Palliative care utilization and racial and ethnic disparities among women with de novo metastatic breast cancer in the United States.

PURPOSE: The potential disparities in palliative care delivery for underrepresented minorities with breast cancer are not well known. We sought to determine whether race and ethnicity impact the receipt of palliative care for patients with metastatic breast cancer (MBC). METHODS: We retrospectively reviewed the National Cancer Database for female patients diagnosed with stage IV breast cancer between 2010 and 2017 who received palliative care following diagnosis of MBC to assess the proportion of patients who received palliative care, including non-curative-intent local-regional or systemic therapy. Multivariable logistic regression analysis was performed to identify variables associated with receiving palliative care. RESULTS: 60,685 patients were diagnosed with de novo MBC. Of these, only 21.4% (n = 12,963) received a palliative care service. Overall, there was a positive trend in palliative care receipt from 18.2% in 2010 to 23.0% in 2017 (P < 0.001), which persisted when stratified by race and ethnicity. Relative to non-Hispanic White women, Asian/Pacific Islander women (aOR 0.80, 95% CI 0.71-0.90, P < 0.001), Hispanic women (adjusted odds ratio [aOR] 0.69, 95% CI 0.63-0.76, P < 0.001), and non-Hispanic Black women (aOR 0.94, 95% CI 0.88-0.99, P = 0.03) were less likely to receive palliative care. CONCLUSIONS: Fewer than 25% of women with MBC received palliative care between 2010 and 2017. While palliative care has significantly increased for all racial/ethnic groups, Hispanic White, Black, and Asian/Pacific Islander women with MBC still receive significantly less palliative care than non-Hispanic White women. Further research is needed to identify the socioeconomic and cultural barriers to palliative care utilization.

Association of Body Mass Index With Outcomes Among Patients With Head and Neck Cancer Treated With Chemoradiotherapy.

Importance: Combined modality therapy, such as chemoradiotherapy, often results in significant morbidity among patients with head and neck cancer. Although the role of body mass index (BMI) varies based on cancer subtypes, its association with treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer remains unclear. Objective: To evaluate the role of BMI in treatment response, tumor recurrence, and survival outcomes among patients with head and neck cancer undergoing chemoradiotherapy. Design, Setting, and Participants: This retrospective, observational, single-institution cohort study conducted at a comprehensive cancer center included 445 patients with nonmetastatic head and neck cancer who underwent chemoradiotherapy from January 1, 2005, to January 31, 2021. Exposure: Normal vs overweight or obese BMI. Main Outcomes and Measures: Metabolic response after chemoradiotherapy, locoregional failure (LRF), distant failure (DF), overall survival (OS), and progression-free survival (PFS), with Bonferroni correction used to adjust for multiple comparisons and P < .025 being considered statistically significant. Results: A total of 445 patients (373 men [83.8%]; median age, 61 years [IQR, 55-66 years]; 107 [24.0%] with normal BMI, 179 [40.2%] with overweight BMI, and 159 [35.7%] with obese BMI) were included for analysis. Median follow-up was 48.1 months (IQR, 24.7-74.9 months). On Cox proportional hazards regression multivariable analysis, only overweight BMI was associated with improved OS (5-year OS, 71.5% vs 58.4%; adjusted hazard ratio [AHR], 0.59 [95% CI, 0.39-0.91]; P = .02) and PFS (5-year PFS, 68.3% vs 50.8%; AHR, 0.51 [95% CI, 0.34-0.75]; P < .001). On logistic multivariable analysis, overweight BMI (91.6% vs 73.8%; adjusted odds ratio [AOR], 0.86 [95% CI, 0.80-0.93]; P < .001) and obese BMI (90.6% vs 73.8%; AOR, 0.89 [95% CI, 0.81-0.96]; P = .005) were associated with complete metabolic response on follow-up positron emission tomography-computed tomography after treatments. On Fine-Gray multivariable analysis, overweight BMI was associated with reduction in LRF (5-year LRF, 7.0% vs 25.9%; AHR, 0.30 [95% CI, 0.12-0.71]; P = .01), but not DF (5-year DF, 17.4% vs 21.5%; AHR, 0.92 [95% CI, 0.47-1.77]; P = .79). Obese BMI was not associated with LRF (5-year LRF, 10.4% vs 25.9%; AHR, 0.63 [95% CI, 0.29-1.37]; P = .24) or DF (5-year DF, 15.0% vs 21.5%; AHR, 0.70 [95% CI, 0.35-1.38]; P = .30). Conclusion: In this cohort study of patients with head and neck cancer, when compared with normal BMI, overweight BMI was an independent factor favorably associated with complete response after treatments, OS, PFS, and LRF. Further investigations are warranted to improve understanding on the role of BMI among patients with head and neck cancer.

Association of pre-treatment lymphocyte-monocyte ratio with survival outcome in patients with head and neck cancer treated with chemoradiation.

BACKGROUND: Given the role of systematic inflammation in cancer progression, lymphocyte-monocyte ratio (LMR) from peripheral blood has been suggested as a biomarker to assess the extent of inflammation in several solid malignancies. However, the role of LMR as a prognostic factor in head and neck cancer was unclear in several meta-analyses, and there is a paucity of literature including patients in North America. We performed an observational cohort study to evaluate the association of LMR with survival outcomes in North American patients with head and neck cancer. METHODS: A single-institution, retrospective database was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation from June 2007 to April 2021 at the Roswell Park Comprehensive Cancer Center. Primary endpoints were overall survival (OS) and cancer-specific survival (CSS). The association of LMR with OS and CSS was examined using nonlinear Cox proportional hazard model using restricted cubic splines (RCS). Cox multivariable analysis (MVA) and Kaplan-Meier method were used to analyze OS and CSS. Pre-radiation LMR was then stratified into high and low based on its median value. Propensity scored matching was used to reduce the selection bias. RESULTS: A total of 476 patients met our criteria. Median follow up was 45.3 months (interquartile range 22.8-74.0). The nonlinear Cox regression model showed that low LMR was associated with worse OS and CSS in a continuous fashion without plateau for both OS and CSS. On Cox MVA, higher LMR as a continuous variable was associated with improved OS (adjusted hazard ratio [aHR] 0,90, 95% confidence interval [CI] 0.82-0.99, p = 0.03) and CSS (aHR 0.83, 95% CI 0.72-0.95, p = 0.009). The median value of LMR was 3.8. After propensity score matching, a total of 186 pairs were matched. Lower LMR than 3.8 remained to be associated with worse OS (HR 1.59, 95% CI 1.12-2.26, p = 0.009) and CSS (HR 1.68, 95% CI 1.08-2.63, p = 0.02). CONCLUSION: Low LMR, both as a continuous variable and dichotomized variable, was associated with worse OS and CSS. Further studies would be warranted to evaluate the role of such prognostic marker to tailor interventions.

Immunotherapeutic Targeting and PET Imaging of DLL3 in Small-Cell Neuroendocrine Prostate Cancer.

Effective treatments for de novo and treatment-emergent small-cell/neuroendocrine (t-SCNC) prostate cancer represent an unmet need for this disease. Using metastatic biopsies from patients with advanced cancer, we demonstrate that delta-like ligand 3 (DLL3) is expressed in de novo and t-SCNC and is associated with reduced survival. We develop a PET agent, [89Zr]-DFO-DLL3-scFv, that detects DLL3 levels in mouse SCNC models. In multiple patient-derived xenograft models, AMG 757 (tarlatamab), a half-life-extended bispecific T-cell engager (BiTE) immunotherapy that redirects CD3-positive T cells to kill DLL3-expressing cells, exhibited potent and durable antitumor activity. Late relapsing tumors after AMG 757 treatment exhibited lower DLL3 levels, suggesting antigen loss as a resistance mechanism, particularly in tumors with heterogeneous DLL3 expression. These findings have been translated into an ongoing clinical trial of AMG 757 in de novo and t-SCNC, with a confirmed objective partial response in a patient with histologically confirmed SCNC. Overall, these results identify DLL3 as a therapeutic target in SCNC and demonstrate that DLL3-targeted BiTE immunotherapy has significant antitumor activity in this aggressive prostate cancer subtype. SIGNIFICANCE: The preclinical and clinical evaluation of DLL3-directed immunotherapy, AMG 757, and development of a PET radiotracer for noninvasive DLL3 detection demonstrate the potential of targeting DLL3 in SCNC prostate cancer.

Association of Pack-Years of Cigarette Smoking With Survival and Tumor Progression Among Patients Treated With Chemoradiation for Head and Neck Cancer.

Importance: After 10 pack-years of smoking was initially established as a threshold for risk stratification, subsequent clinical trials incorporated it to identify candidates for treatment deintensification. However, several recent studies were unable to validate this threshold externally, and the threshold for smoking exposure remains unclear. Objective: To estimate the threshold of pack-years of smoking associated with survival and tumor recurrence among patients with head and neck cancer. Design, Setting, and Participants: This single-institution, cohort study included patients with nonmetastatic head and neck cancer receiving chemoradiation from January 2005 to April 2021. Data were analyzed from January to April 2022. Exposures: Heavy vs light smoking using 22 pack-years as a threshold based on maximizing log-rank test statistic. Main Outcomes and Measures: Overall survival (OS), progression-free survival (PFS), locoregional failure (LRF), and distant failure (DF). Results: A total of 518 patients (427 male [82.4%]; median [IQR] age, 61 [55-66] years) were included. Median (IQR) follow-up was 44.1 (22.3-72.8) months. A nonlinear Cox regression model using restricted cubic splines showed continuous worsening of OS and PFS outcomes as pack-years of smoking increased. The threshold of pack-years to estimate OS and PFS was 22. Cox multivariable analysis (MVA) showed that more than 22 pack-years was associated with worse OS (adjusted hazard ratio [aHR] 1.57; 95% CI, 1.11-2.22; P = .01) and PFS (aHR, 1.38; 95% CI, 1.00-1.89; P = .048). On Fine-Gray MVA, heavy smokers were associated with DF (aHR, 1.71; 95% CI, 1.02-2.88; P = .04), but not LRF (aHR, 1.07; 95% CI, 0.61-1.87; P = .82). When 10 pack-years of smoking were used as a threshold, there was no association for OS (aHR, 1.23; 95% CI, 0.83-1.81; P = .30), PFS (aHR, 1.11; 95% CI, 0.78-1.57; P = .56), LRF (aHR, 1.19; 95% CI, 0.64-2.21; P = .58), and DF (aHR, 1.45; 95% CI, 0.82-2.56; P = .20). Current smoking was associated with worse OS and PFS only among human papillomavirus (HPV)-positive tumors (OS: aHR, 2.81; 95% CI, 1.26-6.29; P = .01; PFS: aHR, 2.51; 95% CI, 1.22-5.14; P = .01). Conclusions and Relevance: In this cohort study of patients treated with definitive chemoradiation, 22 pack-years of smoking was associated with survival and distant metastasis outcomes. Current smoking status was associated with adverse outcomes only among patients with HPV-associated head and neck cancer.

Quality of Life After Stereotactic Body Radiation Therapy or Surgery for Early-Stage NSCLC: A Systematic Review.

Quality of life (QOL) is a key consideration for patients with early-stage NSCLC choosing between treatment options. Currently, it is not well established whether stereotactic body radiation therapy (SBRT) or surgery offers superior QOL in early-stage NSCLC. The objective of this systematic review is to summarize the prospective literature on QOL in patients with early-stage NSCLC after treatment with SBRT or surgery. A comprehensive literature review using PubMed and EMBASE was performed in April 2022. Prospective studies evaluating QOL data across multiple time points in patients with early-stage NSCLC after SBRT or surgery were included. A total of 25 studies involving 1597 SBRT patients and 1652 surgery patients met the inclusion criteria. Across most studies, QOL remained stable after treatment with SBRT. After surgery, QOL initially decreased; however, it often returned to baseline in the next 6 to 12 months. Utilization of video-assisted thoracoscopic surgery and sublobar resection reduced the magnitude of the initial decrease in QOL after surgery and led to faster recovery to baseline. Owing to the heterogeneity of patient populations between studies evaluating SBRT versus surgery, direct comparisons between the two treatments remain difficult to make. Clinicians should appropriately counsel patients with this information to help guide patient-centered discussions on choosing the optimal treatment modality.

Involvement of Rho-Associated Coiled-Coil Containing Kinase (ROCK) in BCR-ABL1 Tyrosine Kinase Inhibitor Cardiovascular Toxicity.

Background: Second- and third-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) are associated with cardiovascular adverse events (CVAEs) in patients with Philadelphia chromosome-positive (Ph+) leukemia. Objectives: We hypothesized that second- and third-generation BCR-ABL1 TKIs may cause CVAEs through the activation of Rho-associated coiled-coil containing kinase (ROCK). Methods: Peripheral blood mononuclear cells from 53 Ph+ patients on TKIs and 15 control patients without Ph+ leukemia were assessed for ROCK activity through capillary electrophoresis (median follow-up = 26 months [Q1-Q3: 5-37 months]). We also investigated the effects of TKIs and ROCK on endothelial dysfunction in vitro, which could contribute to CVAEs. Results: Patients receiving second- and third-generation TKIs had 1.6-fold greater ROCK activity compared with patients receiving imatinib and control patients. Elevated ROCK activity was associated with an increased incidence of CVAEs in Ph+ leukemia patients. In endothelial cells in vitro, we found that dasatinib and ponatinib treatment led to changes in actin intensity and endothelial permeability, which can be reversed by pharmacologic inhibition of ROCK. Ponatinib led to decreased cell proliferation, but this was not accompanied by senescence. Dasatinib and ponatinib treatment led to phosphor-inhibition of endothelial nitric oxide synthase and decreased nitric oxide production. ROCK inhibition reversed endothelial permeability and endothelial nitric oxide synthase-related endothelial dysfunction. Imatinib and nilotinib induce phosphorylation of p190RhoGAP. Conclusions: Our findings suggest ROCK activity may be a prognostic indicator of CVAEs in patients receiving BCR-ABL1 TKIs. With further study, ROCK inhibition may be a promising approach to reduce the incidence of CVAEs associated with second- and third-generation BCR-ABL1 TKIs.

Trends in Postoperative Intensity-Modulated Radiation Therapy Use and Its Association With Survival Among Patients With Incompletely Resected Non-Small Cell Lung Cancer.

Importance: National guidelines allow consideration of postoperative radiation therapy (PORT) among patients with incompletely resected non-small cell lung cancer (NSCLC). However, there is a paucity of prospective data because recently completed trials excluded patients with positive surgical margins. In addition, unlike for locally advanced NSCLC, the role of intensity-modulated radiation therapy (IMRT) for PORT remains unclear. Objective: To evaluate trends of IMRT use for PORT in the US and the association of IMRT with survival outcomes among patients with incompletely resected NSCLC. Design, Setting, and Participants: This retrospective cohort study used data from the National Cancer Database for patients diagnosed between January 2004 and December 2019 with incompletely resected NSCLC who underwent upfront surgery with positive surgical margins followed by PORT. Exposures: IMRT vs 3D conformal radiation therapy (3DCRT) for PORT. Main Outcomes and Measures: The main outcome was overall survival. Multivariable Cox proportional hazards regression assessed the association of IMRT vs 3DCRT with overall survival. Multivariable logistic regression identified variables associated with IMRT. Propensity score matching (1:1) was performed based on variables of interest. Results: A total of 4483 patients (2439 men [54.4%]; median age, 67 years [IQR, 60-73 years]) were included in the analysis. Of those, 2116 (47.2%) underwent 3DCRT and 2367 (52.8%) underwent IMRT. Median follow-up was 48.5 months (IQR, 31.1-77.2 months). The proportion of patients who underwent IMRT increased from 14.3% (13 of 91 patients) in 2004 to 70.7% (33 of 471 patients) in 2019 (P < .001). IMRT was associated with improved overall survival compared with 3DCRT (adjusted hazard ratio, 0.84; 95% CI, 0.78-0.91; P < .001). Similar findings were observed for 1463 propensity score-matched pairs; IMRT was associated with improved 5-year overall survival compared with 3DCRT (37.3% vs 32.2%; hazard ratio, 0.88; 95% CI, 0.80-0.96; P = .003). IMRT use was associated with receipt of treatment at an academic facility (adjusted odds ratio [aOR], 1.15; 95% CI, 1.00-1.33; P = .049), having T4 stage tumors (aOR, 1.50; 95% CI, 1.13-1.99; P = .005) or N2 or N3 stage tumors (aOR, 1.25; 95% CI, 1.04-1.51; P = .02), and receipt of pneumonectomy (aOR, 1.35; 95% CI, 1.02-1.80; P = .04). Conclusion and Relevance: This cohort study found that use of IMRT for PORT among patients with incompletely resected NSCLC increased in the US from 2004 to 2019 and was associated with improved survival compared with 3DCRT. Further studies are warranted to investigate the role of different radiation therapy techniques for PORT.

Defining the optimal threshold and prognostic utility of pre-treatment hemoglobin level as a biomarker for survival outcomes in head and neck cancer patients receiving chemoradiation.

OBJECTIVES: We sought to define the optimal threshold for anemia in North American head and neck cancer patients and evaluate its role as a prognostic biomarker. MATERIALS AND METHODS: A single-institution database was queried for patients with head and neck cancer who underwent chemoradiation from January 2005 to April 2021. An optimal threshold of hemoglobin (Hgb) level was defined based on maximum log-rank test statistic. Cox multivariable analysis (MVA), Kaplan-Meier, and propensity score matching were performed to evaluate treatment outcomes. RESULTS: A total of 496 patients were identified. Threshold for Hgb was determined to be 11.4 for both overall survival (OS) and progression-free survival (PFS). Low Hgb was associated with worse OS (adjusted hazards ratio [aHR] 2.41, 95 % confidence interval [CI] 1.53-3.80, p < 0.001) and PFS (aHR 2.01, 95 % CI 1.30-3.11, p = 0.002). Similar findings were observed among 39 matched pairs for OS (5-year OS 22.3 % vs 49.0 %; HR 2.22, 95 % CI 1.23-4.03, p = 0.008) and PFS (5-year PFS 24.3 % vs 39.1 %; HR 1.78, 95 % CI 1.02-3.12, p = 0.04). Among those with HPV-negative tumors, low Hgb was associated with worse OS (aHR 13.90, 95 % CI 4.66-41.44, p < 0.001) and PFS (aHR 5.24, 95 % CI 2.09-13.18, p < 0.001). However, among those with HPV-positive tumors, low Hgb was not associated with both OS (aHR 1.75, 95 % CI 0.60-5.09, p = 0.31) and PFS (aHR 1.13, 95 % CI 0.41-3.14, p = 0.82). CONCLUSION AND RELEVANCE: Low Hgb below 11.4 was an independent adverse prognostic factor for worse survival. It was also prognostic among patients with HPV-negative tumors, but not for HPV-positive tumors.

Racial/Ethnic Differences and Trends in Pathologic Complete Response Following Neoadjuvant Chemotherapy for Breast Cancer.

The purpose of this study was to evaluate nationwide trends in pathologic complete response (pCR) and its racial variations for breast cancer. The National Cancer Database was queried for women from 2010 to 2017 with non-metastatic breast cancer who underwent neoadjuvant chemotherapy. The primary endpoints, pCR and overall survival, were evaluated using Cochran-Armitage test, logistic, and Cox regression multivariable analyses. A total of 104,161 women were analyzed. Overall, pCR improved from 2010 to 2017 (15.1% to 27.2%, trend p < 0.001). Compared to non-Hispanic White (NHW) women, Hispanic White (HW) women were more likely to have pCR for hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-positive tumors (adjusted odds ratio (aOR) 1.29, 95% confidence interval (CI) 1.08-1.53, p = 0.005). Black women were less likely to have pCR for HR-HER2+ tumors (aOR 0.81, 95% CI 0.73-0.89, p < 0.001) and triple negative (aOR 0.82, 95% CI 0.77-0.87, p < 0.001) tumors, but more likely for HR+HER2- tumors (aOR 1.13, 95% CI 1.03-1.24, p = 0.009). Among patients who achieved pCR, Asian or Pacific Islander (API) women were associated with better survival (adjusted hazards ratio (aHR) 0.52, 95% CI 0.33-0.82, p = 0.005) than NHW women. Despite positive trends in pCR rates, the likelihood of pCR and survival outcomes may be intricately dependent on racial/ethnic groups and tumor receptor subtypes.

Ceftolozane/tazobactam probability of target attainment and outcomes in participants with augmented renal clearance from the randomized phase 3 ASPECT-NP trial.

BACKGROUND: The randomized, double-blind, phase 3 ASPECT-NP trial evaluated the efficacy of 3 g of ceftolozane/tazobactam (C/T) versus 1 g of meropenem infused every 8 h for 8 to 14 days for treatment of adults with hospital-acquired bacterial pneumonia (HABP) or ventilator-associated bacterial pneumonia (VABP). We assessed the probability of target attainment and compared efficacy outcomes from ASPECT-NP in participants with augmented renal clearance (ARC) versus those with normal renal function. METHODS: Baseline renal function was categorized as normal renal function (creatinine clearance 80-130 mL/min) or ARC (creatinine clearance > 130 mL/min). Population pharmacokinetic models informed Monte Carlo simulations to assess probability of target attainment in plasma and pulmonary epithelial lining fluid. Outcomes included 28-day all-cause mortality and clinical cure and per-participant microbiologic cure rates at the test-of-cure visit. RESULTS: A > 99% and > 80% probability of target attainment was demonstrated for ceftolozane and tazobactam, respectively, in simulated plasma and epithelial lining fluid. Within treatment arms, 28-day all-cause mortality rates in participants with normal renal function (C/T, n = 131; meropenem, n = 123) and ARC (C/T, n = 96; meropenem, n = 113) were comparable (data comparisons presented as rate; treatment difference [95% CI]) (C/T: normal renal function, 17.6%; ARC, 17.7%; 0.2 [- 9.6 to 10.6]; meropenem: normal renal function, 20.3%; ARC, 17.7%; - 2.6 [- 12.6 to 7.5]). Clinical cure rates at test-of-cure were also comparable across renal function groups within treatment arms (C/T: normal renal function, 57.3%; ARC, 59.4%; - 2.1 [- 14.8 to 10.8]; meropenem: normal renal function, 59.3%; ARC, 57.5%; 1.8 [- 10.6 to 14.2]). Per-participant microbiologic cure rates at test-of-cure were consistent across renal function groups within treatment arms (C/T: normal renal function, 72.2% [n/N = 70/97]; ARC, 71.4% [n/N = 55/77]; 0.7 [- 12.4 to 14.2]; meropenem: normal renal function, 75.0% [n/N = 66/88]; ARC, 70.0% [n/N = 49/70]; 5.0 [- 8.7 to 19.0]). CONCLUSIONS: C/T and meropenem resulted in 28-day all-cause mortality, clinical cure, and microbiologic cure rates that were comparable between participants with ARC or normal renal function. In conjunction with high probability of target attainment, these results confirm that C/T (3 g) every 8 h is appropriate in patients with HABP/VABP and ARC. Trial registration ClinicalTrials.gov identifier: NCT02070757, registered February 25, 2014; EudraCT: 2012-002862-11.

Evaluation of risk stratification using gene expression assays in patients with breast cancer receiving neoadjuvant chemotherapy.

PURPOSE: To evaluate the association of various gene expression assays with pathologic complete response (pCR) in the setting of neoadjuvant chemotherapy among patients with breast cancer METHODS: The National Cancer Database (NCDB) was queried for women diagnosed between 2010 and 2017 with stage I-III breast cancer who underwent neoadjuvant chemotherapy and either 21-gene recurrence score (RS) or 70-gene signature (GS). Logistic multivariable analysis (MVA) was performed to identify variables associated with pCR. RESULTS: A total of 3009 patients met our inclusion criteria. The median follow up was 48.0 months (interquartile range 32.2-66.7 months). On logistic MVA for all patients, those with a high risk from GS (adjusted odds ratio [aOR] 3.23, 95% confidence interval [CI] 1.49-8.13, p = 0.006) or with RS ≥ 31 (aOR 1.99, 95% CI 1.41-2.82, p < 0.001) were more likely to have pCR. When compared to RS ≥ 31, a high risk from GS was not associated with pCR (aOR 1.01, 95% CI 0.75-1.37, p = 0.94). However, among those with favorable hormone receptor status, similar findings were noted, except that those with a high risk group from GS were less likely to have pCR compared to those with RS ≥ 31 (aOR 0.65, 95% CI 0.43-0.96, p = 0.03). When analyses were repeated using a high risk group from RS defined as RS ≥ 26 among those with favorable hormone receptor status, RS ≥ 26 was not associated with pCR when compared to the high risk from GS (aOR 0.74, 0.50-1.07, p = 0.12). CONCLUSIONS: To our knowledge, this is the largest study using a nationwide oncology database suggesting that high recurrence risk groups in both assays were associated with pCR. Among those with favorable hormone receptor status, RS ≥ 31 may be a more selective prognostic marker for pCR.

The effectiveness of ocriplasmin versus surgery for the treatment of macular holes: A systematic review and meta-analysis.

OBJECTIVE: To conduct a systematic review looking at the effects of ocriplasmin compared to pars plana vitrectomy on macular holes to assess the effectiveness of the treatment options. METHODS: Literature was searched through MEDLINE, EMBASE, CINAHL, Clinical Trials.gov, and ProQuest Dissertations and Theses until June 12, 2018. Conferences held through Association for Research in Vision and Ophthalmology, Canadian Society of Ophthalmology, and American Academy of Ophthalmology were searched until June 18, 2018. A total of 208 records were screened leaving 26. One author independently reviewed them for quality and extracted data. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting guidelines were followed. The adverse events, MH closure rate, change in MH size, and the extent to which the patients' visual acuity is restored by each treatment option; ocriplasmin and vitrectomy. RESULTS: Twenty-six articles were included for qualitative and quantitative analysis. Meta-analysis results showed a 34% closure of macular holes after ocriplasmin treatment compared to 92% after vitrectomy. A significant improvement in visual acuity was seen after vitrectomy (SMD = -1.42; CI: [-1.98, -0.86]) as well as the ocriplasmin treatment (SMD = -0.73; CI: [-0.98, -0.48]). CONCLUSIONS: Results suggested 92% macular hole closure after vitrectomy compared to 34% after ocriplasmin. A significant improvement in visual acuity of patients was seen after both treatments. More good quality randomized controlled trials are required to make strong conclusions.

Sequential introduction of a multistep testing algorithm and nucleic acid amplification testing leading to an increase in Clostridioides difficile detection and a trend toward increased strain diversity.

BACKGROUND: Most clinical microbiology laboratories have replaced toxin immunoassay (EIA) alone with multistep testing (MST) protocols or nucleic acid amplification testing (NAAT) alone for the detection of C. difficile. OBJECTIVE: Study the effect of changing testing strategies on C. difficile detection and strain diversity. DESIGN: Retrospective study. SETTING: A Veterans' Affairs hospital. METHODS: Initially, toxin EIA testing was replaced by an MST approach utilizing a glutamate dehydrogenase (GDH) and toxin EIA followed by tcdB NAAT for discordant results. After 18 months, MST was replaced by a NAAT-only strategy. Available patient stool specimens were cultured for C. difficile. Restriction endonuclease analysis (REA) strain typing and quantitative in vitro toxin testing were performed on recovered isolates. RESULTS: Before MST (toxin EIA), 79 of 708 specimens (11%) were positive, and after MST (MST-A), 121 of 517 specimens (23%) were positive (P < .0001). Prior to NAAT-only testing (MST-B), 80 of the 490 specimens (16%) were positive by MST, and after NAAT-only testing was implemented, 67 of the 368 specimens (18%) were positive (P = nonsignificant). After replacing toxin EIA testing, REA strain group diversity increased (8, 13, 13, and 10 REA groups in the toxin EIA, MST-A, MST-B, and NAAT-only periods, respectively) and in vitro toxin concentration decreased. The average log10 toxin concentration of the isolates were 2.08, 1.88, 1.20 and 1.55 ng/mL for the same periods, respectively. CONCLUSIONS: MST and NAAT had similar detection rates for C. difficile. Compared to toxin testing alone, they detected increased diversity of C. difficile strains, many of which were low toxin producing.

Plasma pharmacokinetics of ceftolozane/tazobactam in pediatric patients with cystic fibrosis.

BACKGROUND: The antipseudomonal cephalosporin/ß-lactamase inhibitor combination ceftolozane/tazobactam could be a potential treatment option for cystic fibrosis (CF) pulmonary exacerbations. The pharmacokinetics (PK) of ceftolozane/tazobactam in children with CF merits further evaluation. METHODS: This is a retrospective subgroup analysis of a phase 1, noncomparative trial that characterized PK, safety, and tolerability of single intravenous doses of ceftolozane/tazobactam in pediatric patients. This analysis compares ceftolozane and tazobactam plasma PK parameters, estimated from a population PK model, between patients with and without CF enrolled in that trial. Individual attainment of PK/pharmacodynamic (PD) targets of ceftolozane and tazobactam (free ceftolozane concentration >4 µg/mL for >30% and free tazobactam concentration >1 µg/mL for 20% of the dosing interval) in patients with and without CF were evaluated. RESULTS: The study enrolled 18 patients aged greater than or equal to 2 to less than 18 years old, which included 9 with CF. Weight-normalized ceftolozane PK parameters were similar between patients with CF (clearance: 0.16 L/h/kg, half-life: 1.54 hours, volume of distribution: 0.26 L/kg) and without CF (clearance: 0.15 L/h/kg, half-life: 1.62 hours, volume of distribution: 0.26 L/kg), as were most weight-normalized tazobactam PK parameters. Weight-normalized tazobactam clearance was higher in patients with CF (0.73 L/h/kg) than patients without CF (0.42 L/h/kg). All patients achieved the prespecified PK/PD targets for ceftolozane and tazobactam. CONCLUSIONS: This retrospective analysis demonstrated generally similar weight-normalized plasma PK parameters for ceftolozane and tazobactam among children with and without CF; thus, projected doses for treatment of pediatric hospital-acquired/ventilator-associated pneumonia, which are higher than the pediatric complicated urinary tract infection/intra-abdominal infection doses, may be appropriate for treatment of CF pulmonary exacerbation.

Effects of socioeconomic status on esophageal adenocarcinoma stage at diagnosis, receipt of treatment, and survival: A population-based cohort study.

The incidence of esophageal adenocarcinoma (EAC) is increasing worldwide and has overtaken squamous histology in occurrence. We studied the impact of socioeconomic status (SES) on EAC stage at diagnosis, receipt of treatment, and survival. A population-based retrospective cohort study was conducted using Ontario Cancer Registry-linked administrative health data. Multinomial logistic regression was used to examine the association between SES (income quintile) and stage at EAC diagnosis and EAC treatment. Survival times following EAC diagnosis were estimated using Kaplan-Meier method. Cox proportional-hazards regression analysis was used to examine the association between SES and EAC survival. Between 2003-2012, 2,125 EAC cases were diagnosed. Median survival for the lowest-SES group was 10.9 months compared to 11.6 months for the highest-SES group; the 5-year survival was 9.8% vs. 15.0%. Compared to individuals in the highest-SES group, individuals in the lowest-SES category experienced no significant difference in EAC treatment (91.6% vs. 93.3%, P = 0.314) and deaths (78.9% vs. 75.6%, P = 0.727). After controlling for covariates, no significant associations were found between SES and cancer stage at diagnosis and EAC treatment. Additionally, after controlling for age, gender, urban/rural residence, birth country, health region, aggregated diagnosis groups, cancer stage, treatment, and year of diagnosis, no significant association was found between SES and EAC survival. Moreover, increased mortality risk was observed among those with older age (P = 0.001), advanced-stage of EAC at diagnosis (P < 0.001), and those receiving chemotherapy alone, radiotherapy alone, or surgery plus chemotherapy (P < 0.001). Adjusted proportional-hazards model findings suggest that there is no association between SES and EAC survival. While the unadjusted model suggests reduced survival among individuals in lower income quintiles, this is no longer significant after adjusting for any covariate. Additionally, there is an apparent association between SES and survival when considering only those individuals diagnosed with stage 0-III EAC. These analyses suggest that the observed direct relationship between SES and survival is explained by patient-level factors including receipt of treatment, something that is potentially modifiable.

Protein 4.1R Exon 16 3' Splice Site Activation Requires Coordination among TIA1, Pcbp1, and RBM39 during Terminal Erythropoiesis.

Exon 16 of protein 4.1R encodes a spectrin/actin-binding peptide critical for erythrocyte membrane stability. Its expression during erythroid differentiation is regulated by alternative pre-mRNA splicing. A UUUUCCCCCC motif situated between the branch point and the 3' splice site is crucial for inclusion. We show that the UUUU region and the last three C residues in this motif are necessary for the binding of splicing factors TIA1 and Pcbp1 and that these proteins appear to act in a collaborative manner to enhance exon 16 inclusion. This element also activates an internal exon when placed in a corresponding intronic position in a heterologous reporter. The impact of these two factors is further enhanced by high levels of RBM39, whose expression rises during erythroid differentiation as exon 16 inclusion increases. TIA1 and Pcbp1 associate in a complex containing RBM39, which interacts with U2AF65 and SF3b155 and promotes U2 snRNP recruitment to the branch point. Our results provide a mechanism for exon 16 3' splice site activation in which a coordinated effort among TIA1, Pcbp1, and RBM39 stabilizes or increases U2 snRNP recruitment, enhances spliceosome A complex formation, and facilitates exon definition through RBM39-mediated splicing regulation.

'Who', 'when' and 'how' in re-irradiation of recurrent painful bone metastases.

Re-irradiation of painful bony metastases is increasingly performed since patients are receiving better systemic treatments and having longer life expectancy, and may also be due to the increase use of initial single fraction radiotherapy. However, randomized control trial on the efficacy of re-irradiation is lacking. A recent meta-analysis concluded with a 58% response rate for pain relief by re-irradiation of symptomatic bone metastases. In this review, the effectiveness of re-irradiation in terms of clinical and economical aspects, and clinical questions on who, when, and how to re-irradiate would be discussed. A brief review of other treatment options and comparison with re-irradiation of bone metastases would be performed.

Prognostic significance of the total dose of cisplatin administered during concurrent chemoradiotherapy in patients with locoregionally advanced nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Concurrent chemoradiotherapy (CRT) confers survival benefit over radiotherapy (RT) alone in the treatment of locoregionally advanced nasopharyngeal carcinoma (NPC). This study explored the prognostic significance of the total dose of cisplatin delivered during CRT. MATERIALS AND METHODS: A retrospective analysis was performed in patients with stage II to IVB NPC (AJCC 6th edition) who participated in 3 prospective studies. All patients received cisplatin at a fixed dose of 40 mg/m(2)/week during a 6-7-weeks course of CRT. Chi-square test was used in the univariate analysis. Relationship between prognostic factors, the total dose of cisplatin administered and time-to-event endpoints were analyzed with the Cox Hazards model. RESULTS: Two hundred and forty-one patients were identified with the following stage distribution: Stage II=13.7%, III=45.2%, IV=41.1%. The median total number of cycles of cisplatin administered per patient was 5 cycles (range 1-8 cycles). At a median follow-up of 56.5 months (range 4.2-200.2 months), 93 patients (38.6%) had relapsed and 85 patients (35.2%) died. For all patients, the total number of cycles of cisplatin delivered was significantly associated with survival in the univariate but not the multivariate analysis. In a sub-group analysis of 142 patients with stage II and III NPC, patients who received more than 5 cycles of cisplatin had significantly better overall survival than those who did not (hazard ratio 0.44; 95% confidence interval, 0.23-0.85; p=0.02). CONCLUSION: Number of cycles of cisplatin delivered is an independent prognostic factor in patients with stage II-III NPC undergoing CRT with weekly cisplatin.