We conducted a prospective, multicenter observational study of adults (n = 1447) and children (n = 144) with candidemia at tertiary care centers in the United States in parallel with a candidemia ...treatment trial that included nonneutropenic adults. Candida albicans was the most common bloodstream isolate recovered from adults and children (45% vs. 49%) and was associated with high mortality (47% among adults vs. 29% among children). Three-month survival was better among children than among adults (76% vs. 54%; P < .001). Most children received amphotericin B as initial therapy, whereas most adults received fluconazole. In adults, Candida parapsilosis fungemia was associated with lower mortality than was non-parapsilosis candidemia (24% vs. 46%; P < .001). Mortality was similar among subjects with Candida glabrata or non-glabrata candidemia; mortality was also similar among subjects with C. glabrata candidemia who received fluconazole rather than other antifungal therapy. Subjects in the observational cohort had higher Acute Physiology and Chronic Health Evaluation II scores than did participants in the clinical trial (18.6 vs. 16.1), which suggests that the former subjects are more often excluded from therapeutic trials.
Meaningful advances in targeted therapy for head and neck squamous cell carcinoma (HNSCC) have been hampered by limited availability of robust preclinical models for translational research. Using an ...impressive array of in vitro and in vivo preclinical HNSCC models, Smith and colleagues demonstrated the efficacy of alpelisib and tipifarnib combination therapy through sustained mTOR inhibition in PIK3CA/HRAS-dysregulated HNSCC, including preliminary evidence of robust antitumor activity in a patient enrolled in a precision medicine trial. This study in this issue of Cancer Research illustrates the value of preclinical avatars for informing biomarker-driven clinical trials to advance precision medicine in HNSCC and other cancers. See related article by Smith et al., p. 3252.
There are currently no clinical strategies utilizing tumor gene expression to inform therapeutic selection for patients with head and neck squamous cell carcinoma (HNSCC). One of the challenges in ...developing predictive biomarkers is the limited characterization of preclinical HNSCC models. Patient-derived xenografts (PDXs) are increasingly recognized as translationally relevant preclinical avatars for human tumors; however, the overall transcriptomic concordance of HNSCC PDXs with primary human HNSCC is understudied, especially in human papillomavirus-associated (HPV+) disease. Here, we characterized 64 HNSCC PDXs (16 HPV+ and 48 HPV-) at the transcriptomic level using RNA-sequencing. The range of human-specific reads per PDX varied from 64.6%-96.5%, with a comparison of the most differentially expressed genes before and after removal of mouse transcripts revealing no significant benefit to filtering out mouse mRNA reads in this cohort. We demonstrate that four previously established HNSCC molecular subtypes found in The Cancer Genome Atlas (TCGA) are also clearly recapitulated in HNSCC PDXs. Unsupervised hierarchical clustering yielded a striking natural division of HNSCC PDXs by HPV status, with C19orf57 (BRME1), a gene previously correlated with positive response to cisplatin in cervical cancer, among the most significantly differentially expressed genes between HPV+ and HPV- PDXs. In vivo experiments demonstrated a possible relationship between increased C19orf57 expression and superior anti-tumor responses of PDXs to cisplatin, which should be investigated further. These findings highlight the value of PDXs as models for HPV+ and HPV- HNSCC, providing a resource for future discovery of predictive biomarkers to guide treatment selection in HNSCC.
Fanconi anemia, the most frequent genetic cause of bone marrow failure, is characterized by an extreme predilection toward multiple malignancies, including a greater than 500-fold incidence of head ...and neck squamous cell carcinoma (HNSCC) relative to the general population. Fanconi anemia-associated HNSCC and esophageal SCC (FA-HNSCC) often present at advanced stages with poor survival. Surgical resection remains the primary treatment for FA-HNSCC, and there is often great reluctance to administer systemic agents and/or radiotherapy to these patients given their susceptibility to DNA damage. The paucity of FA-HNSCC case reports limits evidence-based management, and such cases have not been analyzed collectively in detail. We present a systematic review of FA-HNSCC treatments reported from 1966 to 2020, defining a cohort of 119 patients with FA-HNSCC including 16 esophageal SCCs (131 total primary tumors), who were treated with surgery, radiotherapy, systemic therapy (including cytotoxic agents, EGFR inhibitors, or immune checkpoint inhibitors), or a combination of modalities. We summarize the clinical responses and regimen-associated toxicities by treatment modality. The collective evidence suggests that when possible, surgical resection with curative intent should remain the primary treatment modality for FA-HNSCC. Radiation can be administered with acceptable toxicity in the majority of cases, including patients who have undergone stem cell transplantation. Although there is little justification for cytotoxic chemotherapy, EGFR inhibitors and tyrosine kinase inhibitors may be both safe and effective. Immunotherapy may also be considered. Most oncologists have little personal experience with FA-HNSCC. This review is intended as a comprehensive resource for clinicians.
High rates of recurrence and distant metastasis are a foremost challenge in the management of adenoid cystic carcinoma (ACC), occurring in approximately 40% of all ACC patients. Despite the morbidity ...and mortality resulting from recurrent/metastatic (R/M) disease, there are no FDA-approved systemic agents for these patients. In this review, we summarize pertinent ACC pathophysiology and its implications for different systemic treatment regimens in R/M ACC. We review the evidence for the most widely used systemic agents - cytotoxic chemotherapy and tyrosine kinase inhibitors (TKIs) targeting VEGFR - in addition to immune checkpoint inhibitors and non-TKI biologic agents. Exciting emerging targets for R/M ACC, including inhibitors of Notch signaling, stemness, PRMT5, and Axl, are also discussed. Lastly, we review local therapies for small-volume lung disease in patients with oligometastatic ACC, specifically pulmonary metastasectomy and stereotactic body radiation therapy (SBRT). Future development of targeted molecular agents which exploit the underlying biology of this disease may yield novel therapeutic options to improve clinical outcomes in patients with R/M ACC.
Positive pivotal trials followed by guideline endorsement can be a major driver of change in US national medical practice patterns. We therefore analyzed national trends in the use and outcomes of ...mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion before and after the 2015 publication of pivotal trials and the US guideline update.
We analyzed the National Inpatient Sample from 2012-2016. Ischemic stroke and mechanical thrombectomy patients were identified using ICD-9 and ICD-10. The primary efficacy outcome measure was discharge to home, which strongly correlates with mild degree of disability at discharge. Safety outcomes include in-hospital mortality and in-hospital medical complications.
From 2012-2016, 2,394,550 discharges were recorded with a diagnosis of ischemic stroke, including 39,150 (1.6%) treated with mechanical thrombectomy. The number and proportion of stroke patients undergoing mechanical thrombectomy annually rose from 4,910/452,905 (1.1%) in 2012 to 11,860/509,215 (2.3%) in 2016. The largest annual increase occurred between 2014, when 6,460 stroke patients were treated with thrombectomy, and 2015, when 10,280 underwent thrombectomy. Comparing the pre (Q1 2012 - Q4 2014) and post (Q4 2015 – Q4 2016) RCT/Guideline epochs, in addition to increased thrombectomy rates, the proportion of thrombectomy patients who received IV-tPA decreased (46% to 24%, p<0.001). Rates of mild disability outcome increased from 16% to 20% (p<0.001), while mortality decreased from 15% to 13% (p=0.01). The odds of pulmonary embolism, urinary tract infection, and pneumonia decreased, while intracerebral hemorrhage, septicemia, deep venous thrombosis, shock, and cardiac arrest were unchanged.
In the United States, thrombectomy treatment for acute ischemic stroke increased rapidly and substantially in frequency following publication of positive clinical trials and US guideline update in 2015, accompanied by improved functional outcomes and reduced peri-procedural mortality.
Background
A minority of patients with recurrent/metastatic (R/M) salivary gland cancers (SGCs) benefit from immune checkpoint inhibitors (ICIs), necessitating reliable biomarkers for ICI response ...prediction.
Methods
Retrospective observational study of R/M SGC patients treated with pembrolizumab between 2016 and 2022, with a primary outcome of 6‐month progression‐free survival (PFS) and secondary outcome of 2‐year overall survival (OS). Univariate and multivariable Cox proportional hazards models were employed.
Results
Twenty R/M SGC patients were included. After adjustment, NLR as a continuous variable was independently associated with 6‐month PFS (HR 1.30, 95% CI 1.10–1.54, p = 0.002) and 2‐year OS (HR 1.33, 95% CI 1.07–1.66, p = 0.010). Similarly, NLR ≥ 5 was associated with higher hazards of progression at 6 months (HR 12.85, 95% CI 2.17–76.16, p = 0.005) and death at 2 years (HR 11.25, 95% CI 1.67–75.77, p = 0.013).
Conclusions
Higher pretreatment NLR was independently associated with inferior 6‐month PFS and 2‐year OS in pembrolizumab‐treated R/M SGC patients.
Background. Human bocavirus (HBoV) is a recently discovered parvovirus associated with respiratory tract infections in children. We conducted the first systematic prospective clinical and molecular ...study using nasopharyngeal aspirates (NPAs) and fecal samples. Methods. NPAs negative for influenza virus, parainfluenza virus, respiratory syncytial virus, adenovirus, and coronavirus and fecal samples from patients with acute gastroenteritis were included. On the basis of results from a pilot study using 400 NPAs from all age groups, a prospective 12-month study was conducted to detect HBoV in 1200 NPAs and 1435 fecal samples from patients <18 years old by polymerase chain reaction. The complete genome sequences of HBoVs from 12 NPAs and 12 fecal samples were determined. Results. Of the 400 NPAs collected in the pilot study, 20 (5.0%) were found to contain HBoV, all from children <5 years old. In the subsequent prospective study of pediatric patients, HBoV was detected in 83 (6.9%) of 1200 NPAs. Upper and lower respiratory tract infections were equally common. HBoV was detected in 30 (2.1%) of 1435 fecal samples. Fever and watery diarrhea were the most common symptoms. The seasonality of HBoV in NPAs and fecal samples was similar. Codetection with other pathogens occurred in 33% and 56% of NPAs and fecal samples, respectively, from patients with HBoV infection. Genomes of HBoVs from NPAs and fecal samples displayed minimal sequence variations. Conclusions. HBoV was detected in fecal specimens in children with acute gastroenteritis. A single lineage of HBoV was associated with both respiratory tract and enteric infections.
Background
Guidelines regarding head and neck surgical care have evolved during the coronavirus‐19 (COVID‐19) pandemic. Data on operative management have been limited.
Methods
We compared two cohorts ...of patients undergoing head and neck or reconstructive surgery between March 16, 2019 and April 16, 2019 (pre‐COVID‐19) and March 16, 2020 and April 16, 2020 (COVID‐19) at an academic center. Perioperative, intraoperative, and postoperative outcomes were recorded.
Results
There were 63 operations during COVID‐19 and 84 operations during pre‐COVID‐19. During COVID‐19, a smaller proportion of patients had benign pathology (12% vs 20%, respectively) and underwent thyroid procedures (2% vs 23%) while a greater proportion of patients underwent microvascular reconstruction±ablation (24% vs 12%,). Operative times increased, especially among patients undergoing microvascular reconstruction±ablation (687 ± 112 vs 596 ± 91 minutes, P = .04). Complication rates and length of stay were similar.
Conclusions
During COVID‐19, perioperative outcomes were similar, operative time increased, and there were no recorded transmissions to staff or patients. Continued surgical management of head and neck cancer patients can be provided safely.
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