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Clinical Cancer Research : An Official... Aug 2020Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial,... (Comparative Study)
Comparative Study Randomized Controlled Trial
Randomized Phase II Trial of Carboplatin-Paclitaxel Compared with Carboplatin-Paclitaxel-Trastuzumab in Advanced (Stage III-IV) or Recurrent Uterine Serous Carcinomas that Overexpress Her2/Neu (NCT01367002): Updated Overall Survival Analysis.
PURPOSE
Uterine-serous-carcinoma (USC) is an aggressive variant of endometrial cancer. On the basis of preliminary results of a multicenter, randomized phase II trial, trastuzumab (T), a humanized-mAb targeting Her2/Neu, in combination with carboplatin/paclitaxel (C/P), is recognized as an alternative in treating advanced/recurrent HER2/Neu-positive USC. We report the updated survival analysis of NCT01367002.
PATIENTS AND METHODS
Eligible patients had stage III to IV or recurrent disease. Participants were randomized 1:1 to receive C/P for six cycles ± T followed by maintenance T until progression or toxicity. Progression-free survival (PFS) was the primary endpoint; overall survival (OS) and toxicity were secondary endpoints.
RESULTS
Sixty-one patients were randomized. After a median-follow-up of 25.9 months, 43 progressions and 38 deaths occurred among 58 evaluable patients. Updated median-PFS continued to favor the T-arm, with medians of 8.0 months versus 12.9 months in the control and T-arms (HR = 0.46; 90% CI, 0.28-0.76; = 0.005). Median-PFS was 9.3 months versus 17.7 months among 41 patients with stage III to IV disease undergoing primary treatment (HR = 0.44; 90% CI, 0.23-0.83; = 0.015), and 7.0 months versus 9.2 months among 17 patients with recurrent disease (HR = 0.12; 90% CI, 0.03-0.48; = 0.004). OS was higher in the T compared with the control arm, with medians of 29.6 months versus 24.4 months (HR = 0.58; 90% CI, 0.34-0.99; = 0.046). The benefit was most notable in those with stage III to IV disease, with survival median not reached in the T-arm versus 24.4 months in the control arm (HR = 0.49; 90% CI, 0.25-0.97; = 0.041). Toxicity was not different between arms.
CONCLUSIONS
Addition of T to C/P increased PFS and OS in women with advanced/recurrent HER2/Neu-positive USC, with the greatest benefit seen for the treatment of stage III to IV disease.
Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemotherapy, Adjuvant; Cystadenocarcinoma, Serous; Cytoreduction Surgical Procedures; Drug Administration Schedule; Endometrial Neoplasms; Endometrium; Female; Follow-Up Studies; Humans; Middle Aged; Neoplasm Recurrence, Local; Neoplasm Staging; Paclitaxel; Progression-Free Survival; Receptor, ErbB-2; Survival Analysis; Trastuzumab
PubMed: 32601075
DOI: 10.1158/1078-0432.CCR-20-0953 -
JAMA Mar 2020Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge,... (Comparative Study)
Comparative Study Randomized Controlled Trial
IMPORTANCE
Vasopressors are commonly administered to intensive care unit (ICU) patients to raise blood pressure. Balancing risks and benefits of vasopressors is a challenge, particularly in older patients.
OBJECTIVE
To determine whether reducing exposure to vasopressors through permissive hypotension (mean arterial pressure [MAP] target, 60-65 mm Hg) reduces mortality at 90 days in ICU patients aged 65 years or older with vasodilatory hypotension.
DESIGN, SETTING, AND PARTICIPANTS
A multicenter, pragmatic, randomized clinical trial was conducted in 65 ICUs in the United Kingdom and included 2600 randomized patients aged 65 years or older with vasodilatory hypotension (assessed by treating clinician). The study was conducted from July 2017 to March 2019, and follow-up was completed in August 2019.
INTERVENTIONS
Patients were randomized 1:1 to vasopressors guided either by MAP target (60-65 mm Hg, permissive hypotension) (n = 1291) or according to usual care (at the discretion of treating clinicians) (n = 1307).
MAIN OUTCOME AND MEASURES
The primary clinical outcome was all-cause mortality at 90 days.
RESULTS
Of 2600 randomized patients, after removal of those who declined or had withdrawn consent, 2463 (95%) were included in the analysis of the primary outcome (mean [SD] age 75 years [7 years]; 1387 [57%] men). Patients randomized to the permissive hypotension group had lower exposure to vasopressors compared with those in the usual care group (median duration 33 hours vs 38 hours; difference in medians, -5.0; 95% CI, -7.8 to -2.2 hours; total dose in norepinephrine equivalents median, 17.7 mg vs 26.4 mg; difference in medians, -8.7 mg; 95% CI, -12.8 to -4.6 mg). At 90 days, 500 of 1221 (41.0%) in the permissive hypotension compared with 544 of 1242 (43.8%) in the usual care group had died (absolute risk difference, -2.85%; 95% CI, -6.75 to 1.05; P = .15) (unadjusted relative risk, 0.93; 95% CI, 0.85-1.03). When adjusted for prespecified baseline variables, the odds ratio for 90-day mortality was 0.82 (95% CI, 0.68 to 0.98). Serious adverse events were reported for 79 patients (6.2%) in the permissive care group and 75 patients (5.8%) in the usual care group. The most common serious adverse events were acute renal failure (41 [3.2%] vs 33 [2.5%]) and supraventricular cardiac arrhythmia (12 [0.9%] vs 13 [1.0%]).
CONCLUSIONS AND RELEVANCE
Among patients 65 years or older receiving vasopressors for vasodilatory hypotension, permissive hypotension compared with usual care did not result in a statistically significant reduction in mortality at 90 days. However, the confidence interval around the point estimate for the primary outcome should be considered when interpreting the clinical importance of the study.
TRIAL REGISTRATION
isrctn.org Identifier: ISRCTN10580502.
Topics: Acute Kidney Injury; Aged; Aged, 80 and over; Atrial Premature Complexes; Cognition Disorders; Confidence Intervals; Female; Hospital Mortality; Humans; Hypotension; Intensive Care Units; Kaplan-Meier Estimate; Male; Vasoconstrictor Agents
PubMed: 32049269
DOI: 10.1001/jama.2020.0930 -
Journal of the American College of... Mar 2021In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non-high-density lipoprotein (non-HDL)...
BACKGROUND
In cholesterol guidelines, low-density lipoprotein (LDL) cholesterol remains the primary target while apolipoprotein B (apoB) and non-high-density lipoprotein (non-HDL) cholesterol are secondary targets.
OBJECTIVES
This study sought to determine if elevated apoB and/or non-HDL cholesterol are superior to elevated LDL cholesterol in identifying statin-treated patients at residual risk of all-cause mortality and myocardial infarction.
METHODS
In total, 13,015 statin-treated patients from the Copenhagen General Population Study were included with 8 years median follow-up. Cox regressions among apoB, non-HDL cholesterol, and LDL cholesterol, respectively, and all-cause mortality or myocardial infarction were examined on continuous scales by restricted cubic splines and by categories of concordant and discordant values defined by medians.
RESULTS
High apoB and non-HDL cholesterol were associated with increased risk of all-cause mortality and myocardial infarction, whereas no such associations were found for high LDL cholesterol. Compared with concordant values below medians, discordant apoB above the median with LDL cholesterol below yielded hazard ratios of 1.21 (95% confidence interval [CI]: 1.07 to 1.36) for all-cause mortality and 1.49 (95% CI: 1.15 to 1.92) for myocardial infarction. Corresponding values for high non-HDL cholesterol with low LDL cholesterol were 1.18 (95% CI: 1.02 to 1.36) and 1.78 (95% CI: 1.35 to 2.34). In contrast, discordant high LDL cholesterol with low apoB or non-HDL cholesterol was not associated with increased risk of all-cause mortality or myocardial infarction. Also, discordant high apoB with low non-HDL cholesterol yielded hazard ratios of 1.21 (95% CI: 1.03 to 1.41) for all-cause mortality and of 0.93 (95% CI: 0.62 to 1.40) for myocardial infarction. Furthermore, dual discordant apoB and non-HDL cholesterol above the medians with LDL cholesterol below presented hazard ratios of 1.23 (95% CI: 1.07 to 1.43) for all-cause mortality and 1.82 (95% CI: 1.37 to 2.42) for myocardial infarction.
CONCLUSIONS
In statin-treated patients, elevated apoB and non-HDL cholesterol, but not LDL cholesterol, are associated with residual risk of all-cause mortality and myocardial infarction. Discordance analysis demonstrates that apoB is a more accurate marker of all-cause mortality risk in statin-treated patients than LDL cholesterol or non-HDL cholesterol, and apoB in addition is a more accurate marker of risk of myocardial infarction than LDL cholesterol.
Topics: Aged; Apolipoproteins B; Biomarkers; Causality; Cholesterol, LDL; Denmark; Female; Heart Disease Risk Factors; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hypercholesterolemia; Male; Mortality; Myocardial Infarction; Registries; Risk Assessment
PubMed: 33736827
DOI: 10.1016/j.jacc.2021.01.027 -
Annals of Oncology : Official Journal... Jun 2020In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III...
BACKGROUND
In the PACIFIC trial, durvalumab significantly improved progression-free and overall survival (PFS/OS) versus placebo, with manageable safety, in unresectable, stage III non-small-cell lung cancer (NSCLC) patients without progression after chemoradiotherapy (CRT). We report exploratory analyses of outcomes by tumour cell (TC) programmed death-ligand 1 (PD-L1) expression.
PATIENTS AND METHODS
Patients were randomly assigned (2:1) to intravenous durvalumab 10 mg/kg every 2 weeks or placebo ≤12 months, stratified by age, sex, and smoking history, but not PD-L1 status. Where available, pre-CRT samples were tested for PD-L1 expression (immunohistochemistry) and scored at pre-specified (25%) and post hoc (1%) TC cut-offs. Treatment-effect hazard ratios (HRs) were estimated from unstratified Cox proportional hazards models (Kaplan-Meier-estimated medians).
RESULTS
In total, 713 patients were randomly assigned, 709 of whom received at least 1 dose of study treatment durvalumab (n = 473) or placebo (n = 236). Some 451 (63%) were PD-L1-assessable: 35%, 65%, 67%, 33%, and 32% had TC ≥25%, <25%, ≥1%, <1%, and 1%-24%, respectively. As of 31 January 2019, median follow-up was 33.3 months. Durvalumab improved PFS versus placebo (primary-analysis data cut-off, 13 February 2017) across all subgroups [HR, 95% confidence interval (CI); medians]: TC ≥25% (0.41, 0.26-0.65; 17.8 versus 3.7 months), <25% (0.59, 0.43-0.82; 16.9 versus 6.9 months), ≥1% (0.46, 0.33-0.64; 17.8 versus 5.6 months), <1% (0.73, 0.48-1.11; 10.7 versus 5.6 months), 1%-24% [0.49, 0.30-0.80; not reached (NR) versus 9.0 months], and unknown (0.59, 0.42-0.83; 14.0 versus 6.4 months). Durvalumab improved OS across most subgroups (31 January 2019 data cut-off; HR, 95% CI; medians): TC ≥ 25% (0.50, 0.30-0.83; NR versus 21.1 months), <25% (0.89, 0.63-1.25; 39.7 versus 37.4 months), ≥1% (0.59, 0.41-0.83; NR versus 29.6 months), 1%-24% (0.67, 0.41-1.10; 43.3 versus 30.5 months), and unknown (0.60, 0.43-0.84; 44.2 versus 23.5 months), but not <1% (1.14, 0.71-1.84; 33.1 versus 45.6 months). Safety was similar across subgroups.
CONCLUSIONS
PFS benefit with durvalumab was observed across all subgroups, and OS benefit across all but TC <1%, for which limitations and wide HR CI preclude robust conclusions.
Topics: Antibodies, Monoclonal; B7-H1 Antigen; Carcinoma, Non-Small-Cell Lung; Humans; Lung Neoplasms
PubMed: 32209338
DOI: 10.1016/j.annonc.2020.03.287 -
Frontiers in Medicine 2023Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary...
BACKGROUND
Vascular endothelial growth factor-D (VEGF-D) is the most commonly used biomarker for diagnosing lymphangioleiomyomatosis (LAM). However, lung biopsy is often necessary as well; therefore, defining new biomarkers for LAM is crucial. The aim of this study was to describe the diagnostic accuracy of a variety of biomarkers.
METHODS
We assessed 13 analytes in serum related to extracellular matrix remodeling, lymphatic involvement and angiogenesis in a cohort of patients with LAM, comparing them with patients with other cystic lung diseases (OCLD) and healthy women. A scoring method based on the cut-point of each VEGF-D and metalloproteinase-2 (MMP-2) was used to evaluate the diagnostic performance of the marker combination.
RESULTS
A total of 97 subjects were recruited: 59 (61%) LAM patients, 18 (19%) OCLD patients, and 20 (20%) healthy female controls. MMP-2 was the only extracellular matrix remodeling biomarker able to differentiate LAM patients from OCLD and healthy patients. Serum MMP-2 was higher in LAM patients [median 578 (465-832) ng/ml] than in patients with OCLD and healthy controls [medians 360 (314-546) and 427 (365-513) ng/ml, respectively ( < 0.0001)]. The area under ROC curve (AUC) of MMP-2 was 0.785 and that of VEGF-D 0.815 ( = 0.6214). The sensitivity/specificity profiles of each biomarker (54/92% for MMP-2, 59/95% for VEGF-D) yielded a composite score (-6.36 + 0.0059 × VEGF-D + 0.0069 × MMP-2) with higher accuracy than each component alone (AUC 0.88 and sensitivity/specificity 79/87%).
CONCLUSION
Combining MMP-2 and VEGF-D may increase diagnostic accuracy for LAM.
PubMed: 36817769
DOI: 10.3389/fmed.2023.1079317 -
Ciencia & Saude Coletiva Nov 2022This paper describes the structure and results of Primary Health Care (PHC) in Brazil between 2008 and 2019. The medians of the following variables were calculated: PHC...
This paper describes the structure and results of Primary Health Care (PHC) in Brazil between 2008 and 2019. The medians of the following variables were calculated: PHC spending per inhabitant covered, PHC coverage, and rates of mortality and hospitalizations due to primary care sensitive conditions (PCSC), in 5,565 Brazilian municipalities stratified according to population size and quintile of the Brazilian Deprivation Index (IBP), and the median trend in the period was analyzed. There was a 12% increase in median PHC spending. PHC coverage expanded, with 3,168 municipalities presenting 100% coverage in 2019, compared to 2,632 in 2008. The median rates of PCSC mortality and hospitalizations increased 0.2% and decreased 44.9%, respectively. PHC spending was lower in municipalities with greater socioeconomic deprivation. The bigger the population and the better the socioeconomic conditions were in the municipalities, the lower the PHC coverage. The greater the socioeconomic deprivation was in the municipalities, the higher the median PCSC mortality rates. This study showed that the evolution of PHC was heterogeneous and is associated both with the population size and with the socioeconomic conditions of the municipalities.
Topics: Humans; Brazil; Primary Health Care; Hospitalization; Cities; Population Density; Socioeconomic Factors
PubMed: 36259849
DOI: 10.1590/1413-812320222711.02272022 -
Journal of the National Cancer Institute Sep 2021Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before...
BACKGROUND
Chronic inflammation may promote initiation and progression of pancreatic cancer, but no studies have examined the association between inflammation in the period before diagnosis and pancreatic cancer survival.
METHODS
We prospectively examined the association of prediagnostic plasma levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 with survival among 492 participants from 5 large US prospective cohort studies who developed pancreatic cancer. Using an empirical dietary inflammatory pattern (EDIP) score, we evaluated whether long-term proinflammatory diets were associated with survival among 1153 patients from 2 of the 5 cohorts. Cox proportional hazards regression was used to estimate hazard ratios for death with adjustment for potential confounders. All statistical tests were 2-sided.
RESULTS
Higher prediagnostic levels of C-reactive protein, interleukin-6, and tumor necrosis factor-α receptor 2 were individually associated with reduced survival (Ptrend = .03, .01, and .04, respectively). Compared with patients with a combined inflammatory biomarker score of 0 (all 3 marker levels below medians), those with a score of 3 (all 3 marker levels above medians) had a hazard ratio for death of 1.57 (95% confidence interval = 1.16 to 2.12; Ptrend = .003), corresponding to median overall survival times of 8 vs 5 months. Patients consuming the most proinflammatory diets (EDIP quartile 4) in the prediagnostic period had a hazard ratio for death of 1.34 (95% confidence interval = 1.13 to 1.59; Ptrend = .01), compared with those consuming the least proinflammatory diets (EDIP quartile 1).
CONCLUSION
Prediagnostic levels of inflammatory biomarkers and long-term proinflammatory diets were inversely associated with pancreatic cancer survival.
Topics: Humans; Inflammation; Pancreatic Neoplasms; Proportional Hazards Models; Prospective Studies; Risk Factors
PubMed: 33739411
DOI: 10.1093/jnci/djab040 -
Toxins Mar 2022Animal feed (including forage and silage) can be contaminated with mycotoxins. Here, 200 maize silage samples from around China were collected in 2019 and analyzed for...
Animal feed (including forage and silage) can be contaminated with mycotoxins. Here, 200 maize silage samples from around China were collected in 2019 and analyzed for regulated mycotoxins, masked mycotoxins (deoxynivalenol, 3-acetyldeoxynivalenol, 15-acetyldeoxynivalenol, and deoxynivalenol-3-glucoside), and emerging mycotoxins (beauvericin, enniatins, moniliformin, and alternariol). Deoxynivalenol and zearalenone were detected in 99.5% and 79.5% of the samples, respectively. Other regulated mycotoxins were detected in fewer samples. The highest deoxynivalenol and zearalenone concentrations were 3600 and 830 μg/kg, respectively. The most commonly detected masked mycotoxin was 15-acetyldeoxynivalenol, which was detected in 68.5% of the samples and had median and maximum concentrations of 61.3 and 410 μg/kg, respectively. The emerging mycotoxins beauvericin, alternariol, enniatin A, enniatin B1, and moniliformin were detected in 99.5%, 85%, 80.5%, 72.5%, and 44.5%, respectively, of the samples but at low concentrations (medians <25 μg/kg). The samples tended to contain multiple mycotoxins, e.g., the correlation coefficients for the relationships between the concentrations of beauvericin and deoxynivalenol, deoxynivalenol and zearalenone, and zearalenone and beauvericin were 1.0, 0.995, and 0.995, respectively. The results indicated that there needs to be more awareness of the presence of one or more masked and emerging mycotoxins in maize silage in China.
Topics: Animal Feed; Animals; Food Contamination; Mycotoxins; Silage; Zea mays; Zearalenone
PubMed: 35448850
DOI: 10.3390/toxins14040241 -
Future Oncology (London, England) Jun 2022A systematic review was conducted to understand clinical, economic and health-related quality-of-life outcomes in second-line biliary tract cancer. The review followed... (Meta-Analysis)
Meta-Analysis Review
A systematic review was conducted to understand clinical, economic and health-related quality-of-life outcomes in second-line biliary tract cancer. The review followed established recommendations. The feasibility of network meta-analysis revealed limited networks, thus synthesis was limited to a summary of reported ranges, percentiles and medians. The review included 62 trials and observational studies highly variable with respect to key baseline characteristics. Commonly evaluated second-line treatments included fluoropyrimidine-, gemcitabine- and S-1-based regimens. Across active treatment arms, median overall survival ranged from 3.5 to 15.0 months (median: 6.9), median progression-free survival from 1.4 to 6.5 months (median: 2.9) and objective response from 0 to 36.4%. Outcomes were similar between study types, with a few notable outliers. Treatment-related/emergent adverse events were infrequently reported; no studies reported economic or health-related quality-of-life outcomes. Biliary tract cancer is a difficult-to-treat disease with poor prognosis. Despite evolving treatment landscapes, more recent studies did not show clinical outcome improvement, highlighting an unmet need among advanced/metastatic patients.
Topics: Antineoplastic Combined Chemotherapy Protocols; Bile Duct Neoplasms; Biliary Tract Neoplasms; Humans
PubMed: 35387496
DOI: 10.2217/fon-2021-1302 -
Pain Physician Nov 2022The diagnosis and treatment of neuropathic pain is often clinically challenging, with many patients requiring treatments beyond oral medications. To improve our...
BACKGROUND
The diagnosis and treatment of neuropathic pain is often clinically challenging, with many patients requiring treatments beyond oral medications. To improve our percutaneous treatments, we established a clinical pathway that utilized ultrasound (US) guidance for steroid injection and alcohol ablation for patients with painful neuropathy.
OBJECTIVES
To describe a collaborative neuropathy treatment pathway developed by a neurosurgeon, pain physicians, and a sonologist, describing early clinical experiences and patient-reported outcomes.
STUDY DESIGN
A retrospective case series was performed.
METHODS
Patients that received percutaneous alcohol ablation with US guidance for neuropathy were identified through a retrospective review of a single provider's case log. Demographics and treatment information were collected from the electronic medical record. Patients were surveyed about their symptoms and treatment efficacy. Descriptive statistics were expressed as medians and the interquartile range ([IQR]; 25th and 75th data percentiles). Differences in the median follow-up pain scores were assessed using a Wilcoxon signed-rank test.
RESULTS
Thirty-five patients underwent US-guided alcohol ablation, with the average patient receiving one treatment (range: 1 to 2), having a median duration of 4.8 months until reinjection (IQR: 2.9 to 13.1). The median number of steroid injections that individuals received before US-guided alcohol ablation was 2 (IQR: 1 to 3), and the median interval between steroid injections was 3.7 months (IQR: 2.0 to 9.6). Most (20/35 [57%]) patients responded to the survey, and the median pain scores decreased by 3 units (median: -3, IQR: -6 to 0; P < 0.001) one week following the alcohol ablation. This pain reduction remained significant at one month (P < 0.001) and one year (P = 0.002) following ablation. Most (12/20 [60%]) patients reported that alcohol ablation was more effective in improving their pain than oral pain medications.
LIMITATIONS
Given the small sample size, treatment efficacy for alcohol neurolysis cannot be generalized to the broader population.
CONCLUSIONS
US-guided percutaneous treatments for neuropathic pain present a growing opportunity for interprofessional collaboration between neurosurgery, clinicians who treat chronic pain, and sonologists. US can provide valuable diagnostic information and guide accurate percutaneous treatments in skilled hands. Further studies are warranted to determine whether a US-guided treatment pathway can prevent unnecessary open surgical management.
Topics: Humans; Chronic Pain; Retrospective Studies; Pain Measurement; Ethanol; Neuralgia; Steroids
PubMed: 36375203
DOI: No ID Found