment schedule of etirinotecan pegol 145 mg/m(2) once every 21 days was selected for the expanded phase II study and is preferred for future phase III studies. These findings provide support to directly compare etirinotecan pegol versus one of the approved drugs (eg, pegylated liposomal doxorubicin or topotecan) in platinum-resistant ovarian cancer.