Benjamin L. Witt

The influence of rapid onsite evaluation on the adequacy rate of fine-needle aspiration cytology: a systematic review and meta-analysis.

Rapid onsite evaluation (ROSE) has the potential to improve the adequacy rates of fine-needle aspiration (FNA) cytology. Studies have obtained variable results on the influence of ROSE. We conducted a systematic review and meta-analysis of studies on the influence of ROSE on FNA adequacy. We synthesized evidence across all anatomic locations. We only included studies that contained a control arm and compared cohorts with ROSE against cohorts without ROSE at a single location. We screened 2,179 studies and identified 25 studies that met our inclusion criteria. On average, ROSE improves the adequacy rate by 12%, but there was considerable variability across studies. The adequacy rate with ROSE depends on the non-ROSE adequacy rate. Sixty-five percent of the variability in the adequacy rate with ROSE was found to occur because of differences in the adequacy rate without ROSE. Studies with high non-ROSE adequacy rates showed low improvement after ROSE was implemented. Studies must account for the effect of the non-ROSE adequacy rate to determine the effect of ROSE on FNA adequacy rates.

A comparative needle study: EUS‐FNA procedures using the HD ProCore™ and EchoTip® 22‐gauge needle types

The specific needle sizes/types used in performing endoscopic ultrasound‐guided fine needle aspirations (EUS‐FNA) vary. The HD ProCore™ is a 22‐gauge beveled needle allowing for core biopsy along with aspiration material. In this study we compare this needle with a standard 22‐gauge needle. Between April 1, 2011 and November 15, 2011, 18 patients undergoing EUS‐FNA using the HD ProCore™ needle were compared to a control group of 18 cases using the standard 22‐gauge needle. Smears were assessed for: three‐dimensional clusters, thick obscuring clusters, monolayer sheets, cellularity, crowded obscuring single cells, blood, and nuclear staining. Cell blocks were assessed for cellularity and presence of diagnostic material. Records were reviewed for the overall adequacy, number of FNA passes, and patient follow‐up. Overall, the two needle groups demonstrated similar results for the cytology parameters, amount of diagnostic cell block material, adequacy, and accuracy. The mean number of passes to achieve adequacy varied between the groups [2.94 for the standard 22‐gauge needle group versus 2.11 for the beveled needle group (P=0.03)] with no meaningful difference in case duration between needle groups. No complications were reported. The beveled EUS needle affords similar cytologic interpretability, adequacy, diagnostic accuracy, and amount of cell block material as a standard needle. There was a statistically significant trend toward fewer passes to achieve adequacy with the beveled EUS‐FNA needle. Therefore, the EUS‐FNA needle with a lateral bevel is a diagnostically similar alternative to standard endoscopy needles, the possibility that this beveled needle may improve per pass adequacy requires further verification. Diagn. Cytopathol. 2013;41:1069–1074.

Sox2 Cooperates with Lkb1 Loss in a Mouse Model of Squamous Cell Lung Cancer

SUMMARY Squamous cell carcinoma (SCC) of the lung is the second most common subtype of lung cancer. With limited treatment options, the 5-year survival rate of SCC is only 15%. Although genomic alterations in SCC have been characterized, identifying the alterations that drive SCC is critical for improving treatment strategies. Mouse models of SCC are currently limited. Using lentiviral delivery of Sox2 specifically to the mouse lung, we tested the ability of Sox2 to promote tumorigenesis in multiple tumor suppressor backgrounds. Expression of Sox2, frequently amplified in human SCC, specifically cooperates with loss of Lkb1 to promote squamous lung tumors. Mouse tumors exhibit characteristic histopathology and biomarker expression similar to human SCC. They also mimic human SCCs by activation of therapeutically relevant pathways including STAT and mTOR. This model may be utilized to test the contribution of additional driver alterations in SCC, as well as for preclinical drug discovery.

Rapid Onsite Evaluation Improves the Adequacy of Fine-Needle Aspiration for Thyroid Lesions: A Systematic Review and Meta-Analysis

BACKGROUND Fine-needle aspiration (FNA) with ultrasonography guidance is one of the optimal techniques for the diagnostic evaluation of thyroid nodules. A significant subset of thyroid FNAs continues to be inadequate for interpretation, which potentially leads to increased costs from repeat aspirations. Numerous studies have been published regarding the influence of rapid onsite evaluation (ROSE) by cytopathologists on thyroid FNAs, some indicating that FNA is more likely to be adequate for interpretation with ROSE, while others refute this idea. To our knowledge, no meta-analysis of the literature on this subject has been undertaken. METHODS We searched MEDLINE and EMBASE using the following search string: (needle biopsy) AND (assessment or onsite OR onsite or immediate or rapid)/title or abstract. There were no restrictions on study design, language, anatomic site, or time period. Only studies comparing two arms (with/without ROSE) at a single site were eligible for inclusion. Potentially relevant studies were subjected to a citation search (forward search) and reference search (backward search) using SCOPUS. Statistical calculations were performed using Stata Release 12. Meta-analysis was completed using a random-effect model as implemented in the metan routine in Stata. RESULTS An initial search obtained 2179 studies from MEDLINE and EMBASE, and screening yielded 71 potentially relevant studies. A focused review of this subset resulted in seven full studies and one abstract that met our inclusion criteria. Our citation search using SCOPUS yielded no new studies. Overall, the average adequacy rate was 83% without ROSE compared to 92% with ROSE. Visual inspection of the data suggested that the improvement in adequacy due to ROSE may be related to the adequacy rate without ROSE. Metaregression analysis showed that the change in the adequacy rate was strongly correlated (t=-12.7, p<0.001) with the non-ROSE adequacy rate. In addition, the non-ROSE adequacy rate explained all, but 10% of the residual between study variability in the change in the adequacy rates due to ROSE. CONCLUSIONS ROSE is generally associated with an improvement in adequacy, but the impact of ROSE depends heavily on the initial adequacy rate. Sites with lower initial adequacy rates can benefit the most from the implementation of ROSE.

Ultrasound-guided core needle biopsy of salivary gland lesions: A systematic review and meta-analysis

To obtain summary estimates of the sensitivity and specificity of core needle biopsy for assessment of salivary gland lesions and to investigate sources of variation in accuracy between study locations.

Prior high-risk human papillomavirus testing and papanicolaou test results of 70 invasive cervical carcinomas diagnosed in 2012: Results of a retrospective multicenter study

CONTEXT Persistent high-risk human papillomavirus (hrHPV) infection is essential for the development of cervical cancer and its precursor lesions. High-risk HPV testing has a higher sensitivity than cytology does for detecting cervical epithelial lesions. However, a large study from a single institution showed 31% of patients with invasive cervical cancer had negative baseline hrHPV testing within 5 years preceding the diagnosis. OBJECTIVE To investigate the limitation of hrHPV testing in detecting invasive cervical cancer. DESIGN Cases from 2012 with a histologic diagnosis of invasive cervical carcinoma were retrieved from multiple institutions. From those records, prior hrHPV testing and Papanicolaou test results in the 5 years before the cancer diagnosis were recorded. RESULTS Seventy patients with cervical carcinoma were included in the study. Negative HPV test result rates were 9% (5 of 53), 23% (6 of 26), and 25% (2 of 8) during the periods of less than 1 year, 1 to 3 years, and 3 to 5 years before the histologic diagnoses, respectively. Negative Papanicolaou testing results in the same time intervals were 3.4% (2 of 59), 33% (10 of 30), and 40% (6 of 15). Although the HPV(-) rate seemed to be different among different HPV test methods, no statistical significance was detected because of small sample size. Negative hrHPV rates in patients with adenocarcinoma were similar to those in patients with squamous cell carcinoma. CONCLUSIONS These data expose limitations for the potential use of primary HPV testing. In addition, current screening guidelines recommending cotesting at 5-year intervals should be evaluated further with additional historic data collection because there are women with negative results for both Papanicolaou tests and hrHPV testing within the period of 3 to 5 years before an invasive carcinoma diagnosis.

Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies.

Verification bias in diagnostic accuracy studies for fine- and core needle biopsy of salivary gland lesions in otolaryngology journals: A systematic review and analysis

Diagnostic test accuracy (DTA) studies for needle biopsy are frequently published in otolaryngology journals, but this body of literature has not been assessed for verification bias.

Caspase-2 impacts lung tumorigenesis and chemotherapy response in vivo

Caspase-2 is an atypical caspase that regulates apoptosis, cell cycle arrest and genome maintenance, although the mechanisms are not well understood. Caspase-2 has also been implicated in chemotherapy response in lung cancer, but this function has not been addressed in vivo. Here we show that Caspase-2 functions as a tumor suppressor in Kras-driven lung cancer in vivo. Loss of Caspase-2 leads to enhanced tumor proliferation and progression. Despite being more histologically advanced, Caspase-2-deficient tumors are sensitive to chemotherapy and exhibit a significant reduction in tumor volume following repeated treatment. However, Caspase-2-deficient tumors rapidly rebound from chemotherapy with enhanced proliferation, ultimately hindering long-term therapeutic benefit. In response to DNA damage, Caspase-2 cleaves and inhibits Mdm2 and thereby promotes the stability of the tumor-suppressor p53. Caspase-2 expression levels are significantly reduced in human lung tumors with wild-type p53, in agreement with the model whereby Caspase-2 functions through Mdm2/p53 regulation. Consistently, p53 target genes including p21, cyclin G1 and Msh2 are reduced in Caspase-2-deficient tumors. Finally, we show that phosphorylation of p53-induced protein with a death domain 1 leads to Caspase-2-mediated cleavage of Mdm2, directly impacting p53 levels, activity and chemotherapy response. Together, these studies elucidate a Caspase-2-p53 signaling network that impacts lung tumorigenesis and chemotherapy response in vivo.

Pathologic evaluation of a new endoscopic ultrasound needle designed to obtain core tissue samples: A pilot study

Background and Objectives: Standard endoscopic ultrasound-fine-needle aspiration (EUS-FNA) needles are in widespread use. Meaningful differences between the available needles have been difficult to identify. Recently, a new EUS needle (Shark Core®, Covidien, Dublin, Leinster, Ireland), has been introduced in an attempt to improve diagnostic accuracy, tissue yield, and to potentially obtain a core tissue sample. We performed a pilot study prospectively to evaluate this new needle when compared to a standard EUS-FNA needle. Materials and Methods: Analysis of the first 15 patients undergoing EUS-FNA with the Shark Core needle was performed and it was compared to EUS-FNA in 15 patients who underwent EUS-FNA with a standard needle. Results: The Shark Core needle required fewer needle passes to obtain diagnostic adequacy than the standard needle [(χ2(1) = 11.3, P < 0.001]. The Shark Core needle required 1.5 passes to reach adequacy, whereas the standard needle required three passes. For cases with cell blocks, the Shark Core needle produced diagnostic material in 85% of cases [95% confidence interval (CI): 54–98], whereas the standard needle produced diagnostic material in 38% of the cases (95% CI: 9-76). The Shark Core needle produced actual tissue cores 82% of the time (95% CI: 48–98) and the standard needle produced no tissue cores (95% CI: 0-71) (P = 0.03). Conclusion: This pilot study found that the Shark Core needle had a high rate of producing adequate cytologic material for the diagnosis of pancreatic and peri-pancreatic lesions sampled by EUS with fewer passes required to obtain a definitive diagnosis and with a high rate of tissue cores being obtained when compared to a standard FNA needle.