RESUMEN
Previous work from our group and others has shown that patients with breast cancer can generate a T cell response against specific human epidermal growth factor 2 (HER2) epitopes. In addition, preclinical work has shown that this T cell response can be augmented by Ag-directed mAb therapy. This study evaluated the activity and safety of a combination of dendritic cell (DC) vaccination given with mAb and cytotoxic therapy. We performed a phase I/II study using autologous DCs pulsed with two different HER2 peptides given with trastuzumab and vinorelbine to a study cohort of patients with HER2-overexpressing and a second with HER2 nonoverexpressing metastatic breast cancer. Seventeen patients with HER2-overexpressing and seven with nonoverexpressing disease were treated. Treatment was well tolerated, with one patient removed from therapy because of toxicity and no deaths. Forty-six percent of patients had stable disease after therapy, with 4% achieving a partial response and no complete responses. Immune responses were generated in the majority of patients but did not correlate with clinical response. However, in one patient, who has survived >14 y since treatment in the trial, a robust immune response was demonstrated, with 25% of her T cells specific to one of the peptides in the vaccine at the peak of her response. These data suggest that autologous DC vaccination when given with anti-HER2-directed mAb therapy and vinorelbine is safe and can induce immune responses, including significant T cell clonal expansion, in a subset of patients.
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Neoplasias de la Mama , Neoplasias Mamarias Animales , Humanos , Femenino , Animales , Epítopos/metabolismo , Vinorelbina/metabolismo , Vinorelbina/uso terapéutico , Receptor ErbB-2 , Neoplasias de la Mama/metabolismo , Inmunoterapia , Péptidos/metabolismo , Células Dendríticas , Trastuzumab/uso terapéutico , Trastuzumab/metabolismoRESUMEN
Kaposi sarcoma (KS) is the most common cancer in people living with HIV (PLWH) in many countries where KS-associated herpesvirus is endemic. Treatment has changed little in 20 years, but the disease presentation has. This prospective cohort study enrolled 122 human immunodeficiency virus (HIV) positive KS patients between 2017 and 2019 in Malawi. Participants were treated with bleomycin, vincristine and combination antiretroviral therapy, the local standard of care. One-year overall survival was 61%, and progression-free survival was 58%. The 48-week complete response rate was 35%. RNAseq (n = 78) differentiated two types of KS lesions, those with marked endothelial characteristics and those enriched in inflammatory transcripts. This suggests that different KS lesions are in different disease states consistent with the known heterogeneous clinical response to treatment. In contrast to earlier cohorts, the plasma HIV viral load of KS patients in our study was highly variable. A total of 25% of participants had no detectable HIV; all had detectable KSHV viral load. Our study affirms that many KS cases today develop in PLWH with well-controlled HIV infection and that different KS lesions have differing molecular compositions. Further studies are needed to develop predictive biomarkers for this disease.
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Infecciones por VIH , Herpesvirus Humano 8 , Sarcoma de Kaposi , Humanos , Sarcoma de Kaposi/complicaciones , Sarcoma de Kaposi/tratamiento farmacológico , Sarcoma de Kaposi/epidemiología , Infecciones por VIH/complicaciones , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/epidemiología , VIH , Estudios Prospectivos , Herpesvirus Humano 8/fisiologíaRESUMEN
OBJECTIVES: Compare rates, clinical characteristics, and outcomes of paediatric palliative care consultation in children supported on extracorporeal membrane oxygenation admitted to a single-centre 16-bed cardiac or a 28-bed paediatric ICU. METHODS: Retrospective review of clinical characteristics and outcomes of children (aged 0-21 years) supported on extracorporeal membrane oxygenation between January, 2017 and December, 2019 compared by palliative care consultation. MEASUREMENTS AND RESULTS: One hundred children (N = 100) were supported with extracorporeal membrane oxygenation; 19% received a palliative care consult. Compared to non-consulted children, consulted children had higher disease severity measured by higher complex chronic conditions at the end of extracorporeal membrane oxygenation hospitalisation (5 versus. 3; p < 0.001), longer hospital length of stay (92 days versus 19 days; p < 0.001), and higher use of life-sustaining therapies after decannulation (79% versus 23%; p < 0.001). Consultations occurred mainly for longitudinal psychosocial-spiritual support after patient survived device deployment with a median of 27 days after cannulation. Most children died in the ICU after withdrawal of life-sustaining therapies regardless of consultation status. Over two-thirds of the 44 deaths (84%; n = 37) occurred during extracorporeal membrane oxygenation hospitalisation. CONCLUSIONS: Palliative care consultation was rare showing that palliative care consultation was not viewed as an acute need and only considered when the clinical course became protracted. As a result, there are missed opportunities to involve palliative care earlier and more frequently in the care of extracorporeal membrane survivors and non-survivors and their families.
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Oxigenación por Membrana Extracorpórea , Niño , Humanos , Cuidados Paliativos , Unidades de Cuidado Intensivo Pediátrico , Corazón , Hospitalización , Estudios RetrospectivosRESUMEN
BACKGROUND: Cetuximab is often administered to patients with KRAS wild-type (KRAS-WT) metastatic colorectal cancer (mCRC), although resistance inevitably develops. We hypothesized that co-inhibition of the epidermal growth factor receptor (EGFR) with cetuximab and downstream cyclin-dependent kinases (CDK) 4/6 with palbociclib would be effective for anti-EGFR rechallenge in KRAS-WT mCRC. METHODS: We designed a single-arm, Simon's 2-stage, phase II trial of cetuximab and palbociclib in KRAS-WT mCRC treated with ≥2 prior lines of therapy. We report here on cohort B rechallenging patients with anti-EGFR-based therapy who had disease control of at least 4 months on prior anti-EGFR therapy. Primary endpoint was disease control rate (DCR) at 4 months. RESULTS: Ten evaluable patients were enrolled in this cohort. The 4-month DCR was 20%, which did not fulfill the prespecified 4-month DCR rate to continue. Median progression-free survival was 1.8 months and median overall survival was 6.6 months. Three patients had stable disease, although overall response rate was 0%. Most common treatment-related grades 3-4 adverse events were lymphopenia and leukopenia. CONCLUSION: Selection of patients for anti-EGFR rechallenge using clinical criteria alone was insufficient to identify response to palbociclib + cetuximab. Additional biomarkers are needed to select anti-EGFR rechallenge and circulating tumor DNA (ctDNA) analysis is planned for samples collected in this study. (ClinicalTrials.gov Identifier: NCT03446157).
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Neoplasias Colorrectales , Humanos , Cetuximab/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Proteínas Proto-Oncogénicas B-raf , Proteínas de la Membrana , GTP FosfohidrolasasRESUMEN
BACKGROUND: Adavosertib (AZD1775) is an inhibitor of the Wee1 kinase. The authors conducted a phase 1b trial to evaluate the safety of adavosertib in combination with definitive chemoradiotherapy for patients with newly diagnosed, intermediate-risk/high-risk, locally advanced head and neck squamous cell carcinoma (HNSCC). METHODS: Twelve patients with intermediate-risk/high-risk HNSCC were enrolled, including those with p16-negative tumors of the oropharynx, p16-positive tumors of the oropharynx with ≥10 tobacco pack-years, and tumors of the larynx/hypopharynx regardless of p16 status. All patients were treated with an 8-week course of concurrent intensity-modulated radiotherapy at 70 grays (Gy) (2 Gy daily in weeks 1-7), cisplatin 30 mg/m2 weekly (in weeks 1-7), and adavosertib (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8). The primary objective was to determine the maximum tolerated dose and the recommended phase 2 dose of adavosertib given concurrently with radiation and cisplatin. Secondary objectives were to determine the 12-week objective response rate and progression-free and overall survival. RESULTS: Three patients (25%) experienced a dose-limiting toxicity, including febrile neutropenia (n = 2) and grade 4 thromboembolism (n = 1). Two dose-limiting toxicities occurred with adavosertib at 150 mg. The median follow-up was 14.7 months. The 12-week posttreatment objective response rate determined by positron emission tomography/computed tomography was 100%. The 1-year progression-free and overall survival rates were both 90%. The maximum tolerated dose of adavosertib was 100 mg. CONCLUSIONS: Adavosertib 100 mg (twice daily on Monday, Tuesday, and Wednesday of weeks 1, 2, 4, 5, 7, and 8), in combination with 70 Gy of intensity-modulated radiotherapy and cisplatin 30 mg/m2 , is the recommended phase 2 dose for patients with HNSCC.
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Cisplatino , Neoplasias de Cabeza y Cuello , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Quimioradioterapia/efectos adversos , Quimioradioterapia/métodos , Cisplatino/efectos adversos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/radioterapia , Humanos , Pirazoles , Pirimidinonas , Carcinoma de Células Escamosas de Cabeza y Cuello/tratamiento farmacológico , Carcinoma de Células Escamosas de Cabeza y Cuello/radioterapiaRESUMEN
The ASXL1 and SRSF2 mutations in AML are frequently found in patients with preexisting myeloid malignancies and are individually associated with poor outcomes. In this multi-institutional retrospective analysis, we assessed the genetic features and clinical outcomes of 43 patients with ASXL1mut SRSF2mut AML and compared outcomes to patients with either ASXL1 (n = 57) or SRSF2 (n = 70) mutations. Twenty-six (60%) had secondary-AML (s-AML). Variant allele fractions suggested that SRSF2 mutations preceded ASXL1 mutational events. Median overall survival (OS) was 7.0 months (95% CI:3.8,15.3) and was significantly longer in patients with de novo vs s-AML (15.3 vs 6.4 months, respectively; P = .04 on adjusted analysis). Compared to ASXL1mut SRSF2wt and ASXL1wt SRSF2mut , co-mutated patients had a 1.4 and 1.6 times increase in the probability of death, respectively (P = .049), with a trend towards inferior OS (median OS = 7.0 vs 11.5 vs 10.9 months, respectively; P = .10). Multivariable analysis suggests this difference in OS is attributable to the high proportion of s-AML patients in the co-mutated cohort (60% vs 32% and 23%, respectively). Although this study is limited by the retrospective data collection and the relatively small sample size, these data suggest that ASXL1mut SRSF2mut AML is a distinct subgroup of AML frequently associated with s-AML and differs from ASXL1mut SRSF2wt /ASXL1wt SRSF2mut with respect to etiology and leukemogenesis.
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Leucemia Mieloide Aguda/genética , Mutación , Proteínas Represoras/genética , Factores de Empalme Serina-Arginina/genética , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Transformación Celular Neoplásica/genética , Cocarcinogénesis/genética , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Estimación de Kaplan-Meier , Leucemia Mieloide Aguda/clasificación , Leucemia Mieloide Aguda/mortalidad , Masculino , Persona de Mediana Edad , Pronóstico , Proteínas Represoras/fisiología , Estudios Retrospectivos , Factores de Empalme Serina-Arginina/fisiologíaRESUMEN
OBJECTIVE: Retrospectively apply criteria from Center to Advance Palliative Care to a cohort of children treated in a cardiac ICU and compare children who received a palliative care consultation to those who were eligible for but did not receive one. METHODS: Medical records of children admitted to a cardiac ICU between January 2014 and June 2017 were reviewed. Selected criteria include cardiac ICU length of stay >14 days and/or ≥ 3 hospitalisations within a 6-month period. MEASUREMENTS AND RESULTS: A consultation occurred in 17% (n = 48) of 288 eligible children. Children who received a consult had longer cardiac ICU (27 days versus 17 days; p < 0.001) and hospital (91 days versus 35 days; p < 0.001) lengths of stay, more complex chronic conditions at the end of first hospitalisation (3 versus1; p < 0.001) and the end of the study (4 vs.2; p < 0.001), and higher mortality (42% versus 7%; p < 0.001) when compared with the non-consulted group. Of the 142 pre-natally diagnosed children, only one received a pre-natal consult and 23 received it post-natally. Children who received a consultation (n = 48) were almost 2 months of age at the time of the consult. CONCLUSIONS: Less than a quarter of eligible children received a consultation. The consultation usually occurred in the context of medical complexity, high risk of mortality, and at an older age, suggesting potential opportunities for more and earlier paediatric palliative care involvement in the cardiac ICU. Screening criteria to identify patients for a consultation may increase the use of palliative care services in the cardiac ICU.
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Unidades de Cuidados Intensivos , Cuidados Paliativos , Anciano , Niño , Humanos , Unidades de Cuidado Intensivo Pediátrico , Tiempo de Internación , Prevalencia , Derivación y Consulta , Estudios RetrospectivosRESUMEN
Objective: To describe thyroid dysfunction, factors associated with thyroid recovery, and survival in melanoma patients treated with immune checkpoint inhibitors that developed thyroid immune-related adverse events (irAEs). Methods: This was a retrospective study in a tertiary center from 2010-2017. We reviewed the charts of patients with melanoma that developed thyroid dysfunction after checkpoint inhibitor therapy. Cases with thyroid irAEs were grouped by recovery of thyroid function at 1 year. We collected a timeline of thyroid function tests, medication exposure, and survival and compared variables between the groups. We studied survival in comparison to a matched group without thyroid dysfunction. Results: A total of 186 melanoma patients received checkpoint inhibitors, and 17 (9%) had thyroid irAEs. Median time to abnormal thyroid-stimulating hormone was 38 days and followed a pattern of thyroiditis. Seven of 17 had thyroid recovery. In the no-recovery group, free thyroxine (T4) was often above 2 ng/dL (5/10 in no recovery, 0/7 in recovery; P = .04). In the recovery group, irAE grade was significantly lower, with 7/7 grade 1 (P = .004). Exposure to glucocorticoids was associated with recovery (3/10 in no recovery, 6/7 in recovery; P = .049). There was no difference in overall survival between the thyroid dysfunction group and controls, or between those that received glucocorticoids or not. Conclusion: Certain aspects of thyroid irAEs may correlate with thyroid recovery, including grade 1 thyroid irAEs, exposure to glucocorticoids, and peak free T4 levels less than 2 ng/dL. Thyroid irAEs did not appear to be associated with change in survival nor did exposure to glucocorticoids. Abbreviations: ASCO = American Society of Clinical Oncology; CTLA-4 = cytotoxic T-lymphocyte-associated protein 4; irAE = immune-related adverse event; PD-1 = programmed cell death protein 1; T4 = thyroxine; TSH = thyroid-stimulating hormone.
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Melanoma , Humanos , Nivolumab , Pronóstico , Estudios RetrospectivosRESUMEN
OBJECTIVES: Describe pediatric palliative care consult in children with heart disease; retrospectively apply Center to Advance Palliative Care criteria for pediatric palliative care consults; determine the impact of pediatric palliative care on end of life. DESIGN: A retrospective single-center study. SETTING: A 16-bed cardiac ICU in a university-affiliated tertiary care children's hospital. PATIENTS: Children (0-21 yr old) with heart disease admitted to the cardiac ICU from January 2014 to June 2017. MEASUREMENTS AND MAIN RESULTS: Over 1,000 patients (n = 1, 389) were admitted to the cardiac ICU with 112 (8%) receiving a pediatric palliative care consultation. Patients who received a consult were different from those who did not. Patients who received pediatric palliative care were younger at first hospital admission (median 63 vs 239 d; p = 0.003), had a higher median number of complex chronic conditions at the end of first hospitalization (3 vs 1; p < 0.001), longer cumulative length of stay in the cardiac ICU (11 vs 2 d; p < 0.001) and hospital (60 vs 7 d; p < 0.001), and higher mortality rates (38% vs 3%; p < 0.001). When comparing location and modes of death, patients who received pediatric palliative care were more likely to die at home (24% vs 2%; p = 0.02) and had more comfort care at the end of life (36% vs 2%; p = 0.002) compared to those who did not. The Center to Advance Palliative Care guidelines identified 158 patients who were eligible for pediatric palliative care consultation; however, only 30 patients (19%) in our sample received a consult. CONCLUSIONS: Pediatric palliative care consult rarely occurred in the cardiac ICU. Patients who received a consult were medically complex and experienced high mortality. Comfort care at the end of life and death at home was more common when pediatric palliative care was consulted. Missed referrals were apparent when Center to Advance Palliative Care criteria were retrospectively applied.
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Cardiopatías , Cuidado Terminal , Niño , Cardiopatías/terapia , Humanos , Unidades de Cuidados Intensivos , Tiempo de Internación , Cuidados Paliativos , Estudios RetrospectivosRESUMEN
CRLX101 is a nanoparticle-drug conjugate with a camptothecin payload. We assessed the toxicity and pathologic complete response (pCR) rate of CRLX101 with standard neoadjuvant chemoradiotherapy (CRT) in locally advanced rectal cancer. A single-arm study was conducted with a 3â¯+â¯3 dose escalation phase Ib followed by phase II at the maximum tolerated dose (MTD). Thirty-two patients were enrolled with 29 (91%) patients having T3/4 and 26 (81%) N1/2 disease. In phase Ib, no patient experienced a dose limiting toxicity (DLT) with every other week dosing, while 1/9 patients experienced a DLT with weekly dosing. The weekly MTD was identified as 15 mg/m2. The most common grade 3-4 toxicity was lymphopenia, with only 1 grade 4 event. pCR was achieved in 6/32 (19%) patients overall and 2/6 (33%) patients at the weekly MTD. CRLX101 at 15 mg/m2 weekly with neoadjuvant CRT is a feasible combination strategy with an excellent toxicity profile. Clinicaltrials.gov registration NCT02010567.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Camptotecina/uso terapéutico , Capecitabina/uso terapéutico , Ciclodextrinas/uso terapéutico , Nanopartículas/química , Terapia Neoadyuvante , Neoplasias del Recto/tratamiento farmacológico , Neoplasias del Recto/radioterapia , Adulto , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Camptotecina/efectos adversos , Capecitabina/efectos adversos , Estudios de Cohortes , Ciclodextrinas/efectos adversos , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias del Recto/patologíaRESUMEN
BACKGROUND: Regorafenib, a multikinase inhibitor that inhibits angiogenesis, growth, and proliferation, prolongs survival as monotherapy in patients with refractory colorectal cancer. This international, double-blind, placebo-controlled, multicenter trial assessed the efficacy of regorafenib with folinic acid, fluorouracil, and irinotecan (FOLFIRI) as a second-line treatment for metastatic colorectal cancer. METHODS: Patients with metastatic colorectal cancer who progressed on first-line oxaliplatin and fluoropyrimidine enrolled at 45 sites in the United States and Ireland. Patients, stratified by prior bevacizumab use, were randomized 2:1 to regorafenib or placebo. The treatment consisted of FOLFIRI on days 1 and 2 and days 15 and 16 with 160 mg of regorafenib or placebo on days 4 to 10 and days 18 to 24 of every 28-day cycle. Crossover was not allowed. The primary endpoint was progression-free survival (PFS). Under the assumption of a 75% event rate, 180 patients were required for 135 events to achieve 90% power to detect a hazard ratio (HR) of 0.65 with a 1-sided α value of .1. RESULTS: One hundred eighty-one patients were randomized (120 to regorafenib-FOLFIRI and 61 to placebo-FOLFIRI) with a median age of 62 years. Among these, 117 (65%) received prior bevacizumab or aflibercept. PFS was longer with regorafenib-FOLFIRI than placebo-FOLFIRI (median, 6.1 vs 5.3 months; HR, 0.73; 95% confidence interval [CI], 0.53-1.01; log-rank P = .056). The median overall survival was not longer (HR, 1.01; 95% CI, 0.71-1.44). The response rate was higher with regorafenib-FOLFIRI (34%; 95% CI, 25%-44%) than placebo-FOLFIRI (21%; 95% CI, 11%-33%; P = .07). Grade 3/4 adverse events with a >5% absolute increase from regorafenib included diarrhea, neutropenia, febrile neutropenia, hypophosphatemia, and hypertension. CONCLUSIONS: The addition of regorafenib to FOLFIRI as second-line therapy for metastatic colorectal cancer only modestly prolonged PFS over FOLFIRI alone. Cancer 2018. © 2018 American Cancer Society.
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Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Camptotecina/análogos & derivados , Neoplasias Colorrectales/tratamiento farmacológico , Compuestos de Fenilurea/administración & dosificación , Piridinas/administración & dosificación , Adulto , Anciano , Camptotecina/administración & dosificación , Neoplasias Colorrectales/patología , Método Doble Ciego , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Fluorouracilo/administración & dosificación , Humanos , Irinotecán/administración & dosificación , Estimación de Kaplan-Meier , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Supervivencia sin ProgresiónRESUMEN
OBJECTIVES: To evaluate progression-free survival (PFS) and overall survival (OS) outcomes in women diagnosed with uterine papillary serous carcinoma (UPSC) who have had (UPSCBR+) or have not had (UPSCBR-) an antecedent history of breast cancer and to correlate their outcomes to prior tamoxifen exposure. METHODS: Data were collected for women diagnosed with UPSC at two academic institutions between January 1997 and July 2012. Patient demographics, tumor histology, stage, and treatments were recorded. Patients were divided into two groups: those with and without a personal history of breast cancer. Within the UPSCBR+ cohort, we identified those with a history of tamoxifen use. Cox regression modeling was used to explore associations between selected covariates of interest and the time-to-event outcomes of PFS and OS. RESULTS: Of 323 patients with UPSC, 46 (14%) were UPSCBR+. Of these, 15 (33%) had a history of tamoxifen use. UPSCBR+ patients were older than UPSCBR- (median years, 72 vs. 68, p=0.004). UPSCBR+ women showed no significant difference in PFS or OS compared to UPSCBR- (p=0.64 and p=0.73 respectively), even after controlling for age (p=0.15 and p=0.48 respectively). Within the UPSCBR+ cohort, there was no difference in PFS or OS with or without tamoxifen exposure (p=0.98 and p=0.94 respectively). CONCLUSIONS: There was no difference in PFS or OS between the UPSCBR+ and UPSCBR- cohorts. We did not demonstrate significant OS or PFS differences in women who took tamoxifen prior to their endometrial cancer diagnosis. These findings have implications for counseling, and should be encouraging to women who are facing their second cancer diagnosis.
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Neoplasias de la Mama/epidemiología , Cistadenocarcinoma Papilar/epidemiología , Cistadenocarcinoma Seroso/epidemiología , Antagonistas de Estrógenos/administración & dosificación , Tamoxifeno/administración & dosificación , Neoplasias Uterinas/epidemiología , Anciano , Neoplasias de la Mama/patología , Estudios de Cohortes , Cistadenocarcinoma Papilar/diagnóstico , Cistadenocarcinoma Papilar/patología , Cistadenocarcinoma Seroso/diagnóstico , Cistadenocarcinoma Seroso/patología , Supervivencia sin Enfermedad , Femenino , Humanos , Persona de Mediana Edad , North Carolina/epidemiología , Modelos de Riesgos Proporcionales , Estudios Retrospectivos , Resultado del Tratamiento , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/patologíaRESUMEN
Circulating antibodies (Ab) that specifically bind polyethylene glycol (PEG), a biocompatible polymer routinely used in protein and nanoparticle therapeutics, have been associated with reduced efficacy of and/or adverse reactions to therapeutics modified with or containing PEG. Unlike most antidrug antibodies that are induced following initial drug dosing, anti-PEG Ab can be found in treatment-naïve individuals (i.e., individuals who have never undergone treatment with PEGylated drugs but most likely have been exposed to PEG through other means). Unfortunately, the true prevalence, quantitative levels, and Ab isotype of pre-existing anti-PEG Ab remain poorly understood. Here, using rigorously validated competitive ELISAs with engineered chimeric anti-PEG monoclonal Ab standards, we quantified the levels of anti-PEG IgM and different subclasses of anti-PEG IgG (IgG1-4) in both contemporary and historical human samples. We unexpectedly found, with 90% confidence, detectable levels of anti-PEG Ab in â¼72% of the contemporary specimens (18% IgG, 25% IgM, 30% both IgG and IgM). The vast majority of these samples contained low levels of anti-PEG Ab, with only â¼7% and â¼1% of all specimens possessing anti-PEG IgG and IgM in excess of 500 ng/mL, respectively. IgG2 was the predominant anti-PEG IgG subclass. Anti-PEG Ab's were also observed in â¼56% of serum samples collected during 1970-1999 (20% IgG, 19% IgM, and 16% both IgG and IgM), suggesting that the presence of PEG-specific antibodies may be a longstanding phenomenon. Anti-PEG IgG levels demonstrated correlation with patient age, but not with gender or race. The widespread prevalence of pre-existing anti-PEG Ab, coupled with high Ab levels in a subset of the population, underscores the potential importance of screening patients for anti-PEG Ab levels prior to administration of therapeutics containing PEG.
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Inmunoglobulina G/sangre , Inmunoglobulina G/inmunología , Inmunoglobulina M/sangre , Inmunoglobulina M/inmunología , Polietilenglicoles/análisis , Adulto , Anciano , Reacciones Antígeno-Anticuerpo , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
Currently, presymtomatic hematopoietic stem and progenitor cell transplantation (HSPCT) is the only therapeutic modality that alleviates Krabbe's disease (KD)-induced central nervous system damage. However, all HSPCT-treated patients exhibit severe deterioration in peripheral nervous system function characterized by major motor and expressive language pathologies. We hypothesize that a combination of several mechanisms contribute to this phenomenon, including 1) nonoptimal conditioning protocols with consequent inefficient engraftment and biodistribution of donor-derived cells and 2) insufficient uptake of donor cell-secreted galactocerebrosidease (GALC) secondary to a naturally low expression level of the cation-independent mannose 6-phosphate-receptor (CI-MPR). We have characterized the effects of a busulfan (Bu) based conditioning regimen on the efficacy of HSPCT in prolonging twi mouse average life span. There was no correlation between the efficiency of bone marrow engraftment of donor cells and twi mouse average life span. HSPCT prolonged the average life span of twi mice, which directly correlated with the aggressiveness of the Bu-mediated conditioning protocols. HSPC transduced with lentiviral vectors carrying the GALC cDNA under control of cell-specific promoters were efficiently engrafted in twi mouse bone marrow. To facilitate HSPCT-mediated correction of GALC deficiency in target cells expressing low levels of CI-MPR, a novel GALC fusion protein including the ApoE1 receptor was developed. Efficient cellular uptake of the novel fusion protein was mediated by a mannose-6-phosphate-independent mechanism. The novel findings described here elucidate some of the cellular mechanisms that impede the cure of KD patients by HSPCT and concomitantly open new directions to enhance the therapeutic efficacy of HSPCT protocols for KD. © 2016 The Authors. Journal of Neuroscience Research Published by Wiley Periodicals, Inc.
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Terapia Genética , Trasplante de Células Madre Hematopoyéticas , Leucodistrofia de Células Globoides/terapia , Animales , Antígenos CD/metabolismo , Antimetabolitos/uso terapéutico , Encéfalo/efectos de los fármacos , Encéfalo/metabolismo , Encéfalo/patología , Busulfano/farmacología , Línea Celular Transformada , Cicloserina/uso terapéutico , Modelos Animales de Enfermedad , Femenino , Fibroblastos/metabolismo , Fibroblastos/fisiología , Galactosilceramidasa/genética , Galactosilceramidasa/metabolismo , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Terapia Genética/tendencias , Vectores Genéticos/fisiología , Trasplante de Células Madre Hematopoyéticas/tendencias , Humanos , Inmunosupresores/uso terapéutico , Leucodistrofia de Células Globoides/tratamiento farmacológico , Leucodistrofia de Células Globoides/metabolismo , Leucodistrofia de Células Globoides/patología , Receptor IGF Tipo 2/metabolismo , Receptores de Somatomedina/metabolismoRESUMEN
OBJECTIVE: To determine patients' perceptions of provider-based counseling and behavior changes made by endometrial cancer survivors. MATERIALS AND METHODS: Endometrial cancer survivors (diagnosed from 2011 to 2012) from a single institution were surveyed. Exclusion criteria included persistent or recurrent disease or those actively undergoing treatment. Information collected included demographics, weight assessments, health behaviors, and physician counseling. Statistical analysis was performed using descriptive statistics, Fisher exact test, McNemar test, and the κ statistic as a measure of agreement. RESULTS: Of 233 surveys sent, 46% were returned. Median body mass index was 29.8 kg/m (range, 17.1-64.8 kg/m). Comparing primary care providers with gynecologic oncologists (GOs), 47% (n = 46) versus 25% (n = 23) provided dietary counseling and 62% (n = 60) versus 37% (n = 34) provided physical activity counseling (Fisher exact test, P = 0.001 and P < 0.001, respectively). Only 29% (n = 30) reported being told of the link between endometrial cancer and obesity. Fifty-two percent of responders attempted weight loss after their diagnosis. Fifty-nine percent of responders reported making changes in their diet. Fifty-six percent of patients made dietary changes within 3 months of diagnosis. Forty-eight percent of responders increased physical activity, with 62% implementing changes within 3 to 6 months of their diagnosis. The responders most likely to attempt weight loss were those who received counseling by a provider. All patients reporting attempted weight loss after their cancer diagnosis report being counseled by either a primary care provider or a GO to lose weight. Weight loss counseling was significantly associated with attempting weight loss (P < 0.001). CONCLUSIONS: One third of endometrial cancer survivors report counseling by their GO to lose weight. One half of endometrial cancer survivors reported attempted weight loss. All patients reporting weight loss counseling from their oncologist reported attempted weight loss. Most behavioral change occurred 3 to 6 months after a cancer diagnosis. Obesity in endometrial cancer survivors is not adequately addressed and represents a critical area for improvement.
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Conocimientos, Actitudes y Práctica en Salud , Obesidad/psicología , Sobrevivientes/psicología , Adulto , Anciano , Anciano de 80 o más Años , Consejo Dirigido , Neoplasias Endometriales/etiología , Femenino , Humanos , Estilo de Vida , Persona de Mediana Edad , Obesidad/complicaciones , Encuestas y Cuestionarios , Sobrevivientes/estadística & datos numéricosRESUMEN
BACKGROUND: Platinum plus etoposide is the standard therapy for extensive-stage small cell lung cancer (ES-SCLC) and is associated with significant myelosuppression. We hypothesized that the combination of carboplatin and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) would be better tolerated. We investigated carboplatin with nab-paclitaxel on every-3-week and weekly schedules. METHODS: This noncomparative randomized phase II trial used a two-stage design. The primary objective was objective response rate, and secondary objectives were progression-free survival, overall survival, and toxicity. Patients with ES-SCLC and an Eastern Cooperative Oncology Group performance status ≤2 and no prior chemotherapy were randomized in a 1:1 ratio to arm A (carboplatin area under the curve [AUC] of 6 on day 1 and nab-paclitaxel of 300 mg/m(2) on day 1 every 3 weeks) or arm B (carboplatin AUC of 6 on day 1 and nab-paclitaxel 100 mg/m(2) on days 1, 8, and 15 every 21 days). Response was assessed after every two cycles. RESULTS: Patients required frequent dose reductions, treatment delays, and omission of the weekly therapy. The trial was closed because of slow accrual. CONCLUSION: Carboplatin and nab-paclitaxel demonstrated activity in ES-SCLC but required frequent dose adjustments.
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Paclitaxel Unido a Albúmina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Carboplatino/administración & dosificación , Carcinoma Pulmonar de Células Pequeñas/tratamiento farmacológico , Adulto , Anciano , Albúminas , Supervivencia sin Enfermedad , Femenino , Humanos , Masculino , Persona de Mediana Edad , Nanopartículas/administración & dosificación , Estadificación de Neoplasias , Paclitaxel , Carcinoma Pulmonar de Células Pequeñas/patología , Resultado del TratamientoRESUMEN
OBJECTIVE: Robotic gynecological surgery is feasible in obese patients, but there remain concerns about the safety of this approach because the positioning required for pelvic surgery can exacerbate obesity-related changes in respiratory physiology. The objective of our study was to evaluate pulmonary and all-cause complication rates in obese women undergoing robotic gynecological surgery and to assess variables that may be associated with complications. STUDY DESIGN: A retrospective chart review was performed on obese patients (body mass index of ≥30 kg/m(2)) who underwent robotic gynecological surgery at 2 academic institutions between 2006 and 2012. The primary outcome was pulmonary complications and the secondary outcome was all-cause complications. Univariate and multivariate logistic regression analyses were used to determine the associations between patient baseline variables, operative variables, ventilator parameters, and complications. RESULTS: Of 1032 patients, 146 patients (14%) had any complication, whereas only 33 patients (3%) had a pulmonary complication. Median body mass index was 37 kg/m(2). Only age was significantly associated with a higher risk of pulmonary complications (P = .01). Older age, higher estimated blood loss, and longer case length were associated with a higher rate of all-cause complications (P = .0001, P < .0001, and P = .004, respectively). No other covariates were strongly associated with complications. CONCLUSION: The vast majority of obese patients can successfully tolerate robotic gynecological surgery and have overall low complications rates and even lower rates of pulmonary complications. The degree of obesity was not predictive of successful robotic surgery and subsequent complications.
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Enfermedades de los Genitales Femeninos/epidemiología , Procedimientos Quirúrgicos Ginecológicos/efectos adversos , Enfermedades Pulmonares/epidemiología , Obesidad/epidemiología , Robótica , Adulto , Anciano , Comorbilidad , Femenino , Enfermedades de los Genitales Femeninos/cirugía , Procedimientos Quirúrgicos Ginecológicos/estadística & datos numéricos , Inclinación de Cabeza , Humanos , Modelos Logísticos , Persona de Mediana Edad , Análisis Multivariante , Complicaciones Posoperatorias/epidemiología , Estudios RetrospectivosRESUMEN
BACKGROUND: We examined the distribution of obesity, diabetes, and race in Type I and Type II endometrial cancers (EC) and their associations with clinical outcomes. METHODS: A multi-institutional retrospective analysis of Type I and II EC cases from January 2005 to December 2010 was conducted. Type I (endometrioid), Type II (serous and clear cell), low grade (LG) (grade 1 and 2 endometrioid), and high grade (HG) (grade 3 endometrioid, serous, clear cell) cohorts were compared. Univariate and multivariate analyses were used to determine time-to-recurrence (TTR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: Type I EC patients were more frequently obese than Type II (66% versus 51%, p<0.0001) and had similar rates of diabetes (25% versus 23%, p=0.69). African-Americans (AA) had higher median BMI than Caucasians in both Type I (p<0.001) and II (p<0.001) ECs, and were twice as likely to have diabetes (p<0.001). In Type I EC, DM was associated with worse RFS and OS in unadjusted and adjusted models (RFS HR 1.38, 95%CI 1.01-1.89; OS HR 1.86, 95%CI 1.30-2.67), but not with TTR. BMI was associated with improved TTR in the adjusted analysis for Type I EC (HR 0.98, 95%CI 0.95-1.0), but not with RFS or OS. There was no association between DM or BMI and outcomes in Type II or HG EC. AA race was not associated with RFS or OS on adjusted analyses in any group. CONCLUSIONS: Obesity and diabetes are highly prevalent in Type I and II ECs, especially in AA. DM was associated with worse RFS and OS in Type I EC. Neither DM nor BMI was associated with outcomes in Type II or HG EC.
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Adenocarcinoma de Células Claras/etnología , Carcinoma Endometrioide/etnología , Diabetes Mellitus/etnología , Neoplasias Endometriales/etnología , Obesidad/etnología , Adenocarcinoma de Células Claras/terapia , Negro o Afroamericano/estadística & datos numéricos , Anciano , Asiático/estadística & datos numéricos , Carcinoma/etnología , Carcinoma/patología , Carcinoma/terapia , Carcinoma Endometrioide/terapia , Quimioterapia Adyuvante , Neoplasias Endometriales/patología , Neoplasias Endometriales/terapia , Femenino , Hispánicos o Latinos/estadística & datos numéricos , Humanos , Indígenas Norteamericanos/estadística & datos numéricos , Persona de Mediana Edad , Análisis Multivariante , Radioterapia Adyuvante , Estudios Retrospectivos , Resultado del Tratamiento , Población Blanca/estadística & datos numéricosRESUMEN
OBJECTIVE: Preclinical evidence suggests that metformin exhibits anti-tumorigenic effects in endometrial cancer. We sought to investigate the association of metformin on endometrial cancer outcomes. METHODS: A multi-institutional IRB-approved retrospective cohort analysis was conducted comparing endometrial cancer patients with diabetes mellitus who used metformin (based on medication review at the time of diagnosis) to those who did not use metformin from 2005 to 2010. Metformin use on treatment related outcomes (TTR: time to recurrence; RFS: recurrence free survival; OS: overall survival) were evaluated using univariate and multivariate modeling. RESULTS: 24% (363/1495) endometrial cancer patients were diabetic, of whom 54% used metformin. Metformin users were younger and heavier than non-users, though nearly all were postmenopausal and obese. 75% of both groups had endometrioid histology. Stage, grade, and adjuvant therapy distributions were similar. Metformin users had improved RFS and OS. Non-metformin users had 1.8 times worse RFS (95% CI: 1.1-2.9, p = 0.02) and 2.3 times worse OS (95% CI: 1.3-4.2, p = 0.005) after adjusting for age, stage, grade, histology and adjuvant treatment. Metformin use was not associated with TTR. CONCLUSION: Metformin use was associated with improved RFS and OS but not TTR, most likely due to improving all-cause mortality. Its role in modifying cancer recurrence remains unclear. Prospective studies that capture metformin exposure prior to, during and post endometrial cancer treatment may help define the role of metformin upon cancer specific and overall health outcomes.
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Neoplasias Endometriales/tratamiento farmacológico , Hipoglucemiantes/uso terapéutico , Metformina/uso terapéutico , Anciano , Estudios de Cohortes , Diabetes Mellitus/tratamiento farmacológico , Supervivencia sin Enfermedad , Neoplasias Endometriales/mortalidad , Neoplasias Endometriales/patología , Femenino , Humanos , Persona de Mediana Edad , Pronóstico , Estudios Retrospectivos , Análisis de Supervivencia , Resultado del Tratamiento , Estados Unidos/epidemiologíaRESUMEN
OBJECTIVE: To improve and individualise estimates of treatment outcomes for men diagnosed with prostate cancer, we examined the impact of baseline comorbidity on health-related quality of life (HRQL) outcomes in an analysis of two pooled, prospective cohort studies. PATIENTS AND METHODS: We studied 697 patients from three academic hospitals who received radical prostatectomy (RP), external beam radiation therapy (EBRT), or brachytherapy (BT). Measures of patient-reported bowel, urinary, and sexual symptoms along with physical and mental health were prospectively collected before treatment and 3, 12, 24, and 36 months after treatment. We assessed baseline comorbidity by the validated Index of Co-Existent Disease (ICED), abstracted from medical records. Regression mixed-models were built for each treatment group and HRQL outcome controlling for baseline age, education, marital status, risk group and patient-reported general health. RESULTS: About 71% of patients had one or more comorbid conditions at baseline. After adjusting for covariates, we found baseline comorbidity was independently associated with poorer sexual function after BT (P = 0.04) and RP (P = 0.03) but not EBRT (P = 0.35). Physical health was significantly worse for men receiving BT with more comorbidities (P = 0.02). Baseline comorbid conditions were not associated with urinary incontinence or bowel functioning. CONCLUSIONS: Comorbidity at baseline is significantly associated with poorer sexual function after prostate BT or RP. This information may help patients and their physicians anticipate outcomes after surgical and radiation treatments.