Variability of serum CYFRA 21 - 1 and its susceptibility to clinical characteristics in individuals without cancer: a 4-year retrospective analysis.

BACKGROUND: CYFRA 21 - 1 is a useful marker for diagnosing and monitoring lung cancer. However, its stability remains unclear. Moreover, while its applicability to screening is now being investigated, CYFRA 21 - 1 levels in individuals without cancer, who are targets for cancer screening, have not yet been the focus of research. Therefore, the present study investigated variability in and the factors increasing serum CYFRA 21 - 1 levels. METHODS: This retrospective study recruited 951 individuals undergoing annual medical examinations for six years. We used data obtained in the first four years. Variability in serum CYFRA 21 - 1 levels over a period of four years were investigated. CYFRA 21 - 1 was categorized as normal (≤ 3.5 ng/ml) or elevated (> 3.5 ng/ml). The rate of an elevated level in one visit and the transition from an elevated to normal level between visits were visualized. A multiple logistic regression model was used to study the relationships between the frequency of elevated CYFRA 21 - 1 levels and clinical characteristics, such as age, sex, body mass index, weight changes, and the smoking status. RESULTS: Approximately 5% of subjects had elevated CYFRA 21 - 1 levels once in five tests over four years, while 15% had elevated CYFRA 21 - 1 levels once or more. Among subjects with elevated CYFRA 21 - 1 levels in one blood test, between 63 and 72% had normal levels in the next test. The median CYFRA 21 - 1 level in subjects with elevations in one blood test significantly decreased in the next test at all four time points. The frequency of elevated CYFRA 21 - 1 levels was associated with an older age [odds ratio (OR) = 6.99, 95% confidence interval (CI) = 3.01-16.2], current heavy smoking (OR = 3.46, 95% CI = 1.52-7.9), and weight loss (OR = 1.86, 95% CI = 1.07-3.24). CONCLUSIONS: Variability in and the factors increasing serum CYFRA 21 - 1 levels beyond the cut-off value need to be considered when interpretating CYFRA 21 - 1 test results. The future application of CYFRA 21 - 1 to lung cancer screening may require more than a single measurement.

Age and Smoking Status Affect Serum Cytokeratin 19 Fragment Levels in Individuals Without Cancer.

BACKGROUND/AIM: Lung cancer is a frequent and fatal cancer that is difficult to diagnose in the early stages. CYFRA 21-1 is a serological marker currently used to diagnose and monitor lung cancer; however, its clinical use for screening is controversial. Therefore, the present study investigated the relationship between serum CYFRA 21-1 levels and clinical confounders. PATIENTS AND METHODS: We recruited 3,674 individuals who had never been diagnosed with any cancer. The relationships between high serum CYFRA 21-1 levels (≥3.5 ng/ml) and age, sex, body mass index, and smoking status were investigated. RESULTS: High serum CYFRA 21-1 levels (≥3.5 ng/ml) were detected in 5.1% of all subjects. High serum CYFRA 21-1 levels were observed in 7.3% of current smokers and 4.3% of non-smokers. The proportion of subjects with high serum CYFRA 21-1 levels was markedly higher in the older group (65 years and older, 11%) than in the younger group (younger than 45 years, 2.0%). High serum CYFRA 21-1 levels (≥3.5 ng/ml) were associated with older age [odds ratio (OR)=3.39, 95% confidence interval (CI)=1.79-6.41 for 55-64 years vs. <45 years, and OR=7.34, 95% CI=3.86-13.9 for ≥65 years vs. <45 years, respectively] and current smoking (OR=2.09, 95% CI=1.38-3.15 for current smoker vs. non-smoker). CONCLUSION: High serum CYFRA 21-1 levels were associated with an older age and current smoking, which may be considered as factors influencing CYFRA 21-1 levels.

Phase II Study of S-1 and Paclitaxel Combination Therapy in Patients with Previously Treated Non-Small Cell Lung Cancer.

LESSONS LEARNED: In terms of efficacy and safety, good results were obtained with S-1 and paclitaxel (PTX) combination therapy.The findings suggest that S-1 and PTX combination therapy is a feasible treatment option in patients with previously treated non-small cell lung cancer. BACKGROUND: Although monotherapy with cytotoxic agents, including docetaxel and pemetrexed, is recommended for patients with previously treated advanced non-small cell lung cancer (NSCLC), its outcomes are unsatisfactory. S-1 is an oral fluoropyrimidine agent that consists of tegafur, 5- chloro-2, 4-dihydroxypyridine, and potassium oxonate. S-1 is approved for patients with gastric cancer in 7 Asian countries and 15 European countries. It is also approved for patients with eight type of cancers, including NSCLC, in Japan. We evaluated the efficacy and toxicity of S-1 and paclitaxel (PTX) combination therapy in patients with previously treated NSCLC. METHODS: Oral S-1 was administered thrice weekly on days 1-14 at 80, 100, and 120 mg/day in patients with body surface areas of <1.25, 1.25-1.5, and >1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. Primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Forty patients were enrolled, with response and disease control rates of 27.5% and 75.0%, respectively (Fig. 1). Median PFS and OS were 6.5 and 20.7 months, respectively. Grade 3/4 anemia and thrombocytopenia were seen in five (12%) and one (2%) patients, respectively. Febrile neutropenia occurred in three patients (7%). Common grade 3/4 nonhematological toxicities were stomatitis (5% of patients), diarrhea (7% of patients), and interstitial lung disease (one patient). No treatment-related deaths were observed. CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy, with mild toxicities, in patients with previously treated advanced NSCLC.

Phase I study of S-1 plus paclitaxel combination therapy as a first-line treatment in elderly patients with advanced non-small cell lung cancer.

This phase I study was aimed at determining the maximum tolerated dose (MTD) and recommended dose (RD) for oral S-1 plus paclitaxel combination therapy in elderly patients with non-small cell lung cancer (NSCLC). Chemotherapy-naïve patients (age, >70 years) with stage III/IV NSCLC were treated with paclitaxel intravenously at four dose levels (DLs), 60, 70, 80, and 90 mg/m2, on day 1 and 8, and with S-1 (80 mg/m2) orally on days 1-14 every 3 weeks. MTD was defined as the dose at which two of the initial three patients experienced dose-limiting toxicities (DLTs). Three patients were added when the initial three patients experienced DLTs. The dose administered in three of the six patients with DLTs met the definition of MTD. The RD was defined as a dose 1 DL below the MTD. Fifteen patients including six on DL 1 and three each on DLs 2, 3, and 4 were enrolled. One patient experienced a DLT (febrile neutropenia) at DL 1. The remaining DLTs were noted at DL 4 (in one patient each): febrile neutropenia, grade (G) 3 skin rash, G3 diarrhea, G3 stomatitis, and G3 international normalized ratio (INR) elevation. The MTD of paclitaxel was 90 mg/m2. The RD for both S-1 and paclitaxel was 80 mg/m2 (DL 3). The response rate was 45.5% (8 of 15 patients achieved a partial response). In conclusion, the RD of both S-1 and paclitaxel was 80 mg/m2 in the combination therapy for chemotherapy-naïve patients with advanced NSCLC.

A Phase II Study of S-1 and Paclitaxel Combination Therapy as a First-Line Treatment in Elderly Patients with Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small cell lung cancer showed favorable efficacy.Coadministration of S-1 and paclitaxel in elderly patients with advanced non-small lung cancer showed tolerable toxicity. BACKGROUND: Although monotherapy with cytotoxic agents including docetaxel or vinorelbine are recommended for elderly patients with advanced non-small cell lung cancer (NSCLC), the outcome is not satisfactory. We evaluated the efficacy and safety of S-1 and paclitaxel (PTX) as a first-line cotreatment in elderly patients with advanced NSCLC. METHODS: Oral S-1 was administered on days 1-14 every 3 weeks at 80, 100, and 120 mg per day for patients with body surface area < 1.25 m2, 1.25-1.5 m2, and > 1.5 m2, respectively. PTX was administered at 80 mg/m2 on days 1 and 8. The primary endpoint was response rate, and secondary endpoints were progression-free survival (PFS), overall survival (OS), and safety. RESULTS: Seventeen patients were enrolled with response and disease control rates of 47.1% and 88.2%, respectively. Median PFS and OS were 5.6 and 35.0 months, respectively. Hematological grade 3 or 4 toxicities included leukopenia (55.8%), neutropenia (52.9%), febrile neutropenia (11.8%), and anemia (11.8%). Nonhematological grade 3 toxicities included stomatitis (23.5%), diarrhea (5.9%), and interstitial lung disease (5.9%), and grade 5 toxicities included interstitial lung disease (5.9%). CONCLUSION: This S-1 and PTX cotherapy dose and schedule showed satisfactory efficacy with mild toxicities in elderly patients with advanced NSCLC.

Feasibility Study of Sequentially Alternating EGFR-TKIs and Chemotherapy for Patients with Non-small Cell Lung Cancer.

BACKGROUND/AIM: The purpose of this trial was to evaluate the feasibility and efficacy of alternating platinum-based doublet chemotherapy with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in patients with EGFR-mutant non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naive patients with advanced NSCLC harboring an EGFR mutation were enrolled. All patients underwent induction chemotherapy by sequentially alternating pemetrexed/cisplatin/bevacizumab and EGFR-TKIs followed by maintenance therapy with pemetrexed/bevacizumab and EGFR-TKIs. The primary outcome was the completion rate of the induction therapy. RESULTS: Eighteen eligible patients were enrolled between May 2011 and March 2016. The completion rate of induction therapy was 72.2% (13/18). Unfortunately, one patient developed grade 4 acute renal injury, but no other serious complications concerning this protocol were observed. Furthermore, diarrhea, rashes, and hematological adverse effects were mild. CONCLUSION: The completion rate of induction therapy was promising. Alternating chemotherapy and EGFR-TKIs should be further investigated regarding feasibility and efficacy.

Measurement of exhaled nitric oxide and serum surfactant protein D levels for monitoring radiation pneumonitis following thoracic radiotherapy.

The present study aimed to examine the role of exhaled nitric oxide (eNO) and serum surfactant protein D (SP-D) level in the determination of radiation pneumonitis (RP) after thoracic radiotherapy (RT). The study included 34 treatments for 33 patients, including 16 three-dimensional conformal and 18 stereotactic body RT treatments. eNO levels were measured prior to RT, immediately subsequent to RT, every week during the RT course and at 1, 3, 6, 9 and 12 months following the treatment. The therapy reduced the eNO from 24.3±12.8 ppb prior to RT to 19.0±10.4 ppb immediately subsequent to RT (P=0.04). A total of 5 patients (14%) developed symptomatic RP of grade 2 or higher 3-5 months later, and exhibited an eNO elevation of 2.1±0.68-fold the minimum value, whereas the RP- group exhibited 1.4±0.6-fold elevation (P=0.02). The sensitivity of a cut-off of a 1.4-fold increase in the eNO ratio at the onset of RP was 100%; however, the specificity was 52%, and no predictive alterations to eNO levels were observed prior to the onset of RP. RT was associated with an elevated serum SP-D level at 3-6 months after RT. There was a statistically significant difference in the initial serum SP-D level between RP+ and RP- patients. In conclusion, obtaining the eNO ratio was a useful RP monitoring tool but did not predict RP occurrence in the present setting, whereas serum SP-D level may be a potential predictor for the detection of RP risk.

[A case of microscopic polyangiitis with silicosis].

A 76-year-old man was admitted to our hospital because of increasing size of lung nodules, while he was under observation for silicosis at another hospital. As the result of bronchoscopic biopsy, it was confirmed that they were silicotic nodules. However, he was hospitalized again about one month later due to left spontaneous pneumothorax. The pneumothorax improved immediately by persistent drainage of the thoracic cavity, but he developed a fever on day 9, and ground-glass opacities in both lungs also became exacerbated in spite of our administration of antibiotics. In addition, the level of MPO-ANCA increased markedly and multiple 3-10mm sized purpurae was seen on the right thigh on day 29. Skin biopsy specimens revealed infiltration of histiocytes and lymphocytes around medium-sized vessels in lower dermis. We diagnosed microscopic polyangiitis, then treated with steroid and immunosuppressive therapy. Fever and radiological findings improved significantly from the day after initiation of steroid administration. The patient was discharged on day 92 because of the improvement of his respiratory condition. We report a case of microscopic polyangiitis with silicosis, which markedly improved by steroid and immunosuppressive therapy.

[Two cases of complex sleep apnea syndrome].

Continuous positive airway pressure (CPAP) therapy of obstructive sleep apnea syndrome (OSAS) is widely accepted. Recently it is reported that central type apnea increases in some patients with OSAS with the application of CPAP, and this type of sleep-disordered breathing is called complex sleep apnea syndrome (comp. SAS). However, until now its concept, mechanism and therapy have not been fully established. We treated 2 cases of comp. SAS with CPAP therapy. When we performed a polysomnography (PSG) examination in case 1 one year later, the symptoms had diminished and the central apnea had decreased, indicating the effectiveness CPAP therapy in case 1. In case 2, the symptoms had not diminished one year later. We therefore performed Adaptive Servo-Ventilation (ASV) therapy, resulting in improvement of symptoms and decrease of the central apnea. CPAP is not always effective in comp. SAS, and ASV can be suitable in such cases.

Phase II trial of weekly gemcitabine and split-dose cisplatin for advanced non-small-cell lung cancer.

OBJECTIVE: Cisplatin is widely used for the treatment of non-small-cell lung cancer. However, it can cause unpleasant side effects and also requires prolonged hydration. We conducted a Phase II study of weekly gemcitabine and split-dose cisplatin in patients with advanced non-small-cell lung cancer (NSCLC) in order to reduce toxicity and shorten the time taken by administration. Our aims were to determine the response rate, toxicity and survival time with this regimen in patients with Stage IIIB/IV disease. METHODS: Previously untreated patients with Stage IIIB/IV NSCLC were given gemcitabine (1000 mg/m(2)) and split-dose cisplatin (40 mg/m(2)) on days 1 and 8 at 3-week intervals for four cycles. Gemcitabine was administered over the course of 30 min, and cisplatin was over the course of 60 min on the same days on an outpatient basis. RESULTS: Forty-five patients were enrolled, and all of them were assessable for response and toxicity. None had a complete response and 17 had a partial response (37.8%), for an overall response rate of 37.8% (95% confidence interval, 25.1-52.4%). The survival rate was 56.5% at 1 year and 38.9% at 2 years, with a median survival time of 15.7 months. Leukopenia, neutropenia, anemia and thrombocytopenia were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 35%, 51%, 31% and 13%, respectively. CONCLUSIONS: Weekly gemcitabine and split-dose cisplatin is active and well tolerated in patients with Stage IIIB/IV NSCLC, administered on an outpatient basis without requiring prolonged hydration or hospitalization.

[Small cell lung cancer with Sézary syndrome].

A 69 year-old man was admitted to our hospital with bloody sputum and abnormal shadows in his chest X-ray film and CT. According to the bronchoscopic examination, he was diagnosed as suffering from small cell lung cancer (SCLC). Aside from SCLC, erythroderma, lymphoadenopathy and abnormal lymphoid cells in his peripheral blood were recognized on admission. Considering possible disorder blood complications, we conducted examinations including a biopsy of the skin and superficial lymph nodes, which revealed the characteristics of Sézary syndrome. We provided local treatment for Sézary syndrome and did systemic chemotherapy with carboplatin and etoposide for SCLC. After four cycles of chemotherapy, the patient showed a partial response. We report a very rare case of SCLC with Sézary syndrome in which we were able to provide chemotherapy effectively and safely.

Effect of inducible nitric oxide synthase on apoptosis in Candida-induced acute lung injury.

Excessive nitric oxide (NO) generated by inducible nitric oxide synthase (iNOS) aggravates acute lung injury (ALI) by producing peroxinitrite. We previously showed that the expression of iNOS and lung injury were suppressed by inhalation of a novel iNOS inhibitor, ONO-1714, in mice with Candida-induced ALI, and that nitric oxide produced by iNOS and apoptosis of epithelial cells were found to have a crucial role in Candida-induced ALI. In the present study, we investigated the effect of NO on the apoptosis of alveolar epithelial cells in Candida-induced ALI. Mice were pretreated by inhalation of ONO-1714 or saline (vehicle control of ONO-1714), and were given an intravenous injection of Candida albicans to induce ALI. After 24 h from injection of Candida albicans, we performed bronchoalveolar lavage and removed lung tissues. We assessed apoptosis on the basis of TUNEL staining and caspase 3 activity. Our results showed that apoptosis was suppressed by inhibition of iNOS-derived NO production by ONO-1714 inhalation. The augmented production of NO increased FasL, TNF-alpha, and mRNA production of Bax of lung that induced apoptosis of alveolar epithelial cells. Inhibition of iNOS-derived NO production by ONO-1714 inhalation ameliorated Candida-induced ALI and improved survival by suppressing apoptosis of alveolar epithelial cells.

Phase I/II trial of biweekly docetaxel and cisplatin with concurrent thoracic radiation for stage III non-small-cell lung cancer.

OBJECTIVES: We conducted phase I and II studies of biweekly docetaxel and cisplatin with concurrent radiotherapy, followed by consolidation chemotherapy with the same drugs in patients with locally advanced, unresectable non-small-cell lung cancer (NSCLC). Our objectives were to define the maximum-tolerated dose and dose-limiting toxicity (DLT) in the phase I study, and to determine the response rate, toxicity, and survival rate at the recommended dose (RD) in the phase II study. METHODS: Patients with unresectable stage IIIA and IIIB NSCLC were studied. Six to eight cycles of docetaxel and cisplatin were administered at 2-week intervals. In the phase I study, patients received four dose levels: level 1, docetaxel/cisplatin=30/40 mg/m2; level 2, 35/40; level 3, 40/40; and level 4, 45/40. Radiotherapy was delivered at a rate of 2 Gy per fraction/day up to a total dose of 60 Gy over the course of 6 weeks, during the first three cycles of chemotherapy. RESULTS: DLT comprised neutropenia at level 4 in the phase I study (n=15), and level 3 was considered the RD. In the phase II study (n=46), two patients had a complete response (4.3%) and 34 had a partial response (73.9%), for an overall response rate of 78.2% [95% CI (66.3-90.2%)]. The survival rate was 69.1% at 1 year and 39.6% at 2 years, with a median survival time of 19.1 months. Leukopenia, neutropenia, anemia, and radiation esophagitis were the most common toxic reactions, with Grade > or = 3 reactions occurring at rates of 77, 70, 17, and 8%, respectively. CONCLUSION: Biweekly docetaxel and cisplatin with concurrent RT was active and well tolerated in patients with unresectable stage III NSCLC.

Double-cycle, high-dose ifosfamide, carboplatin, and etoposide followed by peripheral blood stem-cell transplantation for small cell lung cancer.

PURPOSES: To determine the tolerability and feasibility of double-cycle, high-dose chemotherapy followed by peripheral blood stem-cell transplantation (PBSCT) after conventional chemotherapy or chemoradiotherapy for small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with previously untreated SCLC received two cycles of cisplatin, 80 mg/m2, and etoposide, 300 mg/m2 (cisplatin-etoposide [PE]). Later, they were administered high-dose etoposide, 1,500 mg/m2, followed by granulocyte colony-stimulating factor for collection of peripheral blood stem cells. After two additional cycles of PE, the patients received high-dose ifosfamide, 10 g/m2, carboplatin, 1,200 mg/m2, and etoposide, 1,000 mg/m2 (ifosfamide-carboplatin-etoposide [ICE]) followed by PBSCT twice at 3-month to 4-month intervals. Patients with limited disease (LD) concurrently received 50 Gy of irradiation with the last two cycles of PE. RESULTS: Eighteen patients, including 11 patients with LD, were enrolled. Fifteen patients could receive high-dose ICE followed by PBSCT twice, and 3 patients could receive it once. The median number of CD34+ cells collected was 13.11 x 10(6)/kg. The median numbers of days to neutrophil counts > or = 500/microL and platelet counts > or = 50,000/microL were 10 days and 14.5 days after the first PBSCT, and 10 days and 15 days after the second PBSCT, respectively. Grade 3 diarrhea occurred in one cycle, and grade 3 renal toxicity occurred in two cycles. The overall response rate was 100%, with an 83.3% rate of complete or near-complete response. The 2-year and 5-year survival rates were 72% and 55% in patients with LD and 43% and 0% in patients with extensive disease, respectively. CONCLUSION: Double-cycle, high-dose ICE therapy followed by PBSCT is tolerable and feasible even after conventional chemotherapy or chemoradiotherapy in patients with SCLC.

[A case of non-mucin-producing papillary adenocarcinoma with a 19-year clinical history before operation].

A 73-year-old woman was admitted to our hospital for investigation of an abnormal shadow in the right upper lung field. Every year she had a medical check up since 1983 and the abnormal shadow was repeatedly pointed out However, she had not undergone a detailed examination. When she had a medical check up in July 2001, the shadow slightly increased compared with the previous chest film. Chest CT showed the mass with a pleural indentation in the right S3a, measuring 4 x 4 cm in size. Despite examinations including bronchoscopy we could not make a definitive diagnosis. After we explained the situation to her, she decided to have an operation. The biopsy during the operation revealed adenocarcinoma and right upper lobectomy with nodal dissection was performed. The ultimate diagnosis was non-mucin-producing papillary adenocarcinoma. This stage IB case was pT2N0M0. We reported this case because it was a rare slow-growing papillary adenocarcinoma that did not produce mucin and had a 19-year clinical history before operation.

[A case of solitary endobronchial metastasis of prostatic cancer].

We report the case of a 67-year-old man found to have an abnormal chest shadow in February 2003, who was referred to our hospital in April 2003, and was admitted in July 2003 because of the expansion of this shadow. Chest radiography and CT on admission showed a small nodular shadow in the right S6. Bronchoscopy revealed a soft polypoid mass in the lumen of the right B6b ii, which was considered to be an endobronchial neoplasm. A CT scan performed as a routine screening was found to be abnormal and revealed a prostatic tumor that was diagnosed as adenocarcinoma by pathologic examinations of lung and prostate tissue. We confirmed the diagnosis of prostatic cancer and its endobronchial metastasis by immunohistological staining with prostate specific antigen (PSA). An endobronchial metastatic tumor arising from prostatic cancer is a rare phenomenon that appears on the chest radiograph as a solitary mass.