Culture-negative sepsis is a common but relatively understudied condition. The aim of this study was to compare the characteristics and outcomes of culture-negative versus culture-positive severe ...sepsis.
This was a prospective observational cohort study of 1001 patients who were admitted to the medical intensive care unit (ICU) of a university hospital from 2004 to 2009 with severe sepsis. Patients with documented fungal, viral, and parasitic infections were excluded.
There were 415 culture-negative patients (41.5%) and 586 culture-positive patients (58.5%). Gram-positive bacteria were isolated in 257 patients, and gram-negative bacteria in 390 patients. Culture-negative patients were more often women and had fewer comorbidities, less tachycardia, higher blood pressure, lower procalcitonin levels, lower Acute Physiology and Chronic Health Evaluation II (median 25.0 (interquartile range 19.0 to 32.0) versus 27.0 (21.0 to 33.0), P = 0.001) and Sequential Organ Failure Assessment scores, less cardiovascular, central nervous system, and coagulation failures, and less need for vasoactive agents than culture-positive patients. The lungs were a more common site of infection, while urinary tract, soft tissue and skin infections, infective endocarditis and primary bacteremia were less common in culture-negative than in culture-positive patients. Culture-negative patients had a shorter duration of hospital stay (12 days (7.0 to 21.0) versus 15.0 (7.0 to27.0), P = 0.02) and lower ICU mortality than culture-positive patients. Hospital mortality was lower in the culture-negative group (35.9%) than in the culture-positive group (44.0%, P = 0.01), the culture-positive subgroup, which received early appropriate antibiotics (41.9%, P = 0.11), and the culture-positive subgroup, which did not (55.5%, P < 0.001). After adjusting for covariates, culture positivity was not independently associated with mortality on multivariable analysis.
Significant differences between culture-negative and culture-positive sepsis are identified, with the former group having fewer comorbidities, milder severity of illness, shorter hospitalizations, and lower mortality.
Early data on breast cancer screening utilizing digital breast tomosynthesis (DBT) combined with digital mammography (DM) have shown improvements in false-positive and false-negative screening rates ...compared with DM alone. However, these trials were performed at sites where conventional mammographic screening was concurrently performed, possibly leading to selection biases or with complex, multireader algorithms not reflecting general clinical practice. Our study reports the impact on screening outcomes for DBT screening implemented in an entire clinic population.
Recall rates, cancer detection, and positive predictive values of screening were compared for 15571 women screened with DBT and 10728 screened with DM alone prior to DBT implementation at a single breast imaging center. Generalized linear mixed-effects models were used to estimate the odds ratio (OR) for recall rate adjusted for age, race, presence of prior mammograms, breast density and reader. All statistical tests were two-sided.
DBT screening showed a statistically significant reduction in recalls compared to DM alone. For the entire population, there were 16 fewer recalls (8.8% vs 10.4%, P <.001, adjusted OR = 0.80, 95% confidence interval CI = 0.74 to 0.88, P < .001) and 0.9 additional cancers detected per 1000 screened with DBT compared to DM alone. There was a statistically significant increase in PPV1 (6.2% vs 4.4%, P = .047). In women younger than age 50 years screened with DBT, there were 17 fewer recalls (12.3% vs 14.0%, P = .02) and 3.6 additional cancer detected per 1000 screened (5.7 vs 2.2 per 1000, P = .02).
Our data support the clinical implementation of DBT in breast cancer screening; however, larger prospective trials are needed to validate our findings in specific patient subgroups.
•Causes of death recorded on death certificates are susceptible to errors.•Lung cancer deaths can be misclassified as non-lung cancer deaths and vice-versa.•Estimation of cumulative incidence of ...cancer-death requires accurate cause-of-death coding.•Cause-of-death misclassification led to underestimation in cumulative incidence of lung cancer deaths.•Bias in estimation increased with age, especially among those older than 75 years.
Cumulative incidence of lung cancer deaths (LC-CID) is an important metric to understand cancer prognosis and to determine treatment options. However, credible estimates of LC-CID rely on accurate cause-of-death coding in death certificates. Results from lung cancer screening trials estimated 15% under-reporting and 1% over-reporting of lung cancer deaths due to misclassification. This study investigated the impact of cause-of-death misclassification on the estimation of LC-CID.
Patients with stage I/II non-small cell lung cancer (NSCLC) from the Surveillance, Epidemiology, and End Results registry were included. LC-CID was estimated using the competing-risk approach in two ways: (1) reporting observed estimates that ignore potential cause-of-death misclassification and (2) correcting for plausible misclassification rates reported in the literature (15% under-reporting and 1% over-reporting). Bias was quantified as the difference between observed and corrected 10-year LC-CIDs: positive values indicated that observed LC-CID overestimated true LC-CID, whereas negative values indicated the opposite.
Among 66,179 patients, the impact of over-reporting on 10-year LC-CID was negligible across all age groups. In contrast, under-reporting resulted in substantial underestimation of 10-year LC-CID. The biases increased as age increased due to higher LC-CIDs: 10-year LC-CIDs among stage I patients 18-44, 45-59, 60-74 and ≥75 years were 25%, 32%, 41%, and 50%, respectively, and the corresponding biases given the plausible misclassification rates were -4.4%, -5.6%, -7.1%, and -8.6%. Because the observed LC-CIDs among patients with stage II disease were higher than those with stage I disease, the biases were greater among stage II patients, up to -12.5% in the oldest age group.
In lung cancer, LC-CID may be severely underestimated due to under-reporting of lung cancer deaths, particularly among older patients or those with late-stage disease. Future studies that involve such subpopulations should present the corrected LC-CIDs based on plausible misclassification rates alongside the observed LC-CIDs.
We sought to determine the safety and feasibility of esophagectomy after neoadjuvant immunotherapy and chemoradiotherapy in clinical trial patients with locally advanced esophageal cancer.
We ...retrospectively identified patients who were treated with neoadjuvant immunotherapy and chemoradiotherapy (n = 25) or chemoradiotherapy alone (n = 143) at our institution between 2017 and 2020. The primary end point was risk of 30-day major complications (Clavien-Dindo classification system grade ≥ 3), which was assessed between groups using a multivariable log-binomial regression model to obtain adjusted relative risk ratios. Secondary end points were interval to surgery, 30-day readmission rate, and 30-day mortality.
All included patients successfully completed neoadjuvant therapy and underwent esophagectomy with negative margins. Age, sex, performance status, clinical stage, histologic subtype, procedure type, and operative approach were similar between groups. Neoadjuvant immunotherapy was not associated with a statistically significantly increased risk of developing a major pulmonary (relative risk, 1.43; 95% confidence interval, 0.53-3.84; P = .5), anastomotic (relative risk, 1.34; 95% confidence interval, 0.45-3.94; P = .6), or other complication (relative risk, 1.29; 95% confidence interval, 0.26-6.28; P = .8). Median (interquartile range) interval to surgery was 54 days (47-61 days) in the immune checkpoint inhibitor group versus 53 days (47-66 days) in the control group (P = .6). Minimally invasive approaches were successful in 72% of cases, with only 1 conversion. Thirty-day mortality and readmission rates were 0% and 17%, respectively, in the immune checkpoint inhibitor group and 1.4% and 13%, respectively, in the control group.
On the basis of our preliminary experience, esophagectomy appears to be safe and feasible following combined neoadjuvant immunotherapy and standard chemoradiotherapy for locally advanced esophageal cancer.
On the basis of this preliminary experience, esophagectomy appears to be safe and feasible after combined immunotherapy and chemoradiotherapy for esophageal cancer. ICI, Immune checkpoint inhibitor; PET, positron-emission tomography; CT, computed tomography; SUV, standardized uptake value; fx, fraction; AUC, area under the curve. Display omitted
The G1-S checkpoint of the cell cycle is frequently dysregulated in breast cancer. Palbociclib (PD0332991) is an oral inhibitor of CDK4/6. Based upon preclinical/phase I activity, we performed a ...phase II, single-arm trial of palbociclib in advanced breast cancer.
Eligible patients had histologically confirmed, metastatic breast cancer positive for retinoblastoma (Rb) protein and measureable disease. Palbociclib was given at 125 mg orally on days 1 to 21 of a 28-day cycle. Primary objectives were tumor response and tolerability. Secondary objectives included progression-free survival (PFS) and assessment of Rb expression/localization, KI-67, p16 loss, and CCND1 amplification.
Thirty-seven patients were enrolled; 84% hormone-receptor (HR)(+)/Her2(-), 5% HR(+)/Her2(+), and 11% HR(-)/Her2(-), with a median of 2 prior cytotoxic regimens. Two patients had partial response (PR) and 5 had stable disease ≥ 6 months for a clinical benefit rate (CBR = PR + 6moSD) of 19% overall, 21% in HR(+), and 29% in HR(+)/Her2(-) who had progressed through ≥2 prior lines of hormonal therapy. Median PFS overall was 3.7 months 95% confidence interval (CI), 1.9-5.1, but significantly longer for those with HR(+) versus HR(-) disease (P = 0.03) and those who had previously progressed through endocrine therapy for advanced disease (P = 0.02). Grade 3/4 toxicities included neutropenia (51%), anemia (5%), and thrombocytopenia (22%). Twenty-four percent had treatment interruption and 51% had dose reduction, all for cytopenias. No biomarker identified a sensitive tumor population.
Single-agent palbociclib is well tolerated and active in patients with endocrine-resistant, HR(+), Rb-positive breast cancer. Cytopenias were uncomplicated and easily managed with dose reduction.
Spread through air spaces (STAS) is a recently recognized pattern of invasion in lung adenocarcinoma; however, it has not yet been characterized in squamous cell carcinoma (SCC).
We reviewed 445 ...resected stage I to III lung SCCs and investigated the clinical significance of STAS. Cumulative incidence of recurrence and lung cancer–specific death were evaluated by competing risks analyses and overall survival by Cox models.
Of the total 445 patients, 336 (76%) were older than 65 years. Among the 273 patients who died, 91 (33%) died of lung cancer whereas the remaining ones died of competing events or unknown cause. STAS was observed in 132 patients (30%) and the frequency increased with stage. The cumulative incidences of any, distant, and locoregional recurrence as well as lung cancer–specific death were significantly higher in patients with STAS compared with in those without STAS, whereas there was no statistically significant difference in overall survival. In multivariable models for any recurrence and lung cancer–specific death, STAS was an independent predictor for both outcomes (p = 0.034 and 0.016, respectively).
STAS was present in one-third of resected lung SCCs. In competing risks analysis in a cohort in which three-fourths of the patients were elderly, STAS was associated with lung cancer–specific outcomes. Our findings suggest that STAS is one of the most prognostically significant histologic findings in lung SCC.
The efficacy of proteasome inhibition for myeloma is limited by therapeutic resistance, which may be mediated by activation of the autophagy pathway as an alternative mechanism of protein ...degradation. Preclinical studies demonstrate that autophagy inhibition with hydroxychloroquine augments the antimyeloma efficacy of the proteasome inhibitor bortezomib. We conducted a phase I trial combining bortezomib and hydroxychloroquine for relapsed or refractory myeloma. We enrolled 25 patients, including 11 (44%) refractory to prior bortezomib. No protocol-defined dose-limiting toxicities occurred, and we identified a recommended phase 2 dose of hydroxychloroquine 600 mg twice daily with standard doses of bortezomib, at which we observed dose-related gastrointestinal toxicity and cytopenias. Of 22 patients evaluable for response, 3 (14%) had very good partial responses, 3 (14%) had minor responses, and 10 (45%) had a period of stable disease. Electron micrographs of bone marrow plasma cells collected at baseline, after a hydroxychloroquine run-in, and after combined therapy showed therapy-associated increases in autophagic vacuoles, consistent with the combined effects of increased trafficking of misfolded proteins to autophagic vacuoles and inhibition of their degradative capacity. Combined targeting of proteasomal and autophagic protein degradation using bortezomib and hydroxychloroquine is therefore feasible and a potentially useful strategy for improving outcomes in myeloma therapy.
Preclinical studies indicate autophagy inhibition with hydroxychloroquine (HCQ) can augment the efficacy of DNA-damaging therapy. The primary objective of this trial was to determine the maximum ...tolerated dose (MTD) and efficacy of HCQ in combination with radiation therapy (RT) and temozolomide (TMZ) for newly diagnosed glioblastoma (GB). A 3 + 3 phase I trial design followed by a noncomparative phase II study was conducted in GB patients after initial resection. Patients received HCQ (200 to 800 mg oral daily) with RT and concurrent and adjuvant TMZ. Quantitative electron microscopy and immunoblotting were used to assess changes in autophagic vacuoles (AVs) in peripheral blood mononuclear cells (PBMC). Population pharmacokinetic (PK) modeling enabled PK-pharmacodynamic correlations. Sixteen phase I subjects were evaluable for dose-limiting toxicities. At 800 mg HCQ/d, 3/3 subjects experienced Grade 3 and 4 neutropenia and thrombocytopenia, 1 with sepsis. HCQ 600 mg/d was found to be the MTD in this combination. The phase II cohort (n = 76) had a median survival of 15.6 mos with survival rates at 12, 18, and 24 mo of 70%, 36%, and 25%. PK analysis indicated dose-proportional exposure for HCQ. Significant therapy-associated increases in AV and LC3-II were observed in PBMC and correlated with higher HCQ exposure. These data establish that autophagy inhibition is achievable with HCQ, but dose-limiting toxicity prevented escalation to higher doses of HCQ. At HCQ 600 mg/d, autophagy inhibition was not consistently achieved in patients treated with this regimen, and no significant improvement in overall survival was observed. Therefore, a definitive test of the role of autophagy inhibition in the adjuvant setting for glioma patients awaits the development of lower-toxicity compounds that can achieve more consistent inhibition of autophagy than HCQ.
Delaying intubation in patients who fail high-flow nasal cannula (HFNC) may result in increased mortality. The ROX index has been validated to predict HFNC failure among pneumonia patients with acute ...hypoxemic respiratory failure (AHRF), but little information is available for non-pneumonia causes. In this study, we validate the ROX index among AHRF patients due to both pneumonia or non-pneumonia causes, focusing on early prediction.
This was a retrospective observational study in eight Singapore intensive care units from 1 January 2015 to 30 September 2017. All patients >18 years who were treated with HFNC for AHRF were eligible and recruited. Clinical parameters and arterial blood gas values at HFNC initiation and one hour were recorded. HFNC failure was defined as requiring intubation post-HFNC initiation.
HFNC was used in 483 patients with 185 (38.3%) failing HFNC. Among pneumonia patients, the ROX index was most discriminatory in pneumonia patients one hour after HFNC initiation AUC 0.71 (95% CI 0.64-0.79), with a threshold value of <6.06 at one hour predicting HFNC failure (sensitivity 51%, specificity 80%, positive predictive value 61%, negative predictive value 73%). The discriminatory power remained moderate among pneumonia patients upon HFNC initiation AUC 0.65 (95% CI 0.57-0.72), non-pneumonia patients at HFNC initiation AUC 0.62 (95% CI 0.55-0.69) and one hour later AUC 0.63 (95% CI 0.56-0.70).
The ROX index demonstrated moderate discriminatory power among patients with either pneumonia or non-pneumonia-related AHRF at HFNC initiation and one hour later.
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