RESUMO
Xaluritamig (AMG 509) is a six-transmembrane epithelial antigen of the prostate 1 (STEAP1)-targeted T-cell engager designed to facilitate lysis of STEAP1-expressing cancer cells, such as those in advanced prostate cancer. This first-in-human study reports monotherapy dose exploration for patients with metastatic castration-resistant prostate cancer (mCRPC), primarily taxane pretreated. Ninety-seven patients received ≥1 intravenous dose ranging from 0.001 to 2.0 mg weekly or every 2 weeks. MTD was identified as 1.5 mg i.v. weekly via a 3-step dose. The most common treatment-related adverse events were cytokine release syndrome (CRS; 72%), fatigue (45%), and myalgia (34%). CRS occurred primarily during cycle 1 and improved with premedication and step dosing. Prostate-specific antigen (PSA) and RECIST responses across cohorts were encouraging [49% PSA50; 24% objective response rate (ORR)], with greater frequency at target doses ≥0.75 mg (59% PSA50; 41% ORR). Xaluritamig is a novel immunotherapy for prostate cancer that has shown encouraging results supporting further development. SIGNIFICANCE: Xaluritamig demonstrated encouraging responses (PSA and RECIST) compared with historical established treatments for patients with late-line mCRPC. This study provides proof of concept for T-cell engagers as a potential treatment for prostate cancer, validates STEAP1 as a target, and supports further clinical investigation of xaluritamig in prostate cancer. See related commentary by Hage Chehade et al., p. 20. See related article by Nolan-Stevaux et al., p. 90. This article is featured in Selected Articles from This Issue, p. 5.
Assuntos
Antígeno Prostático Específico , Neoplasias de Próstata Resistentes à Castração , Masculino , Humanos , Antígeno Prostático Específico/uso terapêutico , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Imunoterapia , Resultado do Tratamento , Antígenos de Neoplasias , Oxirredutases/uso terapêuticoRESUMO
Surveillance of drug overdose deaths relies on death certificates for identification of the substances that caused death. Drugs and drug classes can be identified through the International Classification of Diseases, Tenth Revision (ICD-10), codes present on death certificates. However, ICD-10 codes do not always provide high levels of specificity in drug identification. To achieve more fine-grained identification of substances on death certificate, the free-text cause-of-death section, completed by the medical certifier, must be analyzed. Current methods for analyzing free-text death certificates rely solely on lookup tables for identifying specific substances, which must be frequently updated and maintained. To improve identification of drugs on death certificates, a deep-learning named-entity recognition model was developed, utilizing data from the Kentucky Drug Overdose Fatality Surveillance System (2014-2019), which achieved an F1-score of 99.13%. This model can identify new drug misspellings and novel substances that are not present on current surveillance lookup tables, enhancing the surveillance of drug overdose deaths.
Assuntos
Atestado de Óbito , Overdose de Drogas , Humanos , Kentucky/epidemiologia , Classificação Internacional de DoençasRESUMO
BACKGROUND: Previous research has revealed under-reporting of personal network members (i.e., alters) in studies involving people who use drugs (PWUD). This analysis (1) characterizes relationships that were more likely to be omitted but later recalled with prompting and (2) identifies network structural characteristics most impacted by these omissions among a sample of PWUD in rural Appalachian Kentucky, an epicenter of the opioid epidemic. METHODS: Data were collected through longitudinal assessments as part of the Social Networks Among Appalachian People (SNAP) study (2008-2017). Study participants completed interviewer-administered questionnaires that collected social network data via free-listing at baseline and six-month intervals. At visit 5, after free-listing, interviewers prompted participants with the names of previously reported alters. We used modified Poisson regression with generalized estimating equations to identify individual- and relationship-level characteristics associated with an alter being reported only after prompting. We examined the impact of including vs. excluding relationships reported after prompting on local and global sociometric network measures (i.e., betweenness centrality, bridging, density, mean degree, transitivity, cliques, and 2-cores). RESULTS: Relationships reported only after prompting were more likely to be immediate family (Adjusted Prevalence Ratio [APR]:1.29; 95% Confidence Interval [CI]: 1.03-1.63) and less likely to involve sex (APR:0.54; 95% CI: 0.43-0.67). Considerable differences were observed for participant positional rankings of betweenness centrality and bridging, and differences in network density and average degree pre- and post-prompting were statistically significant. CONCLUSION: Longitudinal network studies that aim to assess transmission dynamics, information diffusion, or peer influence should consider the effects of omitted relationships.
Assuntos
População Rural , Rede Social , Analgésicos Opioides , Região dos Apalaches/epidemiologia , Humanos , Apoio Social , Inquéritos e QuestionáriosRESUMO
PURPOSE: Results from adjuvant trials evaluating 6 cycles of epirubicin-based chemotherapy regimens suggested these programs may be more effective than 4 cycles of doxorubicin-based chemotherapy. METHOD: NSABP B-36 was a phase III clinical trial originally designed as a 2 × 2 factorial study comparing 6 cycles of 5-FU, epirubicin, and cyclophosphamide (FEC-100) to 4 cycles of conventional doxorubicin and cyclophosphamide (AC) with celecoxib or placebo. Shortly after activation, concerns regarding increased cardiovascular risks among selective COX-2 inhibitors resulted in a decision to remove the celecoxib/placebo from the trial. Women with histologically node-negative invasive breast cancer who had undergone primary surgery with a lumpectomy or total mastectomy were eligible. Primary endpoint was disease-free survival (DFS). RESULTS: Between May 2004 and July 2008, 2722 patients were enrolled. Administration of FEC-100 did not result in improvement in DFS compared to AC (HR 1.09; 95% CI 0.92-1.29, p value = 0.31). The effect of FEC-100 compared to AC on DFS was significantly different for receptor-positive (HR 1.32, 95% CI 1.05-1.66) compared to receptor-negative patients (HR 0.86, 95% CI 0.66-1.11) (treatment-by-receptor status interaction p value = 0.02). There was no statistically significant difference in the effect of treatment on overall survival (OS) with FEC-100 compared to AC (HR 1.06; 95% CI 0.84-1.35, p value = 0.61). Overall, Grade 3 and 4 adverse events were more frequent in the FEC-100 group. CONCLUSION: The results of B-36 do not support use of six-cycle anthracycline-based regimens in node-negative breast cancer. Prolongation of anthracycline-based therapy with FEC-100 does not improve DFS or OS, relative to AC for 4 cycles, and was associated with expected increases in toxicity. A statistically significant interaction between treatment and hormone receptor status favoring AC in hormone-receptor-positive breast cancers is consistent with the hypothesis that optimal duration of chemotherapy may be four cycles in these patients. Late cardiac events and deaths prior to recurrence or second cancer were infrequent on both arms, but slightly higher with FEC-100. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00087178.
Assuntos
Neoplasias da Mama , Antraciclinas/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/cirurgia , Celecoxib/uso terapêutico , Quimioterapia Adjuvante , Ciclofosfamida , Intervalo Livre de Doença , Doxorrubicina/efeitos adversos , Epirubicina , Feminino , Fluoruracila , Humanos , MastectomiaRESUMO
BACKGROUND: The NSABP B-36 compared four cycles of doxorubicin and cyclophosphamide (AC) with six cycles of 5-fluorouracil, epirubicin, and cyclophosphamide (FEC-100) in node-negative early-stage breast cancer. A sub-study within B-36, focusing on symptoms, quality of life (QOL), menstrual history (MH), and cardiac function (CF) was conducted. PATIENTS AND METHODS: Patients completed the QOL questionnaire at baseline, during treatment, and every 6 months through 36 months. FACT-B Trial Outcome Index (TOI), symptom severity, and SF-36 Vitality and Physical Functioning (PF) scales scores were compared between the two groups using a mixed model for repeated measures analysis. MH was collected at baseline and subsequently assessed if menstrual bleeding occurred within 12 months prior to randomization. Post-chemotherapy amenorrhea outcome was examined at 18 months and was defined as lack of menses in the preceding year. Logistic regression was used to test for association of amenorrhea and treatment. CF assessment was done at baseline and 12 months. Correlation analysis was used to address associations between changes in baseline and 12-month PF and concurrent CF changes measured by LVEF. RESULTS: FEC-100 patients had statistically significantly lower TOI scores during chemotherapy (P = 0.02) and at 6 months (P < 0.001); lower Vitality score at 6 months (P < 0.01), and lower PF score during the first year than AC patients. There were no statistically significant QOL score differences between the two groups beyond 12 months. No significant differences in symptom severity between the two groups were observed. Rates of amenorrhea were significantly different between FEC-100 and AC (67.4% vs. 59.1%, P < 0.001). There was no association between changes in LVEF and PF (P = 0.38). CONCLUSIONS: Statistically significant QOL differences between the two groups favored AC; however, the magnitude was small and unlikely to be clinically meaningful. There was a clinical and statistically significant difference in risk for amenorrhea, favoring AC. TRIAL REGISTRY: NCT00087178; Date of registration: 07/08/2004.
Assuntos
Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Quimioterapia Adjuvante , Ciclofosfamida/efeitos adversos , Doxorrubicina/efeitos adversos , Epirubicina/efeitos adversos , Feminino , Fluoruracila/efeitos adversos , Humanos , Avaliação de Resultados em Cuidados de Saúde , Qualidade de VidaRESUMO
Objectives. To examine trends in opioid overdose deaths by race/ethnicity from 2018 to 2019 across 67 HEALing Communities Study (HCS) communities in Kentucky, New York, Massachusetts, and Ohio. Methods. We used state death certificate records to calculate opioid overdose death rates per 100 000 adult residents of the 67 HCS communities for 2018 and 2019. We used Poisson regression to calculate the ratio of 2019 to 2018 rates. We compared changes by race/ethnicity by calculating a ratio of rate ratios (RRR) for each racial/ethnic group compared with non-Hispanic White individuals. Results. Opioid overdose death rates were 38.3 and 39.5 per 100 000 for 2018 and 2019, respectively, without a significant change from 2018 to 2019 (rate ratio = 1.03; 95% confidence interval [CI] = 0.98, 1.08). We estimated a 40% increase in opioid overdose death rate for non-Hispanic Black individuals (RRR = 1.40; 95% CI = 1.22, 1.62) relative to non-Hispanic White individuals but no change among other race/ethnicities. Conclusions. Overall opioid overdose death rates have leveled off but have increased among non-Hispanic Black individuals. Public Health Implications. An antiracist public health approach is needed to address the crisis of opioid-related harms. (Am J Public Health. 2021;111(10):1851-1854. https://doi.org/10.2105/AJPH.2021.306431).
Assuntos
Etnicidade/estatística & dados numéricos , Geografia Médica/estatística & dados numéricos , Overdose de Opiáceos/etnologia , Overdose de Opiáceos/mortalidade , Adulto , Bases de Dados Factuais/estatística & dados numéricos , Humanos , Kentucky , Massachusetts , New York , OhioRESUMO
INTRODUCTION: Rovalpituzumab tesirine (Rova-T) is an antibody-drug conjugate targeting DLL3, a Notch pathway ligand highly expressed on SCLC cells. Rova-T was evaluated alone or in combination with platinum-based chemotherapy (cisplatin or carboplatin combined with etoposide [CE]) in frontline treatment of extensive-stage SCLC. METHODS: One cycle of CE pre-enrollment was permitted (later mandated). The following four cohorts were enrolled: Rova-T monotherapy (0.3 mg/kg, every 6 [q6] wk × 2; cohort 1; n = 4); Rova-T induction (0.3 mg/kg, q6 wk × 2) followed by CE every 21 days (q21) × 4 (cohort 2; n = 5); Rova-T (0.1 or 0.2 mg/kg, q6 wk × 2) overlapping with CE q21 × 4 (cohort 3; n = 14); and Rova-T maintenance (0.3 mg/kg, q6 wk × 2) after CE q21 × 4 (cohort 4; n = 3). RESULTS: A total of 26 patients were dosed (cohort 3: 14; cohorts 1, 2, and 4 combined: 12). Median age was 66 years, and 73% had Eastern Cooperative Oncology Group performance status of 1. In cohort 3, seven patients (50%) had confirmed objective responses, with a median progression-free survival of 5.2 months and median overall survival of 10.3 months. Compared with cohorts 1, 2, and 4 combined, cohort 3 had lower frequency of some Rova-T-related adverse events of special interest, such as pleural effusion (0 versus 33%), pericardial effusion (0 versus 17%), ascites (0 versus 8%), peripheral edema (36% versus 42%), generalized edema (0 versus 8%), pneumonia (7% versus 25%), and hypoalbuminemia (0 versus 17%). CONCLUSIONS: Lower Rova-T doses may be associated with lower incidence of some Rova-T-related adverse events of special interest. Rova-T 0.2 mg/kg plus CE (cohort 3) was tolerable; however, there was no clear efficacy benefit of adding Rova-T to CE.
Assuntos
Imunoconjugados , Neoplasias Pulmonares , Carcinoma de Pequenas Células do Pulmão , Idoso , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Benzodiazepinonas/uso terapêutico , Carboplatina/uso terapêutico , Etoposídeo/uso terapêutico , Humanos , Imunoconjugados/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Carcinoma de Pequenas Células do Pulmão/tratamento farmacológicoRESUMO
BACKGROUND: Despite advances, there continues to be unmet need in breast cancer. Combining anti-programmed death-ligand 1 (PD-L1) cancer immunotherapy atezolizumab with other targeted therapies may enhance T-cell-dependent cytolytic antitumor activity. METHODS: This open-label, phase Ib study evaluated the safety of atezolizumab-based combinations with antibody-dependent cellular cytotoxicity or antibody-drug conjugate (ADC) agents. Patients with unresectable human epidermal growth factor receptor 2-positive (HER2+) locally advanced or metastatic breast cancer (mBC) received atezolizumab with trastuzumab/pertuzumab, atezolizumab with the ADC ado-trastuzumab emtansine (T-DM1), or atezolizumab with trastuzumab/pertuzumab and docetaxel. In an early-breast cancer (eBC) "window of opportunity" study, patients with operable HER2+ locally advanced or inflammatory eBC received neoadjuvant atezolizumab with trastuzumab/pertuzumab or atezolizumab/T-DM1, followed by docetaxel, carboplatin, and trastuzumab/pertuzumab. Exploratory outcomes included tumor response and biomarkers. RESULTS: By March 15, 2019, 73 patients were enrolled. Safety findings were consistent with the treatment components' individual profiles. Objective responses were observed in 2 of 6 and 5 of 14 patients in 2 mBC cohorts receiving atezolizumab/T-DM1 and in 6 of 6 patients with mBC receiving atezolizumab, trastuzumab/pertuzumab, and docetaxel. PD-L1 in immune cells was the only biomarker that increased with atezolizumab/T-DM1. In the window of opportunity cohorts, PD-L1 levels and CD8+ T-cell infiltration increased from baseline in HER2+ eBC tumors receiving atezolizumab with trastuzumab/pertuzumab or T-DM1, irrespective of response. Despite increases in T-cell and B-cell gene signatures with trastuzumab/pertuzumab, but not T-DM1, neither combination promoted T-cell receptor clonal expansion. CONCLUSION: Atezolizumab with antibody-dependent cellular cytotoxicity or ADC agents appears safe and may activate the adaptive immune system of patients with HER2+ eBC tumors more than those with mBC tumors.
Assuntos
Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Microambiente Tumoral , Adulto , Neoplasias da Mama/patologia , Docetaxel/uso terapêutico , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Receptor ErbB-2/metabolismo , Taxoides/uso terapêutico , Trastuzumab/uso terapêuticoRESUMO
Inadequately designed culverts can be physical barriers to fish passage if they increase the velocity of water flow in the environment, alter natural turbulence patterns or fail to provide adequate water depth. They may also act as behavioural barriers to fish passage if they affect the willingness of fish species to enter or pass through the structure due to altered ambient light conditions. To understand how reduced light intensity might affect fish behaviour in culverts, the authors performed a behavioural choice experiment quantifying the amount of time individual fish spent in dark and illuminated areas of a controlled experimental channel. They found that behavioural responses were largely reflective of the species' diel activity patterns; the diurnal species Craterocephalus stercusmuscarum and Retropinna semoni preferred illuminated regions, whereas the nocturnal/crepuscular Macquaria novemaculeata preferred the darkened region of the channel. Bidyanus bidyanus were strongly rheotactic, and their behaviour was influenced more by water flow direction than ambient light level. The authors then determined that a threshold light intensity of only c. 100-200 lx (cf. midday sunlight c. 100,000 lx) was required to overcome the behavioural barrier in c. 70% of the diurnally active C. stercusmuscarum and R. semoni tested. When these values were placed into an environmental context, 15 road-crossing (3.4-7.0 m long) box (c. 1 m × 1 m, height × width) and pipe (c. 1 m diameter) culverts sampled in Brisbane, Australia, recorded light intensities in the centre of the structure that were below the threshold for C. stercusmuscarum and R. semoni movement and could potentially be a barrier to their passage through the structure. Attention is required to better understand the impacts of low light intensity in culverts on fish passage and to prioritize restoration.
Assuntos
Aprendizagem da Esquiva/efeitos da radiação , Ecossistema , Peixes/fisiologia , Luz , Animais , Austrália , Comportamento de Escolha/efeitos da radiaçãoRESUMO
BACKGROUND: Timely data is key to effective public health responses to epidemics. Drug overdose deaths are identified in surveillance systems through ICD-10 codes present on death certificates. ICD-10 coding takes time, but free-text information is available on death certificates prior to ICD-10 coding. The objective of this study was to develop a machine learning method to classify free-text death certificates as drug overdoses to provide faster drug overdose mortality surveillance. METHODS: Using 2017-2018 Kentucky death certificate data, free-text fields were tokenized and features were created from these tokens using natural language processing (NLP). Word, bigram, and trigram features were created as well as features indicating the part-of-speech of each word. These features were then used to train machine learning classifiers on 2017 data. The resulting models were tested on 2018 Kentucky data and compared to a simple rule-based classification approach. Documented code for this method is available for reuse and extensions: https://github.com/pjward5656/dcnlp. RESULTS: The top scoring machine learning model achieved 0.96 positive predictive value (PPV) and 0.98 sensitivity for an F-score of 0.97 in identification of fatal drug overdoses on test data. This machine learning model achieved significantly higher performance for sensitivity (p<0.001) than the rule-based approach. Additional feature engineering may improve the model's prediction. This model can be deployed on death certificates as soon as the free-text is available, eliminating the time needed to code the death certificates. CONCLUSION: Machine learning using natural language processing is a relatively new approach in the context of surveillance of health conditions. This method presents an accessible application of machine learning that improves the timeliness of drug overdose mortality surveillance. As such, it can be employed to inform public health responses to the drug overdose epidemic in near-real time as opposed to several weeks following events.
Assuntos
Overdose de Drogas/mortalidade , Causas de Morte , Overdose de Drogas/diagnóstico , Overdose de Drogas/epidemiologia , Humanos , Classificação Internacional de Doenças , Kentucky/epidemiologia , Aprendizado de Máquina , Vigilância em Saúde PúblicaRESUMO
BACKGROUND: Over a one year period, swabs of 820 beef carcasses were tested for the presence of Shiga toxin-producing Escherichia coli by performing Polymerase Chain Reaction (PCR) in a novel technology termed "cassette PCR", in comparison to conventional liquid PCR. Cassette PCR is inexpensive and ready-to-use. The operator need only add the sample and press "go". Cassette PCR can simultaneously test multiple samples for multiple targets. Carcass swab samples were first tested for the presence of STEC genes (O157, eae, stx1 and stx2). Samples were considered to be pathogenic if positive for eae plus stx1 and/or stx2. For samples scored as pathogenic, further testing screened for 6 additional high frequency O-antigens (O26, O45, O103, O111, O121, and O145). RESULTS: Of the 820 samples, 41% were pathogenic and 30% were O157 positive. Of these, 19% of samples were positive for O157 and carried potentially pathogenic E. coli (eae plus stx1 and/or stx2). Of all samples identified as carrying pathogenic E. coli, 18.9, 38.8, 41.4, 0, 36.1, and 4.1% respectively were positive for O26, O45, O103, O111, O121, and O145. To validate cassette PCR testing, conventional PCR using STEC primers was performed on each of the 820 samples. Only 148 of 3280 cassette PCR tests were discordant with conventional PCR results. However, further fractional testing showed that 110 of these 148 PCRs reflected low numbers of E. coli in the enrichment broth and could be explained as due to Poisson limiting dilution of the template, affecting both cassette PCR and conventional PCR. Of the remaining 38 discordant tests, 27 initial capillary PCRs and 10 initial conventional tests were nominally discordant between cassette and conventional PCR, perhaps reflecting human/technical error on both sides of the comparison. CONCLUSIONS: Contaminated beef carcass swabs were often complex, likely harboring more than one strain of pathogenic E. coli. Cassette PCR had 98.8% concordance with parallel conventional PCR for detection of STEC genes. This indicates that cassette PCR is highly reliable for detecting multiple pathogens in beef carcass swabs from processing plants.
Assuntos
Proteínas de Escherichia coli/genética , Reação em Cadeia da Polimerase Multiplex , Carne Vermelha/microbiologia , Escherichia coli Shiga Toxigênica/isolamento & purificação , Adesinas Bacterianas/genética , Animais , Bovinos , Infecções por Escherichia coli , Microbiologia de Alimentos/métodos , Genes Bacterianos , Antígenos O/genética , Carne Vermelha/toxicidade , Toxina Shiga I/genética , Toxina Shiga II/genética , Escherichia coli Shiga Toxigênica/genéticaRESUMO
BACKGROUND: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein (Hsp) 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). METHODS: Patients were randomized 1:1 to Arm A (carboplatin/pemetrexed plus apatorsen) or Arm B (carboplatin/pemetrexed plus placebo). Treatment was administered in 21-day cycles, with restaging every two cycles, until progression or intolerable toxicity. Serum Hsp27 levels were analyzed at baseline and during treatment. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), objective response rate, and toxicity. RESULTS: The trial enrolled 155 patients (median age 66 years; 44% Eastern Cooperative Oncology Group performance status 0). Toxicities were similar in the 2 treatment arms; cytopenias, nausea, vomiting, and fatigue were the most frequent treatment-related adverse events. Median PFS and OS were 6.0 and 10.8 months, respectively, for Arm A, and 4.9 and 11.8 months for Arm B (differences not statistically significant). Overall response rates were 27% for Arm A and 32% for Arm B. Sixteen patients (12%) had high serum levels of Hsp27 at baseline. In this small group, patients who received apatorsen had median PFS of 10.8 months, and those who received placebo had median PFS 4.8 months. CONCLUSION: The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting. IMPLICATIONS FOR PRACTICE: This randomized, double-blinded, phase II trial evaluated the efficacy of carboplatin and pemetrexed plus either apatorsen, an antisense oligonucleotide targeting heat shock protein 27 mRNA, or placebo in patients with previously untreated metastatic nonsquamous non-small cell lung cancer (NSCLC). The addition of apatorsen to carboplatin and pemetrexed was well tolerated but did not improve outcomes in patients with metastatic nonsquamous NSCLC cancer in the first-line setting.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carboplatina/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Neoplasias Pulmonares/tratamento farmacológico , Oligonucleotídeos/uso terapêutico , Pemetrexede/uso terapêutico , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Carboplatina/farmacologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Estadiamento de Neoplasias , Oligonucleotídeos/farmacologia , Pemetrexede/farmacologiaRESUMO
BACKGROUND: Eribulin mesylate is a non-taxane microtubule inhibitor effective in the treatment of metastatic breast cancer refractory to anthracyclines and taxanes. In preclinical studies, additional mechanisms of eribulin included reversal of epithelial mesenchymal transition and tumor vascular remodeling. The present study compared the safety and efficacy of eribulin plus cyclophosphamide (ErC) to docetaxel plus cyclophosphamide (TC) as neoadjuvant therapy for operable HER2- breast cancer. PATIENTS AND METHODS: Women with invasive HER2- breast adenocarcinoma with no distant metastases were eligible. After a 10-patient safety lead-in, the patients were randomized 2:1 to receive either ErC (eribulin 1.4 mg/m2 on days 1 and 8 plus cyclophosphamide 600 mg/m2 on day 1) or TC (docetaxel 75 mg/m2 plus cyclophosphamide 600 mg/m2 on day 1) administered every 21 days for 6 cycles, followed by surgery. The pathologic complete response (pCR) rate was the primary endpoint. Tumor samples collected at baseline and at surgery were assayed for select epithelial mesenchymal transition and vascular density markers: E-cadherin, vimentin, and CD31 expression. RESULTS: A total of 76 patients were enrolled. Of the 76 patients, 10 received ErC in the lead-in phase and 66 were randomized to ErC (n = 44) or TC (n = 22). The pCR rates with ErC and TC were 13% and 9%, respectively. Both regimens produced frequent neutropenia and peripheral neuropathy. Both regimens increased vascular density as measured by CD31 staining. CONCLUSION: The neoadjuvant regimens of ErC and TC resulted in relatively low pCR rates in this patient population. No unexpected toxicities were observed. Our results also provided no suggestion that ErC is a neoadjuvant treatment with greater efficacy than that of standard regimens.
Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Carcinoma Lobular/tratamento farmacológico , Terapia Neoadjuvante/mortalidade , Adulto , Idoso , Neoplasias da Mama/patologia , Carcinoma Ductal de Mama/secundário , Carcinoma Lobular/secundário , Ciclofosfamida/administração & dosagem , Docetaxel/administração & dosagem , Feminino , Seguimentos , Furanos/administração & dosagem , Humanos , Cetonas/administração & dosagem , Metástase Linfática , Pessoa de Meia-Idade , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Taxa de SobrevidaRESUMO
BACKGROUND: Geosocial networking apps have made sexual partner-seeking easier for men who have sex with men, raising both challenges and opportunities for human immunodeficiency virus and sexually transmitted infection prevention and research. Most studies on men who have sex with men geosocial networking app use have been conducted in large urban areas, despite research indicating similar patterns of online- and app-based sex-seeking among men who have sex with men in rural and midsize cities. OBJECTIVE: The goal of our research was to examine the spatial distribution of geosocial networking app usage and characterize areas with increasing numbers of partner-seeking men who have sex with men in a midsize city in the South. METHODS: Data collection points (n=62) were spaced in 2-mile increments along 9 routes (112 miles) covering the county encompassing the city. At each point, staff logged into 3 different geosocial networking apps to record the number of geosocial networking app users within a 1-mile radius. Data were collected separately during weekday daytime (9:00 AM to 4:00 PM) and weekend nighttime (8:00 PM to 12:00 AM) hours. Empirical Bayesian kriging was used to create a raster estimating the number of app users throughout the county. Raster values were summarized for each of the county's 208 Census block groups and used as the outcome measure (ie, geosocial networking app usage). Negative binomial regression and Wilcoxon signed rank sum tests were used to examine Census block group variables (eg, median income, median age) associated with geosocial networking app usage and temporal differences in app usage, respectively. RESULTS: The number of geosocial networking app users within a 1-mile radius of the data collection points ranged from 0 to 36 during weekday daytime hours and 0 to 39 during weekend nighttime hours. In adjusted analyses, Census block group median income and percent Hispanic ethnicity were negatively associated with geosocial networking app usage for all 3 geosocial networking apps during weekday daytime and weekend nighttime hours. Population density and the presence of businesses were positively associated with geosocial networking app usage for all 3 geosocial networking apps during both times. CONCLUSIONS: In this midsize city, geosocial networking app usage was highest in areas that were more population-dense, were lower income, and had more businesses. This research is an example of how geosocial networking apps' geospatial capabilities can be used to better understand patterns of virtual partner-seeking among men who have sex with men.
Assuntos
Demografia/métodos , Homossexualidade Masculina/estatística & dados numéricos , Aplicativos Móveis/tendências , Parceiros Sexuais/psicologia , Rede Social , Adulto , Estudos Epidemiológicos , Energia Geotérmica , Homossexualidade Masculina/psicologia , Humanos , MasculinoRESUMO
BACKGROUND: Lapatinib is an oral small molecule tyrosine kinase epidermal growth factor receptor-1/HER2 inhibitor that crosses the blood-brain barrier and is active against central nervous system (CNS) metastases. Cabazitaxel is a taxoid that is effective against taxane-resistant metastatic breast cancer (MBC) and has distinguished itself by its ability to cross the blood-brain barrier. The present phase II study (ClinicalTrials.gov identifier, NCT01934894) evaluated the combination of these agents to treat HER2+ MBC patients with CNS metastases. MATERIALS AND METHODS: Patients with HER2+ MBC and ≥ 1 untreated or progressive, measurable CNS metastasis were eligible. Using a 3+3 dose escalation design, patients were treated with escalating doses of intravenous cabazitaxel every 21 days and oral lapatinib daily in 21-day treatment cycles. Intracranial disease restaging was performed every 2 cycles for the first 8 cycles and then every 3 cycles until progression or unacceptable toxicity. RESULTS: Eleven patients were treated at 2 dose levels. Six patients were treated at dose level 1 (intravenous cabazitaxel 20 mg/m2 plus oral lapatinib 1000 mg daily), and five were treated at dose level 2 (intravenous cabazitaxel 25 mg/m2 plus oral lapatinib 1000 mg daily). The most common treatment-related adverse events were myelosuppression, diarrhea, fatigue, and skin toxicity. A total of 5 dose-limiting toxicity events occurred. No intra- or extracranial objective responses were observed. CONCLUSION: The combination of cabazitaxel plus lapatinib was not feasible because of toxicity and because no objective CNS activity was seen in the 5 evaluable patients. The role of cabazitaxel to treat breast cancer patients with CNS metastases remains undefined.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Neoplasias do Sistema Nervoso Central/tratamento farmacológico , Lapatinib/administração & dosagem , Taxoides/administração & dosagem , Adulto , Idoso , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias do Sistema Nervoso Central/patologia , Neoplasias do Sistema Nervoso Central/secundário , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos , Feminino , Humanos , Lapatinib/efeitos adversos , Masculino , Dose Máxima Tolerável , Pessoa de Meia-Idade , Inibidores de Proteínas Quinases/administração & dosagem , Inibidores de Proteínas Quinases/efeitos adversos , Receptor ErbB-2/metabolismo , Taxoides/efeitos adversos , Falha de TratamentoRESUMO
BACKGROUND: Triple-negative breast cancer (TNBC) is a subtype with poor prognosis, and treatment options are limited to chemotherapy. Because the epidermal growth factor receptor (EGFR) is overexpressed in up to 70% of these tumors, this phase II trial was designed to evaluate the efficacy and safety of panitumumab in combination with gemcitabine and carboplatin as first- or second-line treatment for metastatic TNBC. PATIENTS AND METHODS: Adult women with metastatic TNBC with a maximum of 1 previous chemotherapy regimen were eligible. Patients received gemcitabine intravenous (I.V.) 1500 mg/m2, carboplatin area under the concentration-time curve = 2.5 I.V., and panitumumab 6 mg/kg I.V. every 2 weeks. Treatment continued until disease progression or unacceptable toxicity, with disease evaluations every 6 weeks. The primary end point was progression-free survival (PFS). Archival tissue was collected for correlative analysis, to include phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha, p53, phosphatase and tensin homolog, EGFR, and status. RESULTS: Between May 2010 and August 2012, 71 women (median age, 54 years; 14% de novo stage IV) were treated. At a median follow-up of 11 months, the median PFS was 4.4 months (95% confidence interval, 3.2-5.5 months). The objective response rate was 42% (complete response, 1; partial response, 29). Treatment-related toxicity included: rash, 50 patients (70%), fatigue, 37 patients (52%), neutropenia, 32 patients (45%; 2 episodes of febrile neutropenia), and thrombocytopenia, 32 patients (45%). CONCLUSION: Although the addition of panitumumab was feasible, the results of this trial do not support combination of panitumumab with gemcitabine and carboplatin in the treatment of patients with TNBC.
Assuntos
Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Neoplasias de Mama Triplo Negativas/mortalidade , Administração Intravenosa , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Antineoplásicos/administração & dosagem , Antineoplásicos/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Carboplatina/administração & dosagem , Carboplatina/efeitos adversos , Carboplatina/uso terapêutico , Classe I de Fosfatidilinositol 3-Quinases , Desoxicitidina/administração & dosagem , Desoxicitidina/efeitos adversos , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapêutico , Intervalo Livre de Doença , Receptores ErbB/metabolismo , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , PTEN Fosfo-Hidrolase/metabolismo , Panitumumabe , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Transdução de Sinais/efeitos dos fármacos , Resultado do Tratamento , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologia , Proteína Supressora de Tumor p53/metabolismo , GencitabinaRESUMO
BACKGROUND: National Surgical Adjuvant Breast and Bowel Project R-04 was designed to determine whether the oral fluoropyrimidine capecitabine could be substituted for continuous infusion 5-FU in the curative setting of stage II/III rectal cancer during neoadjuvant radiation therapy and whether the addition of oxaliplatin could further enhance the activity of fluoropyrimidine-sensitized radiation. METHODS: Patients with clinical stage II or III rectal cancer undergoing preoperative radiation were randomly assigned to one of four chemotherapy regimens in a 2x2 design: CVI 5-FU or oral capecitabine with or without oxaliplatin. The primary endpoint was local-regional tumor control. Time-to-event endpoint distributions were estimated using the Kaplan-Meier method. Hazard ratios were estimated from Cox proportional hazard models. All statistical tests were two-sided. RESULTS: Among 1608 randomized patients there were no statistically significant differences between regimens using 5-FU vs capecitabine in three-year local-regional tumor event rates (11.2% vs 11.8%), 5-year DFS (66.4% vs 67.7%), or 5-year OS (79.9% vs 80.8%); or for oxaliplatin vs no oxaliplatin for the three endpoints of local-regional events, DFS, and OS (11.2% vs 12.1%, 69.2% vs 64.2%, and 81.3% vs 79.0%). The addition of oxaliplatin was associated with statistically significantly more overall and grade 3-4 diarrhea (P < .0001). Three-year rates of local-regional recurrence among patients who underwent R0 resection ranged from 3.1 to 5.1% depending on the study arm. CONCLUSIONS: Continuous infusion 5-FU produced outcomes for local-regional control, DFS, and OS similar to those obtained with oral capecitabine combined with radiation. This study establishes capecitabine as a standard of care in the pre-operative rectal setting. Oxaliplatin did not improve the local-regional failure rate, DFS, or OS for any patient risk group but did add considerable toxicity.
Assuntos
Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Desoxicitidina/análogos & derivados , Fluoruracila/análogos & derivados , Fluoruracila/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Adulto , Idoso , Capecitabina , Quimioterapia Adjuvante , Desoxicitidina/administração & dosagem , Desoxicitidina/uso terapêutico , Esquema de Medicação , Feminino , Fluoruracila/administração & dosagem , Humanos , Masculino , Pessoa de Meia-Idade , Compostos Organoplatínicos/administração & dosagem , Oxaliplatina , Radioterapia Adjuvante , Neoplasias Retais/cirurgia , Resultado do TratamentoRESUMO
Left untreated, scapholunate dissociation can lead to posttraumatic wrist arthritis. Multiple surgical procedures have been designed to reduce the scapholunate interval, restore normal wrist kinematics, and prevent the development of arthritis. Unfortunately, current surgical procedures have not been shown to consistently maintain radiographic alignment at long-term follow-up and result in decreased wrist range of motion and strength compared with the contralateral side. The purpose of this article is to review the current reconstructive options for scapholunate ligament tears without evidence of radiographic arthritis.