Comparison of daily anti-hypertensive effects of amlodipine and nifedipine coat-core using ambulatory blood pressure monitoring - utility of "hypobaric curve" and "hypobaric area".

When selecting anti-hypertensives, most physicians do not consider daily blood pressure (BP) variation. To evaluate the effectiveness of anti-hypertensives on the temporal profile of BP, we proposed three new parameters obtained by ambulatory BP monitoring and evaluated these parameters by comparing 5 mg of amlodipine and 40 mg of nifedipine coat-core. Hypobaric values were determined by subtracting BP data collected before administration of the drug from those collected after drug treatment at the corresponding time of day. The hypobaric curve was drawn by plotting the hypobaric values in chronological order, with the time at which the drug was taken set as the starting point. The hypobaric area was the area encircled between the 0 mmHg level line and the hypobaric curve. For amlodipine, the hypobaric areas of systolic blood pressure (SBP) and diastolic blood pressure (DBP) were -19,110 mmHg/min and -10,695 mmHg/min, respectively. Systolic BP decreased -13.3 mmHg, and DBP BP -7.4 mmHg as daily averages. For nifedipine coat-core, the hypobaric areas of SBP and DBP were -32,235 mmHg/min and -18,150 mmHg/min, respectively. Systolic BP decreased -22.3 mmHg and DBP -12.6 mmHg as daily averages. From the hypobaric curves, the trough-to-peak ratios of amlodipine and nifedipine coat-core were measured as 0.67 and 0.60, respectively. The total anti-hypertensive power of nifedipine coat-core, measured by the hypobaric area, was 1.69 times more potent than that of amlodipine. These parameters seem to be useful for evaluating the daily temporal profile of the BP-lowering effects of anti-hypertensive drugs.

Giant cell lung carcinoma in a man with acquired immunodeficiency syndrome.

A 66-year-old man, who was discovered to have human immunodeficiency virus (HIV) infection 22 months previously and was treated with highly active antiretroviral (HAART) therapy, developed giant cell carcinoma of the lung. In English literature, this is the first case of such cell type of lung cancer during HAART therapy. Since giant cell carcinoma of the lung occurs mainly in elderly men who smoke heavily, there may not be a possibility that the HIV or HAART was causative in our patient.

Lung cancer patients with previous or simultaneous the upper aerodigestive cancers.

There have been few reports on clinical characteristics of lung cancer patients with previous or simultaneous upper aerodigestive cancers. To evaluate them, we conducted a retrospective study. The medical records of all lung cancer patients at our division from January 1984 through July 2008 were reviewed. Twenty-one (1.7%) of 1242 patients had previous or simultaneous upper aerodigestive cancers. Twenty patients were smokers. For non-small cell lung cancer (NSCLC), 6 patients underwent surgical resection and 3 were treated with chemotherapy. Three small cell lung cancer (SCLC) patients had chemotherapy. None of the severe complication related to the comorbidities were observed. The median survival for NSCLC and SCLC patients was 15 and 6 months, respectively. For patients with upper aerodigestive cancers, smoking cessation, a chest radiograph or computed tomography scan at least yearly and swift evaluation of signs or symptoms that are suggestive of lung cancer should be recommended.

A re-evaluation of squamous cell carcinoma antigen (SCC) as a serum marker for non-small cell lung cancer.

Squamous cell carcinoma antigen (SCC) is still a widely used tumor marker for monitoring non-small cell lung cancer (NSCLC), although recent reports discourage its routine use because of low sensitivity. This is a study evaluating the efficacy of SCC and CYFRA21-1 in diagnosing NSCLC. A chart review was performed in a university hospital in Japan, covering a period of 10 years, up to October 2004. During the study period, 142 (35.5%) among 400 NSCLC patients diagnosed, received serum assays of both SCC and CYFRA21-1. Elevated SCC and CYFRA21-1 levels were found in 29.6% and 59.2% of patients, respectively. SCC sensitivity was only 13.0% but CYFRA21-1 sensitivity rose to 73.9% in metastatic patients. The adjunct of SCC increased the CYFRA21-1 sensitivity by 6.3% in the overall population and by only 2.2% for patients with metastases. SCC determination should be considered an inefficient method as a potential diagnosing tool for NSCLC patients, and it provides no additional value when used in combination with CYFRA21-1.

Lung cancer patients with previous or simultaneous urologic cancers.

STUDY OBJECTIVES: There have been few reports on clinical characteristics of lung cancer patients with previous or simultaneous urologic cancers. Additionally, it was scarcely reported whether these patients could tolerate standard therapy. To evaluate them, we conducted a retrospective study. METHODS: The records of patients with lung cancer who had previously or simultaneously urological cancers seen in our division between January 1985 and August 2007 were reviewed. RESULTS: During the study period, 1,105 patients with lung cancer were seen at our division. Thirteen (1.2%) had previous or simultaneous urological cancers (11 males). Eleven patients were smokers. The diagnosis of urological cancers preceded the diagnosis of lung cancer in all but three patients, for whom the diagnosis of urologic cancers was made during the workup of primary lung cancer. Histologically, the lung cancers included six squamous cell carcinomas, four adenocarcinomas, and three small cell lung cancers. Four underwent surgical resection. Six were treated with platinum-containing chemotherapy, but none of them developed severe renal toxicity. The median survival following the diagnosis of lung carcinoma for NSCLC patients was 18 months, and for SCLC it was 24 months. The cause of death in the 12 patients who died in the study period was directly related to lung cancer, and recurrence of urological cancers was observed in none of the patients. CONCLUSIONS: For patients with urological cancers, smoking cessation, a chest radiograph or CT scan at least yearly and swift evaluation of signs or symptoms that are suggestive of lung cancer should be recommended.

Overexpression of GATA-3 protects against the development of hypersensitivity pneumonitis.

RATIONALE: Hypersensitivity pneumonitis (HP) is mediated by a Th1 immune response. Transcription factor GATA binding protein-3 (GATA-3) is believed to be a key regulator of Th2 differentiation and thus might play regulatory roles in the pathogenesis of hypersensitivity pneumonitis (HP). OBJECTIVES: We examined the effect of GATA-3 overexpression on the development of HP in mice. METHODS: Wild-type C57BL/6 mice and GATA-3-overexpressing mice of the same background were used in this study. HP was induced by repeated exposure to Saccharopolyspora rectivirgula, the causative antigen of farmer's lung. MEASUREMENTS AND MAIN RESULTS: Antigen exposure resulted in a marked inflammatory response with enhanced pulmonary expression of T-bet and the Th1 cytokine interferon (IFN)-gamma in wild-type mice. The degree of pulmonary inflammation was much less severe in GATA-3-overexpressing mice. The induction of T-bet and IFN-gamma genes was suppressed, but a significant induction of Th2 cytokines, including IL-5 and IL-13, was observed in the lungs of GATA-3-overexpressing mice after antigen exposure. Supplementation with recombinant IFN-gamma enhanced lung inflammatory responses in GATA-3-overexpressing mice to the level of wild-type mice. Because antigen-induced IFN-gamma production predominantly occurred in CD4+ T cells, nude mice were transferred with CD4+ T cells from either wild-type or GATA-3-overexpressing mice and subsequently exposed to antigen. Lung inflammatory responses were significantly lower in nude mice transferred with CD4+ T cells from GATA-3-overexpressing mice than in those with wild-type CD4+ T cells, with a reduction of lung IFN-gamma level. CONCLUSIONS: These results indicate that overexpression of GATA-3 attenuates the development of HP by correcting the Th1-polarizing condition.

Prognostic value of tumor disappearance rate on computed tomography in advanced-stage lung adenocarcinoma.

BACKGROUND: The proportion of tumor disappearance rate (TDR) on conventional computed tomography (CT) is associated with less aggressive biology, and patients with small peripheral adenocarcinoma accompanied by the TDR component showed better prognosis. These findings led us to the idea that even advanced-stage adenocarcinomas with a higher TDR in the primary lesion on CT might suggest slowly progressing cancer. This study was designed to determine the value of the TDR area in the primary site of advanced-stage lung adenocarcinoma with CT and correlate the CT findings with clinical outcome. PATIENTS AND METHODS: In 103 patients with stage IIIB and IV lung adenocarcinoma, CT appearances and clinical data were reviewed retrospectively. Three methods were used in the evaluation of the TDR area: method I, consolidation on mediastinal windows/mass on lung windows > 75% or not; method II, maximum diameter on mediastinal windows/maximum diameter on lung windows (diameter ratio) > 75% or not; and method III, TDR area on lung windows > 25% or not. RESULTS: In univariate analysis, patients with lung adenocarcinoma with TDR have a more favorable prognosis than those without TDR in all 3 methods (method I, P = 0.001; method II, P = 0.024; method III, P = 0.014; log-rank test). In multivariate analysis, a favorable prognosis in patients with adenocarcinoma with TDR was shown in method I (P = 0.015) and method III (P = 0.006). CONCLUSION: As shown in patients with small peripheral lung adenocarcinoma, those with TDR on CT tended to have a good prognosis in contrast to those without TDR, even in patients with advanced-stage lung adenocarcinoma. Prospective study to confirm these results will be required.

Long-term survivors after chemotherapy in advanced non-small cell lung cancer.

BACKGROUND: Chemotherapy is considered to have a marginal impact on survival. The purpose of this study was to evaluate the rate of long-term survival in patients treated with chemotherapy for advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: The case records of 109 patients with NSCLC treated with chemotherapy from March 1998 to March 2007 were reviewed. RESULTS: Fourteen (12.8%) and seven (6.4%) patients survived for more than two or three years, respectively. All of the 14 patients had performance status (PS) 0 or 1, and they were given a platinum-containing chemotherapy as initial treatment. By means of univariate analysis, good PS and gefitinib therapy were proved to be good prognostic factors. With Cox's model analysis, these two variables were confirmed as significant determinants of survival. CONCLUSION: A small but definite proportion of patients with locally-advanced and metastatic NSCLC might potentially survive for more than 2 years with appropriate chemotherapy.

A long-term survivor with pulmonary large-cell neuroendocrine carcinoma.

Pulmonary large-cell neuroendocrine carcinoma (LCNEC) has been characterized by highly aggressive behavior, with early spread to both regional lymph nodes and distant sites and a rapidly fatal course. In fact, no reports have described an advanced pulmonary LCNEC patient who has had long-term survival. A patient with large-sized pulmonary LCNEC, who is free of disease 11 years after surgery and postoperative chemotherapy, was reported.

Late fatal recurrence in gefitinib-treated NSCLC patients.

Gefitinib is a selective epidermal growth factor receptor tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. Long-term survival in patients with metastatic non-small-cell lung carcinoma (NSCLC) treated with gefitinib has recently been reported. We showed herein two cases of fatal rapid recurrence after a long-term disease control by gefitinib. The biology of fatal aggressive recurrence of gefitinib-treated NSCLC is not well characterized. Regardless of the mechanism, however, physicians treating patients with gefitinib should be alert to the possibility of fatal rapid recurrence after a long-term disease control by this drug.

Psychotropic drugs for terminally ill patients with respiratory disease.

Utilization of psychotropic drugs including hypnotics, sedatives, and parenteral morphine for terminally ill patients with respiratory disease has not been reported precisely. To better understand these drugs for dying patients with respiratory disease, we focused on the last month of life of them. A chart review, which was focused on symptoms and managements, in the last month of life of 337 patients who died of respiratory disease between April 2000 and March 2005 were performed. Hypnotics were prescribed in 35.8% and 23.2% of patients with malignant and non-malignant disease, respectively. Sedatives such as haloperidol and midazolam were utilized in 34.4% of patients with malignant disease, and 30.4% of those with non-malignant disease. Sixty-seven percent of patients with malignant and 22.4% of those with non-malignant disease had parenteral morphine. In patients with malignant disease, three of the main reasons for administration of morphine were pain, dyspnea, or terminal restlessness. In all of the patients with non-malignant disease, however, parenteral morphine was prescribed for the treatment of dyspnea. Our results showed that psychotropic drugs and parenteral morphine are required in some of terminally ill patients with respiratory disease. Although careful individualization of medication is appropriate, guideline for the prescribing psychotropic drugs for these patients will be required.

Co-morbid illnesses in patients with respiratory disease.

With the rising age, more patients will be diagnosed with one or more other serious illnesses. This study was undertaken to evaluate the frequency of co-morbid illnesses in patients with respiratory diseases, and to compare the frequency between the elderly and the younger patients. We performed chart review of 2764 patients with respiratory disease who admitted in three hospitals in Japan between January 1990 and March 2005. Co-morbid illnesses were observed in 69.5% of 2764 patients with respiratory disease. In 1150 patients 70 years or older, 83.9% of them had co-morbid illnesses. The prevalence of co-morbid illnesses in patients with respiratory disease clearly rose with increasing age (p= 0.0001), the largest increase occurring after the age of 50. Charlson index in patients with respiratory disease clearly rose with increasing age (p= 0.0001). In both elderly (>or= 70 years) or younger (< 70 years) groups of patients, co-morbid illnesses did not influence on the choice of diagnostic procedure. Although the presence of co-morbid illnesses in our patients with non-malignant respiratory disease did not influence on the choice of treatment, however, the presence of co-morbid illnesses in elderly patients with malignant respiratory disease apparently discouraged the choice of standard therapy. Clinical research should address appropriate therapies not only for the elderly patients without co-morbid illness but also for those with co-morbid illnesses. Being aware of the co-morbid illnesses will allow improved management and the planning of appropriate support to a wide range of elderly patients with respiratory disease with important and peculiar needs for care.

Prospective study of fever and pneumonia after flexible fiberoptic bronchoscopy in older people.

OBJECTIVES: To assess the frequency of fever and pneumonia after fiberoptic bronchoscopy (FOB) in older people and to evaluate increased risk for these two adverse events with increasing age. DESIGN: Prospective study. SETTING: University hospital system. PARTICIPANTS: Three hundred fifty-eight patients, with 165 (46.1%) patients aged 70 and older, undergoing bronchoscopy. MEASUREMENTS: Indications, abnormal bronchoscopic findings, sampling procedures, final diagnosis, and fever and pneumonia after bronchoscopy. RESULTS: With regard to the indication for bronchoscopy and abnormal bronchoscopic findings, there was no statistical difference between elderly patients (> or =70) and younger patients (<70). Procedures such as forceps biopsy, brushing, and curetting were not performed more often in elderly patients, although final diagnosis of lung cancer was significantly more common in the elderly group (P=.002). The overall incidence of fever after FOB was 6.7%, and that of pneumonia after FOB was 5.6%. The patients aged 70 and older had an incidence of fever after FOB of 3.6% and an incidence of pneumonia of 4.2%, which were not higher than those in patients younger than 70. CONCLUSION: Increasing age is not associated with increasing fever and pneumonia after FOB, and chronological age should not be considered a limiting factor in the decision of whether to perform FOB when it is clinically indicated.

T cell receptor BV gene repertoire of lymphocytes in bronchoalveolar lavage fluid of polymyositis/dermatomyositis patients with interstitial pneumonitis.

We analyzed the T cell receptor (TCR) repertoire of bronchoalveolar lavage fluid (BALF) lymphocytes from polymyositis (PM) and dermatomyositis (DM) patients with interstitial pneumonitis (IP) to elucidate the pathogenic mechanisms of IP in these disorders. Samples from 2 PM patients, 1 DM patient and 3 healthy controls were used. RNA was isolated from BALF, cDNAs were synthesized, and family PCR and Southern blot analysis were performed by primers specific for TCR BV1-25 and TCR BC to determine TCR repertoire. We examined single-strand conformation polymorphism (SSCP) to evaluate T cell clonality. The CDR3 region of TCR BV genes in BALF T cells were determined by DNA sequencer. Our examination showed that TCR repertoire of T cells in BALF was heterogeneous both in patients with PM/DM and control subjects. SSCP analysis demonstrated an increased number of accumulated T cell clones in BALF of three PM/DM patients, but not in the healthy subjects and the junctional sequence analysis showed the presence of conserved amino acid motifs (RGS, GLA, LQG, SGG, DRG, GTS, TSGR, GGS, GQA, GAG, GTG) in the TCR-CDR3 region of BALF lymphocytes from PM/DM patients, which were not detected in the control. Our findings suggest that T cells in BALF may recognize the restricted antigen and accumulate via antigen-driven stimulation, suggesting that T cells may play a crucial role in the development of IP in patients with PM/DM.

Simultaneous measurements of KL-6 and SP-D in patients undergoing thoracic radiotherapy.

PURPOSE: Radiation pneumonitis (RP) is a serious complication in patients undergoing thoracic radiotherapy (TRT). Serum KL-6 and SP-D have been shown to increase in several kinds of interstitial pneumonia. To evaluate their clinical usefulness in detecting RP, we serially measured them in patients receiving TRT. MATERIALS AND METHODS: Thirty-nine patients, who received TRT for lung cancer between July 1999 and April 2004, were prospectively studied. Serum levels of KL-6 and SP-D were measured using enzyme-linked immunosorbent assays. Patients were followed up until August 2004 or their deaths. RESULTS: During the period, RP occurred in 19 patients. In five patients with diffuse RP extended outside the radiation field, serum KL-6 levels increased, reaching more than 1,000 U/mL. Serum KL-6 levels at 40 Gy in patients who developed RP were higher than those without it (p = 0.0363, Mann-Whitney U test). In addition, serum KL-6 levels at 40 Gy in patients who developed RP were higher than those of pretreatment (p = 0.0126, Wilcoxon signed rank test). On the other hand, there were no statistical differences between sp-d at 40 Gy and those before TRT (P = 0.1165). CONCLUSIONS: Increased KL-6 at 40 Gy compared with those before treatment in patients undergoing TRT may be of clinical significance. KL-6 proved to be a useful indicator for estimating RP, while usefulness of SP-D was not confirmed in this study.

Cytokeratin 19 fragment in patients with nonmalignant respiratory diseases.

STUDY OBJECTIVE: Cytokeratin 19 fragment (CYFRA) is a specific tumor marker in patients with lung cancer; however, it has been reported that serum CYFRA levels are elevated in some patients with nonmalignant respiratory diseases such as interstitial pulmonary fibrosis (IPF) and collagen disease-associated pulmonary fibrosis (CDPF). To investigate the serum CYFRA levels in nonmalignant respiratory diseases in detail, we studied 413 patients with respiratory diseases. DESIGN: Retrospective study. SETTING: University hospital. PATIENTS: Four hundred thirteen patients with nonmalignant respiratory diseases and lung cancer. MEASUREMENTS AND RESULTS: Serum CYFRA levels were measured with a commercially available enzyme immunoassay kit. Immunohistochemical study was performed using monoclonal antibody Ks 19.1 (Rosch Diagnosica; Bern, Switzerland) on surgically resected or autopsied lung specimens. Gel electrophoresis and immunoblotting was performed with serum samples. In 149 patients with nonmalignant diseases except IPF and CDPF, the ratio of patients with > 3.5 ng/mL of serum CYFRA was 13.4%. In 13 of 30 patients (43.3%) with IPF and CDPF, the serum CYFRA levels were abnormally elevated. The 95th percentile serum CYFRA level of the patients with nonmalignant respiratory diseases was 6.2 ng/mL, and none of them had CYFRA levels > 20.3 ng/mL. Survival in patients with IPF and CDPF with elevated serum CYFRA levels were significantly lower than in those with normal range (p = 0.0335). Western blotting using serum from nonmalignant lung diseases and patients with lung cancer showed no apparent difference between them. An immunohistochemical study indicated CYFRA was selectively expressed in the pulmonary epithelial cells that covered the remodeling alveolar septi in nonmalignant respiratory disease. CONCLUSION: Serum CYFRA was elevated in some nonmalignant respiratory diseases, especially in IPF and CDPF. The value of serum CYFRA would reflect the severity of lung injury in nonmalignant respiratory diseases and might be related to the prognosis in patients with IPF and CDPF.

In vivo advantage of combined administration with CPT-11 and 5-fluorouracil in rats.

In vivo effect of a bolus combination with 5-fluorouracil (5-FU) and CPT-11 was studied against experimental rat lung cancer, SLC cells. 5-FU and CPT-11, when administrated individually, showed dose-dependent inhibition against the tumor (ID50, 7.0 mg/kg/day and 16.0 mg/kg/day, respectively). 5-FU synergistically enhanced the sensitivity of the tumor cells to CPT-11 and permitted the administration of approximately a one-third lower dose of CPT-11 to obtain the same inhibition against the tumor cell growth. The ID50 of CPT-11 alone (16.0 mg/kg/day) was reduced to 4.8 mg/kg/day when combined with 5-FU at 2.5 mg/kg. There were no deaths caused by toxicity in the combination group, and for lower doses (less than 4 mg/kg/day) of CPT-11 combined with 2.5 mg/kg/day of 5-FU, all rats showed less than 10% body weight loss at the end of the experiments. When the tumor weights were evaluated by using isoeffect plot analysis, the data points resulting from the combination showed a synergistic interaction between these agents. There was no significant increase of toxicity as assessed by the body weight. The results might support for the use of the combination of 5-FU and CPT-11 in cancer chemotherapy.

Outcome of patients with lung cancer detected incidentally.

Lung cancers in the early stages are sometimes detected incidentally. The aim of this study is to evaluate the outcome of patients with lung cancer detected incidentally and to compare to those in whom the malignancy was detected by symptoms. Untreated patients with lung cancer, who were admitted to our division over a 28-year period up to 2003, were analyzed with reference to their reasons for detection of the cancer. During the period, 1168 patients were diagnosed, and 173 (14.8%) of them were detected incidentally. As lung cancers detected incidentally were more often at operable stage (stage IA-IIIA) (p=0.0001), surgical treatment was chosen more frequently in the incidentally diagnosed group (p=0.0001). The outcome with lung cancer patients detected incidentally was more favorable than that of the patients detected by the symptoms (multivariate analysis, p=0.0001). The incidental detection of lung cancer contributes to improvement of the outcome. This study demonstrated a careful review of chest radiography obtained at routine or preoperative examination is important especially for the high-risk patients such as elderly and those with smoking history.

Radiotherapy for elderly non-small cell lung cancer patients.

Elderly patients with lung cancer tend to have significant coexisting diseases and less aggressive treatment is often required. To investigate the clinicopathological features of non-small cell lung cancer (NSCLC) in elderly patients who were treated with radiotherapy, we reviewed the medical records at our division. Among the 189 patients 70 years or older between 1992 and 2001, 28 (14.8%) patients were treated with radiotherapy (elderly group). In the elderly group, there was a medical history of chronic obstructive pulmonary disease (COPD) (57.1%), cardiovascular disease (32.1%), diabetes mellitus (18.5%), malignant disease (18.5%), or cerebrovascular disease (10.7%). Moreover, in the elderly group, 17 (60.7%) patients had two or three coexisting diseases. There was statistical difference between the elderly group and the younger group (less than 70 years patients) with regard to COPD (p<0.001). Also there was statistical difference between the elderly group and the younger group with regard to number of coexisting diseases (p=0.002). In the elderly group, forced expiratory volume in one second (FEV1), forced expiratory volume (FVC), FEV1/FVC and diffusing capacity of the lung for carbon monoxide (DLCO) were statistically significant impaired to compare with those in the younger group (p<0.001, p=0.030, p<0.001 and p=0.024, respectively). In the elderly group, 10.7% of patients had concurrent chemoradiotherapy, however, 38.5% of patients of the younger group received concurrent chemoradiotherapy. There was a statistical difference between the two groups (p=0.026). Adequate palliative care to provide prolonged quality survival is an appropriate primary goal of therapy for lung cancer in the elderly and radiotherapy is thought be one of the less invasive treatments.

Time from finding abnormality on mass-screening to final diagnosis of lung cancer.

Mass-screening for lung cancer is rather a unique system in Japan. This study illustrates time from finding abnormality on mass-screening to final diagnosis of lung cancer. Among the 517 patients with lung cancer who were admitted to our hospital over a 10-year period up to December 2001, 83 (16.1%) were detected by mass-screening. We reviewed medical records of the 83 patients and determined the intervals from the mass-screening to the pathological diagnosis with clinical staging. Time from the mass-screening to the date of hospital visit was <2 months in 62 (74.7%) cases. Five (6.0%) patients visited hospital more than 6 months after the mass-screening. With respect to the interval, there was no statistical difference in gender (p=0.0680) and age (p=0.1532). Among 60 patients who were referred from outside, on average, patients visited our hospital 0.5 month after they first sought medical attention at nearby clinic, and at our hospital 0.5 month was required to make a pathological diagnosis of lung cancer with TNM staging. There was a statistical difference in survival between the patients who were diagnosed <4 months and the patients who were diagnosed >4 months from the screening (p=0.0487). The interval in most cases was acceptable. However, further improvements are still needed to minimize the delay and to maximize the benefits of early cancer detection.