Risk for stroke and myocardial infarction with abiraterone versus enzalutamide in metastatic prostate cancer patients.

BACKGROUND: Abiraterone and enzalutamide use is associated with significant cardiovascular (CV) morbidity in clinical trials, but the magnitude and clinical relevance of this association in real-world prostate cancer (PC) population remain unknown. MATERIALS AND METHODS: We retrospectively reviewed the MarketScan claims databases (1 January 2013 to 30 September 2018) to identify adults with diagnosis of metastatic PC who received treatment with androgen deprivation therapy (ADT) and novel antiandrogen agents (abiraterone or enzalutamide). The primary CV outcome measure was composite outcome of acute myocardial infarction (MI) or stroke. Secondary outcomes were individual risks of MI or stroke. We used an intention-to-treat approach to analyze the CV outcomes associated with drug exposure among patients with metastatic PC. Cox regression model was used to estimate the independent association of two drugs with CV risk after adjustment for age, baseline atrial fibrillation, and Charlson Comorbidity Index. RESULTS: A total of 6294 patients with metastatic PC who were treated with ADT and either abiraterone or enzalutamide were included in the final analysis. Of these, 4017 (63.8%) patients used abiraterone and 2217 (32.2%) patients used enzalutamide. During the study period, 255 (6.3%) primary endpoint events occurred, resulting in an incidence rate of 4.3 per 100 patient-years. In multivariable analysis, abiraterone use was associated with a 31% increased risk of MI or stroke compared to enzalutamide (hazard ratio 1.31; 95% confidence interval 1.05-1.63; P = 0.01). The incidence rate was similar in patients who switched initial therapy from abiraterone to enzalutamide or vice versa (5.0 versus 5.6 per 100 patient-years, respectively). CONCLUSIONS: To our knowledge, this is the first real-world assessment of MI and stroke among metastatic PC patients receiving novel anti-androgens. Our findings of increased MI and stroke risk with abiraterone compared with enzalutamide are consistent with data from clinical trials and suggest that enzalutamide may be preferable for prostate cancer patients at high CV risk.

Androgen receptor mutations in patients with castration-resistant prostate cancer treated with apalutamide.

BACKGROUND: Mutations in the androgen receptor (AR) ligand-binding domain (LBD), such as F877L and T878A, have been associated with resistance to next-generation AR-directed therapies. ARN-509-001 was a phase I/II study that evaluated apalutamide activity in castration-resistant prostate cancer (CRPC). Here, we evaluated the type and frequency of 11 relevant AR-LBD mutations in apalutamide-treated CRPC patients. PATIENTS AND METHODS: Blood samples from men with nonmetastatic CRPC (nmCRPC) and metastatic CRPC (mCRPC) pre- or post-abiraterone acetate and prednisone (AAP) treatment (≥6 months' exposure) were evaluated at baseline and disease progression in trial ARN-509-001. Mutations were detected in circulating tumor DNA using a digital polymerase chain reaction-based method known as BEAMing (beads, emulsification, amplification and magnetics) (Sysmex Inostics' GmbH). RESULTS: Of the 97 total patients, 51 had nmCRPC, 25 had AAP-naïve mCRPC, and 21 had post-AAP mCRPC. Ninety-three were assessable for the mutation analysis at baseline and 82 of the 93 at progression. The overall frequency of detected AR mutations at baseline was 7/93 (7.5%) and at progression was 6/82 (7.3%). Three of the 82 (3.7%) mCRPC patients (2 AAP-naïve and 1 post-AAP) acquired AR F877L during apalutamide treatment. At baseline, 3 of the 93 (3.2%) post-AAP patients had detectable AR T878A, which was lost after apalutamide treatment in 1 patient who continued apalutamide treatment for 12 months. CONCLUSIONS: The overall frequency of detected mutations at baseline (7.5%) and progression (7.3%) using the sensitive BEAMing assay was low, suggesting that, based on this assay, AR-LBD mutations such as F877L and T878A are not common contributors to de novo or acquired resistance to apalutamide. CLINICALTRIALS.GOV IDENTIFIER: NCT01171898.

Phase I/II trial of cabazitaxel plus abiraterone in patients with metastatic castration-resistant prostate cancer (mCRPC) progressing after docetaxel and abiraterone.

Background: Abiraterone and cabazitaxel improve survival in patients with metastatic castration-resistant prostate cancer (mCRPC). We conducted an open-label phase I/II trial of cabazitaxel plus abiraterone to assess the antitumor activity and tolerability in patients with progressive mCRPC after docetaxel (phase I), and after docetaxel and abiraterone (phase II) (NCT01511536). Patients and methods: The primary objectives were to determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of cabazitaxel plus abiraterone (phase I), and the prostate-specific antigen (PSA) response defined as a ≥ 50% decrease confirmed ≥3 weeks later with this combination (phase II). Results: Ten patients were enrolled in the phase I component; nine were evaluable. No DLTs were identified. The MTD was established as the approved doses for both drugs (cabazitaxel 25 mg/m2 every 3 weeks and abiraterone 1000 mg once daily). Daily abiraterone treatment did not impact on cabazitaxel clearance. Twenty-seven patients received cabazitaxel plus abiraterone plus prednisone (5 mg twice daily) in phase II. The median number of cycles administered (cabazitaxel) was seven (range: 1-28). Grade 3-4 treatment-emergent adverse events included asthenia (in 5 patients; 14%), neutropenia (in 5 patients; 14%) and diarrhea (in 3 patients; 8%). Nine patients (24%) required dose reductions of cabazitaxel. Of 26 evaluable patients, 12 achieved a PSA response [46%; 95% confidence interval (CI): 26.6-66.6%]. Median PSA-progression-free survival was 6.9 months (95% CI: 4.1-10.3 months). Of 14 patients with measurable disease at baseline, 3 (21%) achieved a partial response per response evaluation criteria in solid tumors. Conclusions: The combination of cabazitaxel and abiraterone has a manageable safety profile and shows antitumor activity in patients previously treated with docetaxel and abiraterone.

Does Gleason score at initial diagnosis predict efficacy of abiraterone acetate therapy in patients with metastatic castration-resistant prostate cancer? An analysis of abiraterone acetate phase III trials.

BACKGROUND: The usefulness of Gleason score (<8 or ≥8) at initial diagnosis as a predictive marker of response to abiraterone acetate (AA) plus prednisone in patients with metastatic castration-resistant prostate cancer (mCRPC) was explored retrospectively. PATIENTS AND METHODS: Initial diagnosis Gleason score was obtained in 1048 of 1195 (COU-AA-301, post-docetaxel) and 996 of 1088 (COU-AA-302, chemotherapy-naïve) patients treated with AA 1 g plus prednisone 5 mg twice daily by mouth or placebo plus prednisone. Efficacy end points included radiographic progression-free survival (rPFS) and overall survival (OS). Distributions and medians were estimated by Kaplan-Meier method and hazard ratio (HR) and 95% confidence interval (CI) by Cox model. RESULTS: Baseline characteristics were similar across studies and treatment groups. Regardless of Gleason score, AA treatment significantly improved rPFS in post-docetaxel [Gleason score <8: median, 6.4 versus 5.5 months (HR = 0.70; 95% CI 0.56-0.86), P = 0.0009 and Gleason score ≥8: median, 5.6 versus 2.9 months (HR = 0.58; 95% CI 0.48-0.72), P < 0.0001] and chemotherapy-naïve patients [Gleason score <8: median, 16.5 versus 8.2 months (HR = 0.50; 95% CI 0.40-0.62), P < 0.0001 and Gleason score ≥8: median, 13.8 versus 8.2 months (HR = 0.61; 95% CI 0.49-0.76), P < 0.0001]. Clinical benefit of AA treatment was also observed for OS, prostate-specific antigen (PSA) response, objective response and time to PSA progression across studies and Gleason score subgroups. CONCLUSION: OS and rPFS trends demonstrate AA treatment benefit in patients with pre- or post-chemotherapy mCRPC regardless of Gleason score at initial diagnosis. The initial diagnostic Gleason score in patients with mCRPC should not be considered in the decision to treat with AA, as tumour metastases may no longer reflect the histology at the time of diagnosis. CLINICAL TRIALS NUMBER: COU-AA-301 (NCT00638690); COU-AA-302 (NCT00887198).

A prognostic index model for predicting overall survival in patients with metastatic castration-resistant prostate cancer treated with abiraterone acetate after docetaxel.

BACKGROUND: Few prognostic models for overall survival (OS) are available for patients with metastatic castration-resistant prostate cancer (mCRPC) treated with recently approved agents. We developed a prognostic index model using readily available clinical and laboratory factors from a phase III trial of abiraterone acetate (hereafter abiraterone) in combination with prednisone in post-docetaxel mCRPC. PATIENTS AND METHODS: Baseline data were available from 762 patients treated with abiraterone-prednisone. Factors were assessed for association with OS through a univariate Cox model and used in a multivariate Cox model with a stepwise procedure to identify those of significance. Data were validated using an independent, external, population-based cohort. RESULTS: Six risk factors individually associated with poor prognosis were included in the final model: lactate dehydrogenase > upper limit of normal (ULN) [hazard ratio (HR) = 2.31], Eastern Cooperative Oncology Group performance status of 2 (HR = 2.19), presence of liver metastases (HR = 2.00), albumin ≤4 g/dl (HR = 1.54), alkaline phosphatase > ULN (HR = 1.38) and time from start of initial androgen-deprivation therapy to start of treatment ≤36 months (HR = 1.30). Patients were categorized into good (n = 369, 46%), intermediate (n = 321, 40%) and poor (n = 107, 13%) prognosis groups based on the number of risk factors and relative HRs. The C-index was 0.70 ± 0.014. The model was validated by the external dataset (n = 286). CONCLUSION: This analysis identified six factors used to model survival in mCRPC and categorized patients into three distinct risk groups. Prognostic stratification with this model could assist clinical practice decisions for follow-up and monitoring, and may aid in clinical trial design. TRIAL REGISTRATION NUMBERS: NCT00638690.

Inhibition of the androgen receptor by mineralocorticoids at levels physiologically achieved in serum in patients treated with abiraterone acetate.

BACKGROUND: Abiraterone acetate (AA), a highly potent CYP17A1 inhibitor, has demonstrated marked clinical benefit in patients with metastatic castration-resistant prostate cancer (CRPC). Phase I trials of AA without prednisone showed significant elevation of serum mineralocorticoid concentrations. The aim of this study was to elucidate the biological significance of elevated mineralocorticoid levels on androgen receptor (AR) activity in prostate cancer (PC) cells. METHODS: Fluorescence resonance energy transfer (FRET) assay was used to assess the effect of mineralocorticoids on androgen-induced conformational change of the AR. LAPC4, LNCaP and LN-AR cells that were cultured and treated with androgens were exposed to mineralocorticoids at varying concentrations, including levels measured in the serum of AA-treated patients in a phase I trial. AR-dependent transcriptional activity and cell growth were measured in these cell lines to determine the biological impact of mineralocorticoids on PC cells. RESULTS: Corticosterone (CS) and deoxycorticosterone (DOC) inhibited androgen-induced conformational change of the AR in the FRET assay. CS inhibited AR-dependent transcriptional activity and cell growth at concentrations comparable to those measured in the serum of AA-treated patients. DOC inhibited AR transcriptional activity and cell growth at 10-fold greater concentrations than measured in the serum of AA-treated patients. CONCLUSIONS: Mineralocorticoids directly inhibit androgen-induced conformational change of the AR. CS inhibits AR transcriptional activity and PC cell growth at concentrations found in the serum of patients treated with AA. Further investigation of the potential therapeutic implications of mineralocorticoids in AA-treated CRPC patients is warranted.

Androgen dynamics and serum PSA in patients treated with abiraterone acetate.

BACKGROUND: We analyzed the potential of abiraterone acetate (henceforth abiraterone) to reduce androgen levels below lower limits of quantification (LLOQ) and explored the association with changes in PSA decline in metastatic castration-resistant prostate cancer (mCRPC) patients. METHODS: COU-AA-301 is a 2:1 randomized, double-blind, placebo-controlled study comparing abiraterone (1000 mg q.d.) plus low-dose prednisone (5 mg b.i.d.) with placebo plus prednisone in mCRPC patients post docetaxel. Serum testosterone, androstenedione and dehydroepiandrosterone sulfate from baseline to week 12 were measured by novel ultrasensitive two-dimensional liquid chromatography coupled to tandem mass spectrometry assays in a subset of subjects in each arm (abiraterone plus prednisone, n=80; prednisone, n=38). The association between PSA response (< or =50% baseline) and undetectable androgens (week 12 androgen level below LLOQ) was analyzed using logistic regression. RESULTS: A significantly greater reduction in serum androgens was observed with abiraterone plus prednisone versus prednisone (all P < or = 0.0003), reaching undetectable levels for testosterone (47.2% versus 0%, respectively). A positive association was observed between achieving undetectable serum androgens and PSA decline (testosterone: odds ratio=1.54; 95% confidence interval: 0.546-4.347). Reduction of androgens to undetectable levels did not occur in all patients achieving a PSA response, and a PSA response did not occur in all patients achieving undetectable androgen levels. CONCLUSIONS: Abiraterone plus prednisone significantly reduced serum androgens, as measured by ultrasensitive assays and was generally associated with PSA response. However, androgen decline did not uniformly predict PSA decline suggesting ligand-independent or other mechanisms for mCRPC progression.

Development and clinical utility of abiraterone acetate as an androgen synthesis inhibitor.

In April 2011, abiraterone acetate (AA) was approved by the US Food and Drug Administration (FDA) for the treatment of metastatic castration-resistant prostate cancer (CRPC) after chemotherapy. The development of AA is the direct result of our increased understanding of the intricacies of the androgen receptor (AR) pathway and its natural evolution in prostate cancer cells over the course of treatment. In this paper we review the biology of the AR and how it led to the rational design of AA. We also examine the clinical development of AA, its current use, and questions to be addressed for future development.

Single Question in Delirium (SQiD): testing its efficacy against psychiatrist interview, the Confusion Assessment Method and the Memorial Delirium Assessment Scale.

UNLABELLED: In this study we address the research question; How sensitive is a single question in delirium case finding? Of 33 'target' admissions, consent was obtained from 21 patients. The single question: 'Do you think [name of patient] has been more confused lately?' was put to friend or family. Results of the Single Question in Delirium (SQiD) were compared to psychiatrist interview (ΨI) which was the reference standard. The Confusion Assessment Method (CAM) and two other tools were also applied. Compared with ΨI, the SQiD achieved a sensitivity and specificity of 80% (95% CI 28.3-99.49%) and 71% (41.90-91.61%) respectively. The CAM demonstrated a negative predictive value (NPV) of 80% (51.91-95.67%) and the SQiD showed a NPV of 91% (58.72-99.77%). Kappa correlation of SQiD with the ΨI was 0.431 (p = 0.023). The CAM had a kappa value of 0.37 (p = 0.050). A further important finding in our study was that the CAM had only 40% sensitivity in the hands of minimally trained clinical users. CONCLUSION: The SQiD demonstrates potential as a simple clinical tool worthy or further investigation.

Androgen deprivation therapy in locally advanced and metastatic prostate cancer.

Numerous studies have been performed testing the efficacy of early androgen deprivation (AD) in patients with localized and locally advanced prostate cancer. A systematic review of recent publications that report on the use of AD in non-metastatic prostate cancer patients was performed. Recently published mature randomized trials of AD plus local therapy were evaluated plus 2 large datasets on the use of AD for patients with serologic relapse after local therapy. Four mature randomized studies demonstrate an overall survival benefit to the use of AD in conjunction with definitive local therapy (3 with radiation and 1 with surgery). One retrospective analysis suggests that AD administered at early after serologic progression improves overall survival, and one retrospective analysis shows a reduction in metastasis-free survival but has not yet shown an overall survival benefit. In virtually all analyses, patients with high-risk features benefited from early AD when compared to deferred therapy. Consideration of AD is therefore warranted early in the clinical course of high-risk patients.

Angiogenesis inhibitors. New agents in cancer therapy.

Tumours that do not develop a blood supply cannot grow larger than 1 to 2mm3. The growth of a tumour blood supply, called angiogenesis, is a complex process that greatly increases the likelihood of metastatic spread and aggressive tumour behaviour. Molecular processes involved in angiogenesis include stimulation of endothelial growth by tumour cytokine production (vascular endothelial growth factor), degradation of extracellular matrix proteins by metalloproteinases, and migration of endothelial cells mediated by cell membrane adhesion molecules called integrins. These processes are being targeted by several new types of agents broadly classified as angiogenesis inhibitors. Additionally, endogenous angiogenesis inhibitors have been discovered and one of them, endostatin, is currently undergoing clinical trials. The unique targets of these drugs make them distinct from traditional cytotoxic chemotherapeutic agents. Unlike cytotoxic chemotherapy, in which the biological effect of the drug produces the antitumour effect as well as the toxic effect, angiogenesis inhibitors may produce their biological effect independently of the toxic effect. This fact raises important questions among clinical investigators as to what is the most effective way to administer these drugs and monitor their effects. This paper details some of the scientific evidence making angiogenesis an important therapeutic target as well as issues regarding the structure of clinical trials with these new anticancer agents.

Recent improvement in results of coronary bypass surgery in octogenarians.

BACKGROUND: Because of concerns regarding the cost-effectiveness of coronary artery surgery in patients 80 years and older, a review of a large experience is appropriate. METHODS: The records of 404 consecutive patients 80 years of age or older having isolated coronary bypass surgery (CABG) from 1985 through 1996 were reviewed. Patients were divided equally into an early and later group. Hospital mortality, complications including major arrhythmias, wound infections and separations, re-explorations, peri-operative Q-wave myocardial infarctions, major organ dysfunction, stroke, time to extubation, post-operative hospital (LOS) and intensive care unit (ICU) lengths of stay were compared. A logistic regression risk model was used to assess the relative contributions of improved technique versus more favorable patient selection. RESULTS: Comparison of the two groups revealed the following: overall hospital mortality decreased from 12.9% to 5.4% (p = 0.003), more markedly so with elective procedures where hospital mortality decreased from 8.1% to 1.2% (p = 0.04). There were significant decreases in time to extubation (2.8 +/- 9.3 days versus 1.2 +/- 2.8 days; p = 0.02), post-operative intensive care unit stay (4.9 +/- 7.1 days versus 2.9 +/- 3.7 days; p = 0.0004), post-operative complication rate (34.2% versus 22.8%; p = 0.03), and post-operative hospital length of stay (14.2 +/- 14.7 days versus 9.8 +/- 9.8 days; p = 0.0005). Post-operative stroke decreased from 7.4% to 5.9%. Mean estimated risk for the two groups was 8.2 +/- 10.2% versus 8.2 +/- 11.4%. CONCLUSION: Coronary surgery can be performed with acceptable risk in octogenarians. Results have improved over the past few years. This improvement is probably not attributable to patient selection.

Recovery from ischemic acute renal failure: independence from dialysis membrane type.

Exposure to complement-activating cellulosic dialysis membranes has been claimed to adversely affect the course of acute renal failure. To test this hypothesis, male Sprague-Dawley rats were allocated to two groups: in group I, acute renal failure was induced by bilateral renal artery clamping, while group II animals underwent a sham procedure. In each group, the rats were further allocated to undergo hemodialysis with either a Cuprophan, a Hemophan, or a PAN miniDialyzer membrane 3 and 7 days after surgery or no dialysis. The renal function was measured by inulin clearance on the days following dialysis. Temporary occlusion of the renal arteries led to a rapid increase in serum urea and creatinine levels that peaked between 24 and 48 h after surgery and declined slowly thereafter. Peak urea values were similar in the acute renal failure groups. The hemodialysis sessions were well tolerated. Degree and rate of recovery were similar in all acute renal failure groups irrespective of whether they underwent dialysis or not or the type of the dialysis membrane. Complete recovery was observed in all the acute renal failure groups by the end of the observation period. Our findings refute the hypothesis that in ischemic acute renal failure exposure to complement-activating cellulosic dialysis membranes impairs the recovery of renal function.

Intraoperative autotransfusion in vascular surgery.

To determine the impact of intraoperative autotransfusion on vascular surgical care, data related to 304 major vascular surgical operations performed over a 42-month period were retrospectively analyzed. Procedures included abdominal aortic aneurysmectomy (N = 152), aortobilateral femoral bypass (N = 60), thoracoabdominal aortic aneurysmectomy (N = 20), and other vascular procedures (N = 68). Fifty percent of the transfusion requirement was met by autotransfusion for the average patient. The per patient average volumes (liters) autotransfused were as follows: elective abdominal aortic aneurysmectomy, 0.87 L and nonelective, 1.45 L; elective aortobilateral femoral bypass, 0.63 L; elective thoracoabdominal aortic aneurysmectomy, 2.47 L, and nonelective, 2.15 L; and elective other, 0.53 L and nonelective, 1.30 L. Results of immediate postoperative and hospital discharge hemoglobin, hematocrit, and coagulation studies (prothrombin time, partial thromboplastin time, and platelets) did not differ from results of preoperative studies in any group. Neither mortality nor morbidity was related to intraoperative autotransfusion. These data suggest that intraoperative autotransfusion is a safe blood replacement method during major vascular surgical operations.

Recurrent femoral anastomotic aneurysms. A 30-year experience.

Of the 1771 patients who underwent aortofemoral bypass grafting (AFB) during the 30-year period of 1957-1986, 43 noninfected recurrent femoral anastomotic aneurysms (RFAA) developed in 28 patients. Thirty-six RFAAs were treated surgically, with one death and no amputations occurring. Seven small RFAAs (less than 2.0 cm) were treated expectantly without complications. Using univariate and multivariate analyses, clinical characteristics and other factors influencing results in patients with RFAAs were compared to two control groups: patients who had undergone AFB without the development of femoral anastomotic aneurysms (FAAs) and patients who had undergone FAA repairs but without recurrence of FAA. Comparative analyses suggested: 1) local wound complications after initial AFB or FAA repair increased risk of a RFAA (p less than 0.03); 2) development of an FAA within 4.5 years after AFB increased risk of a RFAA (p less than 0.0002); 3) following an FAA repair, risk of a RFAA was almost three times greater for women than for men (p less than 0.05); and 4) patients with arteriosclerotic heart disease (ASHD) were less likely to develop RFAA than those without ASHD (p less than 0.05). Among the 20 additional variables analyzed--including hypertension, smoking, diabetes mellitus, and etiology of primary vascular disease--no statistically significant influence on the development of RFAAs could be detected.

Protection from endotoxemia: a rat model of plasmapheresis and specific adsorption with polymyxin B.

Polymyxin B (PB), a cyclic polypeptide antibiotic, has potent antiendotoxin properties but is associated with significant toxicity when given parenterally. As an alternative, PB was immobilized on a solid phase (Sepharose 4B; Pharmacia, Uppsala, Sweden), and a system of plasmapheresis was developed in the conscious rat, with specific on-line plasma adsorption of endotoxin by a PB-Sepharose column. PB-Sepharose columns removed 94% of a challenge dose of 5 micrograms of endotoxin in vitro. Rats were pretreated with lead acetate so that they were sensitized to endotoxin and then given 10 micrograms of endotoxin/kg intraarterially. After 15 min plasmapheresis was begun and continued for 90 min. Animals whose plasma was perfused over PB-Sepharose were protected from endotoxin-induced leukopenia (P less than .01), thrombocytopenia (P less than .001), and death (four of four survivors compared with none of four controls). Thus plasmapheresis with on-line removal of endotoxin is a safe and highly effective means of protecting animals from the effects of endotoxemia.

The effect of 5-fluorouracil on DNA synthesis in the rat liver undergoing compensatory hyperplasia after partial hepatectomy.

An investigation has been made into the effects of 5-fluorouracil (5FU) on DNA synthesis after partial hepatectomy. Animals underwent in vivo isolated liver perfusion with 5-fluorouracil followed by partial hepatectomy or Sham hepatectomy. Controls consisted of animals whose liver was perfused with 0.9% saline. Liver weight and DNA synthesis were recorded at various times following 5-fluorouracil perfusion and partial hepatectomy and control procedures. The results have shown that perfusion with large concentrations of the cytotoxic agent (5 FU) can be performed without apparent serious side effects on liver weight and with only minimal delay in liver cell proliferation.

The outcome of patients with pleural effusion of indeterminate cause at thoracotomy.

In 51 patients, the cause for pleural effusion remained indeterminate immediately after thoracotomy. Thirty-one (60.8%) had no recurrence of the effusion, and no cause became apparent during a follow-up period of from 1 1/2 to 15 years. Two patients (3.9%) died relatively soon after thoracotomy, but death was not clearly related to the pleural effusion. In 18 patients (35.3%), the cause of the effusion became apparent from 12 days to 6 years after thoracotomy. In 13 of these 18 patients, malignancy (6 patients with lymphoma, 4 with malignant pleural mesothelioma, and 3 with other malignancy) was ultimately diagnosed. In 3 of the 18 patients, the ultimate diagnosis was a collagen-vascular disease, and 1 patient each had the yellow-nail syndrome and mitral stenosis.