In patients with a history suggestive of asthma, diagnosis is usually confirmed by spirometry with bronchodilator response (BDR) or confirmatory methacholine challenge testing (MCT).
We examined the ...proportion of participants with negative BDR testing who had a positive MCT (and its predictors) result and characteristics of MCT, including effects of controller medication tapering and temporal variability (and predictors of MCT result change), and concordance between MCT and pulmonologist asthma diagnosis.
Adults with self-reported physician-diagnosed asthma were recruited by random-digit dialing across Canada. Subjects performed spirometry with BDR testing and returned for MCT if testing was nondiagnostic for asthma. Subjects on controllers underwent medication tapering with serial MCTs over 3 to 6 weeks. Subjects with a negative MCT (the provocative concentration of methacholine that results in a 20% drop in FEV1 PC20 > 8 mg/mL) off medications were examined by a pulmonologist and had serial MCTs after 6 and 12 months.
Of 500 subjects (50.5 ± 16.6 years old, 68.0% female) with a negative BDR test for asthma, 215 (43.0%) had a positive MCT. Subjects with prebronchodilator airflow limitation were more likely to have a positive MCT (OR, 1.90; 95% CI, 1.17-3.04). MCT converted from negative to positive, with medication tapering in 18 of 94 (19.1%) participants, and spontaneously over time in 25 of 165 (15.2%) participants. Of 231 subjects with negative MCT, 28 (12.1%) subsequently received an asthma diagnosis from a pulmonologist.
In subjects with a self-reported physician diagnosis of asthma, absence of bronchodilator reversibility had a negative predictive value of only 57% to exclude asthma. A finding of spirometric airflow limitation significantly increased chances of asthma. MCT results varied with medication taper and over time, and pulmonologists were sometimes prepared to give a clinical diagnosis of asthma despite negative MCT. Correspondingly, in patients for whom a high clinical suspicion of asthma exists, repeat testing appears to be warranted.
Epidermal growth factor receptor (EGFR) mutation testing has become critical in the treatment of patients with advanced non–small-cell lung cancer. This study involves a large cohort and ...epidemiologically unselected series of EGFR mutation testing for patients with nonsquamous non–small-cell lung cancer in a North American population to determine sample-related factors that influence success in clinical EGFR testing.
Data from consecutive cases of Canadian province-wide testing at a centralized diagnostic laboratory for a 24-month period were reviewed. Samples were tested for exon-19 deletion and exon-21 L858R mutations using a validated polymerase chain reaction method with 1% to 5% detection sensitivity.
From 2651 samples submitted, 2404 samples were tested with 2293 samples eligible for analysis (1780 histology and 513 cytology specimens). The overall test-failure rate was 5.4% with overall mutation rate of 20.6%. No significant differences in the failure rate, mutation rate, or mutation type were found between histology and cytology samples. Although tumor cellularity was significantly associated with test-success or mutation rates in histology and cytology specimens, respectively, mutations could be detected in all specimen types. Significant rates of EGFR mutation were detected in cases with thyroid transcription factor (TTF)-1–negative immunohistochemistry (6.7%) and mucinous component (9.0%).
EGFR mutation testing should be attempted in any specimen, whether histologic or cytologic. Samples should not be excluded from testing based on TTF-1 status or histologic features. Pathologists should report the amount of available tumor for testing. However, suboptimal samples with a negative EGFR mutation result should be considered for repeat testing with an alternate sample.
There is great interest in repurposing the commonly prescribed anti-diabetic drug metformin for cancer therapy. Intracellular uptake and retention of metformin is affected by the expression of ...organic cation transporters (OCT) 1-3 and by multidrug and toxic compound extrusion (MATE) 1-2. Inside cells, metformin inhibits mitochondrial function, which leads to reduced oxygen consumption and inhibition of proliferation. Reduced oxygen consumption can lead to improved tumor oxygenation and radiation response.
Here we sought to determine if there is an association between the effects of metformin on inhibiting oxygen consumption, proliferation and expression of OCTs and MATEs in a panel of 19 cancer cell lines.
There was relatively large variability in the anti-proliferative response of different cell lines to metformin, with a subset of cell lines being very resistant. In contrast, all cell lines demonstrated sensitivity to the inhibition of oxygen consumption by metformin, with relatively small variation. The expression of OCT1 correlated with expression of both OCT2 and OCT3. OCT1 and OCT2 were relatively uniformly expressed, whereas expression of OCT3, MATE1 and MATE2 showed substantial variation across lines. There were statistically significant associations between resistance to inhibition of proliferation and MATE2 expression, as well as between sensitivity to inhibition of oxygen consumption and OCT3 expression. One cell line (LNCaP) with high OCT3 and low MATE2 expression in concert, had substantially higher intracellular metformin concentration than other cell lines, and was exquisitely sensitive to both anti-proliferative and anti-respiratory effects. In all other cell lines, the concentration of metformin required to inhibit oxygen consumption acutely in vitro was substantially higher than that achieved in the plasma of diabetic patients. However, administering anti-diabetic doses of metformin to tumor-bearing mice resulted in intratumoral accumulation of metformin and reduced hypoxic tumor fractions.
All cancer cells are susceptible to inhibition of oxygen consumption by metformin, which results in reduced hypoxic tumor fractions beneficial for the response to radiotherapy. High MATE2 expression may result in resistance to the anti-proliferative effect of metformin and should be considered as a negative predictive biomarker in clinical trials.
To evaluate whether clinical risk factors could further distinguish children with intermediate-risk Hodgkin lymphoma (HL) with rapid early and complete anatomic response (RER/CR) who benefit ...significantly from involved-field RT (IFRT) from those who do not, and thereby aid refinement of treatment selection.
Children with intermediate-risk HL treated on the Children's Oncology Group AHOD 0031 trial who achieved RER/CR with 4 cycles of chemotherapy, and who were randomized to 21-Gy IFRT or no additional therapy (n=716) were the subject of this study. Recursive partitioning analysis was used to identify factors associated with clinically and statistically significant improvement in event-free survival (EFS) after randomization to IFRT. Bootstrap sampling was used to evaluate the robustness of the findings.
Although most RER/CR patients did not benefit significantly from IFRT, those with a combination of anemia and bulky limited-stage disease (n=190) had significantly better 4-year EFS with the addition of IFRT (89.3% vs 77.9% without IFRT; P=.019); this benefit was consistently reproduced in bootstrap analyses and after adjusting for other prognostic factors.
Although most patients achieving RER/CR had favorable outcomes with 4 cycles of chemotherapy alone, those children with initial bulky stage I/II disease and anemia had significantly better EFS with the addition of IFRT as part of combined-modality therapy. Further work evaluating the interaction of clinical and biologic factors and imaging response is needed to further optimize and refine treatment selection.
The study aimed to determine the relationship between T2-weighted magnetic resonance imaging (MRI) signal and histologic sub-patterns in prostate cancer areas with different Gleason grades.
MR images ...of prostates (n = 25) were obtained prior to radical prostatectomy. These were processed as whole-mount specimens with tumors and the peripheral zone was annotated digitally by two pathologists. Gleason grade 3 was the most prevalent grade and was subdivided into packed, intermediate, and sparse based on gland-to-stroma ratio. Large cribriform, intraductal carcinoma, and small cribriform glands (grade 4 group) were separately annotated but grouped together for statistical analysis. The log MRI signal intensity for each contoured region (n = 809) was measured, and pairwise comparisons were performed using the open-source software R version 3.0.1.
Packed grade 3 sub-pattern has a significantly lower MRI intensity than the grade 4 group (P < 0.00001). Sparse grade 3 has a significantly higher MRI intensity than the packed grade 3 sub-pattern (P < 0.0001). No significant difference in MRI intensity was observed between the Gleason grade 4 group and the sparse sub-pattern grade 3 group (P = 0.54). In multivariable analysis adjusting for peripheral zone, the P values maintained significance (packed grade 3 group vs grade 4 group, P < 0.001; and sparse grade 3 sub-pattern vs packed grade 3 sub-pattern, P < 0.001).
This study demonstrated that T2-weighted MRI signal is dependent on histologic sub-patterns within Gleason grades 3 and 4 cancers, which may have implications for directed biopsy sampling and patient management.
Background
Since the Intergroup 0116 study was published in 2000, adjuvant postoperative chemoradiotherapy using CT-planned and 3D conformal/intensity-modulated radiotherapy has been offered ...routinely to fit patients with resected gastric cancer at Princess Margaret Hospital .The objective of this study was to analyze patterns of disease recurrence with respect to the radiotherapy volumes.
Methods
For the date and site (local, locoregional, or distant) of the first recurrence, medical records were reviewed for all patients treated at Princess Margaret Hospital with adjuvant chemoradiotherapy for resected gastric adenocarcinoma (January 1, 2000 to November 30, 2009). Patients whose recurrences were limited to local and/or regional sites were selected for further analysis. Available diagnostic imaging of the recurrence site was registered to the original planning radiotherapy dataset for contouring. If necessary to respect changes in anatomy, the contour was translocated on the basis of anatomic descriptors. The center of mass for each recurrence was identified as a point and its location was categorized according to the isodose encompassing it; in field (90 % or more), marginal (50–89 %), or out of field (less than 50 %).
Results
Of all 197 patients, 14 (7 %) had isolated locoregional failure, constituting 20 % of all 71 patients with a recurrence. Successful fusions were feasible in five cases. Of these recurrences, four were in field and one was marginal. In a further four cases, visual inspection was used, showing one in-field recurrence, one marginal recurrence, and two out-of-field recurrences. In five patients, either a useable original dataset or diagnostic imaging of the recurrence was not available.
Conclusions
The rates of isolated local/locoregional tumor recurrence in this study were low. Of the small number of recurrences available for analysis, most (five of nine) were in field. Further studies involving a larger cohort of patients might allow a more meaningful analysis of trends in the recurrence site with evolving radiotherapy techniques.
Prostate adenocarcinoma (CaP) patients are classified into low-, intermediate-, and high-risk groups that reflect relative survival categories. While there are accepted treatment regimens for low- ...and high-risk patients, intermediate-risk patients pose a clinical dilemma, as treatment outcomes are highly variable for these individuals. A better understanding of the factors that regulate the progression of CaP is required to delineate risk. For example, aberrant activation of the Hedgehog (Hh) pathway is implicated in CaP progression. Here, we identify the serine protease inhibitor protease nexin 1 (PN1) as a negative regulator of Hh signaling in prostate. Using human CaP cell lines and a mouse xenograft model of CaP, we demonstrate that PN1 regulates Hh signaling by decreasing protein levels of the Hh ligand Sonic (SHH) and its downstream effectors. Furthermore, we show that SHH expression enhanced tumor growth while overexpression of PN1 inhibited tumor growth and angiogenesis in mice. Finally, using comparative genome hybridization, we found that genetic alterations in Hh pathway genes correlated with worse clinical outcomes in intermediate-risk CaP patients, indicating the importance of this pathway in CaP.
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