Results of the Southwest Oncology Group phase II evaluation (study S0031) of ZD1839 for advanced transitional cell carcinoma of the urothelium

Study Type – Prognosis (inception cohort)
Level of Evidence 1b

OBJECTIVE

To evaluate the epidermal growth factor receptor (EGFR)‐targeted agent ZD1839 in patients who failed one previous chemotherapeutic regimen for metastatic transitional cell carcinoma (TCC), and to correlate patterns of response with the expression of EGFR.

PATIENTS AND METHODS

Thirty‐one patients with metastatic TCC of the urothelial tract were treated with ZD1839 500 mg oral daily. Patients were required to have a pretreatment biopsy to assess EGF expression.

RESULTS

The median progression‐free survival was 2 months, with only two patients (6.5%) surviving past 6 months with no disease progression. Thirty patients were evaluable for toxicity; there was grade 4 cerebrovascular ischaemia and an increase in creatinine level. All patients were evaluable for response, with one confirmed partial response (3%; 95% confidence interval, CI, 0–17%) in a patient with pulmonary metastases. All patients have died, and the estimated median (95% CI) survival is 3 (2–7) months.

CONCLUSIONS

ZD1839 is ineffective as a second‐line agent for urothelial carcinoma.     

Targeting of ��v-Integrins in Stem/Progenitor Cells and Supportive Microenvironment Impairs Bone Metastasis in Human Prostate Cancer

Acquisition of an invasive phenotype by cancer cells is a requirement for bone metastasis. Transformed epithelial cells can switch to a motile, mesenchymal phenotype by epithelial-mesenchymal transition (EMT). Recently, it has been shown that EMT is functionally linked to prostate cancer stem cells, which are not only critically involved in prostate cancer maintenance but also in bone metastasis. We showed that treatment with the non-peptide α_v-integrin antagonist GLPG0187 dose-dependently increased the E-cadherin/vimentin ratio, rendering the cells a more epithelial, sessile phenotype. In addition, GLPG0187 dose-dependently diminished the size of the aldehyde dehydrogenase high subpopulation of prostate cancer cells, suggesting that α_v-integrin plays an important role in maintaining the prostate cancer stem/progenitor pool. Our data show that GLPG0187 is a potent inhibitor of osteoclastic bone resorption and angiogenesis in vitro and in vivo. Real-time bioluminescent imaging in preclinical models of prostate cancer demonstrated that blocking α_v-integrins by GLPG0187 markedly reduced their metastatic tumor growth according to preventive and curative protocols. Bone tumor burden was significantly lower in the preventive protocol. In addition, the number of bone metastases/mouse was significantly inhibited. In the curative protocol, the progression of bone metastases and the formation of new bone metastases during the treatment period was significantly inhibited. In conclusion, we demonstrate that targeting of integrins by GLPG0187 can inhibit the de novo formation and progression of bone metastases in prostate cancer by antitumor (including inhibition of EMT and the size of the prostate cancer stem cell population), antiresorptive, and antiangiogenic mechanisms.     

Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case�Ccontrol study

Objective

Finasteride reduces prostate cancer risk by blocking the conversion of testosterone to dihydrotestosterone. However, whether finasteride affects estrogens levels or change in estrogens affects prostate cancer risk is unknown.

Methods

These questions were investigated in a case?Ccontrol study nested within the prostate cancer prevention trial (PCPT) with 1,798 biopsy-proven prostate cancer cases and 1,798 matched controls.

Results

Among men on placebo, no relationship of serum estrogens with risk of prostate cancer was found. Among those on finasteride, those in the highest quartile of baseline estrogen levels had a moderately increased risk of Gleason score < 7 prostate cancer (for estrone, odds ratio [OR] = 1.51, 95% confidence interval [CI] = 1.06?C2.15; for estradiol, OR = 1.50, 95% CI = 1.03?C2.18). Finasteride treatment increased serum estrogen concentrations; however, these changes were not associated with prostate cancer risk.

Conclusion

Our findings confirm those from previous studies that there are no associations of serum estrogen with prostate cancer risk in untreated men. In addition, finasteride results in a modest increase in serum estrogen levels, which are not related to prostate cancer risk. Whether finasteride is less effective in men with high serum estrogens, or finasteride interacts with estrogen to increase cancer risk, is uncertain and warrants further investigation.     

Patient centredness and the outcome of primary care consultations with patients with depression in areas of high and low socioeconomic deprivation

Background

Most patients with depression are managed in general practice. In deprived areas, depression is more common and poorer outcomes have been reported.

Aim

To compare general practice consultations and early outcomes for patients with depression living in areas of high or low socioeconomic deprivation.

Design and setting

Secondary data analysis of a prospective observational study involving 25 GPs and 356 consultations in deprived areas, and 20 GPs and 303 consultations in more affluent areas, with follow-up at 1 month.

Method

Validated measures were used to (a) objectively assess the patient centredness of consultations, and (b) record patient perceptions of GP empathy.

Results

PHQ-9 scores >10 (suggestive of caseness for moderate to severe depression) were significantly more common in deprived than in affluent areas (30.1% versus 18.5%, P<0.001). Patients with depression in deprived areas had more multimorbidity (65.4% versus 48.2%, P<0.05). Perceived GP empathy and observer-rated patient-centred communication were significantly lower in consultations in deprived areas. Outcomes at 1 month were significantly worse (persistent caseness 71.4% deprived, 43.2% affluent, P = 0.01). After multilevel multiregression modelling, observer-rated patient centredness in the consultation was predictive of improvement in PHQ-9 score in both affluent and deprived areas.

Conclusion

In deprived areas, patients with depression are more common and early outcomes are poorer compared with affluent areas. Patient-centred consulting appears to improve early outcome but may be difficult to achieve in deprived areas because of the inverse care law and the burden of multimorbidity.     

New methods for using computer-aided detection information for the detection of lung nodules on chest radiographs

Objective:

To investigate two new methods of using computer-aided detection (CAD) system information for the detection of lung nodules on chest radiographs. We evaluated an interactive CAD application and an independent combination of radiologists and CAD scores.

Methods:

300 posteroanterior and lateral digital chest radiographs were selected, including 111 with a solitary pulmonary nodule (average diameter, 16 mm). Both nodule and control cases were verified by CT. Six radiologists and six residents reviewed the chest radiographs without CAD and with CAD (ClearRead +Detect™ 5.2; Riverain Technologies, Miamisburg, OH) in two reading sessions. The CAD system was used in an interactive manner; CAD marks, accompanied by a score of suspicion, remained hidden unless the location was queried by the radiologist. Jackknife alternative free response receiver operating characteristics multireader multicase analysis was used to measure detection performance. Area under the curve (AUC) and partial AUC (pAUC) between a specificity of 80% and 100% served as the measure for detection performance. We also evaluated the results of a weighted combination of CAD scores and reader scores, at the location of reader findings.

Results:

AUC for the observers without CAD was 0.824. No significant improvement was seen with interactive use of CAD (AUC = 0.834; p = 0.15). Independent combination significantly improved detection performance (AUC = 0.834; p = 0.006). pAUCs without and with interactive CAD were similar (0.128), but improved with independent combination (0.137).

Conclusion:

Interactive CAD did not improve reader performance for the detection of lung nodules on chest radiographs. Independent combination of reader and CAD scores improved the detection performance of lung nodules.

Advances in knowledge:

(1) Interactive use of currently available CAD software did not improve the radiologists'' detection performance of lung nodules on chest radiographs. (2) Independently combining the interpretations of the radiologist and the CAD system improved detection of lung nodules on chest radiographs.Chest radiography can be considered the workhorse of the radiology department. It is being used for the detection and diagnosis of multiple diseases, including lung nodules, which may represent early lung cancer. Since a chest radiograph is a two-dimensional image, overprojection of multiple anatomical structures is inevitable. This so-called anatomical noise substantially impedes interpretation of chest radiographs. Multiple studies have shown that a substantial amount of lung cancers are missed, ranging from 19% to 26%,^1,2 and even up to 90%.^3–5 More recent studies have shown that the problem of missing lung nodules is still present with the most modern digital radiographic technology.^6,7 Abnormalities can be missed as a result of inadequate search, perception errors or interpretation errors. It has been stated that interpretation by the radiologist is the most important factor for missing lung cancer on chest radiographs.^8,9To reduce miss rates, computer-aided detection (CAD) systems have been developed. Thus far, all studies dealing with chest radiography apply CAD as a second reader to the radiologist, meaning that the CAD marks are made available only after the radiologist has made a primary review. It remains the reader''s discretion to accept or disregard the CAD marks. Results of these studies were contradictory: some found an increased accuracy for the detection of lung nodules,^10–12 whereas other studies reported an increase in sensitivity only at the expense of loss in specificity.^13–16 One problem ameliorating the potential of CAD is the radiologist''s limited ability to reliably discriminate between true-positive (TP) and false-positive (FP) CAD marks.We therefore decided to explore alternative methods of using CAD information. First, we used CAD interactively. In the interactive mode, CAD marks remained hidden unless the radiologist queried a position in the image by clicking with the mouse on that location. If a CAD mark was present in this location, it was shown to the radiologist together with a score of suspicion. Such an interactive CAD system had been shown to be beneficial in chest radiography in an observer study that only used non-radiologists.¹⁷ Second, we computed a mathematical combination of reader and CAD scores. With this method, observers did not need to view the CAD marks at all during their reading of the images, but a mathematical combination of the reader and the CAD scores was computed afterwards. Both methods have been reported to outperform the use of CAD as a second reader for lesion detection in mammograms.^18–20The purpose of this observer study was to test the impact of these two alternative methods of using CAD information on nodule detection on chest radiographs. To optimize baseline performance without CAD, digitally bone-suppressed images (BSIs) were added to the original chest radiographs. BSIs have been shown to improve accuracy for the detection of focal lesions on chest radiographs;^21–24 a further increase in detection performance beyond that of BSIs by adding CAD has also been documented.²⁵     

Migraine without aura: genome-wide association analysis identifies several novel susceptibility

We discuss the comments on our article “Sleep quality, arousal and pain thresholds in migraineurs. A blinded controlled polysomnographic study” published in JHP 2013 Feb 14;14(1):12. We hypothesize that migraineurs need more sleep than healthy controls and more sleep than they manage to achieve. Some migraineurs probably have a decreased ability to process incoming stimuli. Increased spontaneous pain may follow either sleep restriction or sleep disturbance. A comparison of migraineurs with attack onset related to sleep, migraineurs with attack onset not related to sleep and controls will be reported in another paper.