Early pharmacodynamic assessment using ¹8F-fluorodeoxyglucose positron-emission tomography on molecular targeted therapy and cytotoxic chemotherapy for clinical outcome prediction.

Early prediction of therapeutic outcome is important in determining whether the ongoing therapy is beneficial. In addition to anatomical response determined using the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, recent studies have indicated that change in tumor glucose use on or after treatment correlates with histopathologic tumor regression and patient outcomes. This Perspective discusses the use of (18)F-fluorodeoxyglucose-positron emission tomography (FDG-PET) for pharmacodynamic evaluation in a very early phase of treatment to predict clinical outcomes in patients with advanced non-small-cell lung cancer. We conducted a study to assess whether early metabolic response determined using FDG-PET correlated with clinical outcomes in patients treated with gefitinib or those treated with carboplatin plus paclitaxel (CP). Early metabolic response to gefitinib, but not CP, correlated with the late metabolic response, anatomical response, progression-free survival, and even overall survival. A rapid effect of molecular targeted agents might not be aptly evaluated using the conventional criteria, eg, RECIST, in a very early phase of treatment before volumetric shrinkage of the tumor. Based on the findings of several studies, and on the findings from our study, use of FDG-PET might enable prediction of clinical outcomes at a very early stage of treatment, especially in patients treated with molecular targeted agents with rapid clinical efficacy.

Malignant pleural effusion from lung adenocarcinoma treated by gefitinib.

Small molecule inhibitors targeting epidermal growth factor receptor (EGFR) are known to be active against non-small cell lung cancer (NSCLC) although the pharmacodynamics of these agents on malignant pleural effusion (MPE) remains unclear. Here we describe a case of lung adenocarcinoma with massive MPE treated successfully by gefitinib and chest drainage. Using sequential MPE samples before and during gefitinib therapy, the morphological changes and apoptosis of cancer cells were analyzed. Apoptosis of cancer cells was detected as early as 4 hours on, but not before, gefitinib therapy, suggesting that the pharmacodynamic assessment of such molecular targeting agents might be feasible for MPE.

Cytological characteristics of pulmonary pleomorphic and giant cell carcinomas.

OBJECTIVE: To establish cytological features of pulmonary pleomorphic carcinoma (PC) or giant cell carcinoma (GC), we evaluated the cytological characteristics of these tumors using a multidisciplinary approach. STUDY DESIGN: Samples from 13 surgically resected and histologically confirmed PC or GC patients were collected from our institutes. Eight cases without prior chemotherapy before surgery were selected, and cytological features were analyzed. RESULTS: The background contained numerous lymphocytes and neutrophils. The tumor cells were arranged in flat loose clusters, but some were in fascicles. The shape of the tumor cell was spindle or pleomorphic, and the sizes of the tumor cells varied by more than 5-fold. The tumor cells had an abundant, thick and well-demarcated cytoplasm. The location of the nucleus was centrifugal, and the nucleus was oval or irregularly shaped. Multinucleated giant cells were frequently observed. The size of the nucleus was more than 5 times that of normal lymphocytes, and its size also varied by more than 5-fold. The nuclear membrane was thin, and nuclear chromatin was coarsely granular, while the nucleolus was single and round. CONCLUSION: PC or GC has characteristic cytological features, however, spindle cells tended to be hardly observed in cytological specimens in some cases.

[Renal salt-wasting syndrome progressing to severe hyponatremia after chemotherapy--a case report].

A 66-year-old woman with small-cell lung cancer was administered chemo-radiotherapy consisting of cisplatin (CDDP) and etoposide (ETP). From day 3, she developed vomiting and hyponatremia that persisted despite fluid infusion and cortico-steroid administration. On day 7, the hyponatremia worsened (serum sodium level, 109 mEq/L), leading to disturbed consciousness and convulsions. The serum sodium level gradually increased after intravenous administration of hypertonic saline; on day 22, the serum sodium level was almost normal without any neurological implication. We diagnosed this clinical condition as renal salt-wasting syndrome (RSWS) on the basis of dehydration and high urinary sodium excretion at the onset. In the second course of chemotherapy, CDDP was replaced with carboplatin (CBDCA); consequently, hyponatremia was not observed. Hyponatremia that develops after the administration of CDDP may be due to not only the syndrome of inappropriate secretion of anti diuretic hormone (SIADH) but also RSWS. When RSWS is suspected, hypertonic saline should be administered.

A feasibility and efficacy study on bronchoscopy with a virtual navigation system.

OBJECTIVE: The purpose of this study was to evaluate the diagnostic accuracy of bronchoscopy with virtual bronchoscopy (VB) navigation. PATIENTS AND METHODS: Forty-two consecutive patients with ≤30-mm diameter peripheral pulmonary shadows or lesions that were difficult or impossible to identify on plain x-rays regardless of size were selected. Before bronchoscopy, multidetector computed tomography was performed, and VB images were created. Then, ultrathin bronchoscopy was carried out with VB navigation followed by conventional 4-mm diameter bronchoscopy. RESULTS: Thirty-seven patients were finally enrolled. There were 12 re-examination cases in which earlier conventional bronchoscopy was nondiagnostic. Diagnosis was established in 28 patients (25 malignant and 3 benign lesions), with the diagnostic yield of 75.7% (sensitivity 86.2%, specificity 62.5%, positive predictive value 89.3%, negative predictive value 55.6%, and accuracy 81.1%). The diagnostic yield for lesions of diameter ≤20 mm, 21 to 30 mm, and ≥31 mm were 76.9%, 76.5%, and 71.4%, respectively, for all patients, and 90%, 84.6%, and 83.3%, respectively, for malignant cases. The diagnostic yield in patients who underwent re-examinations was 83.3% for all cases and 88.9% for malignant cases. Three patients had completely invisible shadows on x-ray fluoroscopy and all of these cases were diagnosed on bronchoscopy. No statistically significant difference was observed between the diagnostic yield for the different sizes, pathology, and number of bronchoscopies required. CONCLUSIONS: Bronchoscopy with VB navigation yielded high accuracy even for small peripheral pulmonary nodules and shadows that were difficult or impossible to identify on plain x-rays, even for patients in whom earlier conventional bronchoscopy was nondiagnostic.

[The contribution of widely used devices in the diagnosis of peripheral pulmonary lesions in patients presenting with respiratory distress].

PURPOSE: We retrospectively reviewed the contribution of widely used devices such as the standard fiberoptic bronchoscope in the diagnosis of peripheral pulmonary lesions (PPLs) in patients who presented with respiratory distress. SUBJECT: We performed bronchoscopy for 106 PPLs in January-December 2007, and diagnosed access to the lesions to be difficult. METHOD: For these lesions, we applied Sasada transbronchial angled forceps (STAF), transbronchial needle aspiration cytology (TBAC), thin bronchoscopy, and ultra-thin bronchoscopy, which are widely used devices, after routinely performing biopsy with standard forceps and saved each specimen separately, and finally compared the pathological diagnosis. RESULTS: The diagnostic yield obtained with specimens using standard forceps was 36.8%; however, the overall diagnosis was improved to 70.8% after we used these other devices and methods. We achieved diagnosis with STAF (10 lesions), followed by thin bronchoscopy (5 lesions), and ultra-thin bronchoscopy (14 lesions). No diagnosis was made by TBAC. CONCLUSION: We conclude that these widely employed devices can contribute to improvements in the diagnosis of cases of respiratory distress in which arrival to the lesions is difficult.

[A case of malignant lymphoma successfully diagnosed using Sasada transbronchial angled biopsy forceps].

A 68-year-old man was referred to our hospital due to general fatigue, fever and weight loss. His chest radiograph showed a nodule (2.8 cm) in the right middle lobe. Computed tomography and positron emission tomography showed multiple metastases to the bone, liver and lymph nodes. The lung nodule was not accessible by standard transbronchial forceps. However, biopsy specimens obtained using Sasada Transbronchial Angled Biopsy Forceps (STAF) pathologically confirmed the diagnosis of malignant lymphoma. We report the case, and discuss the utility of STAF for lung lesions that are difficult to access with standard forceps.

A new electrocautery pleural biopsy technique using an insulated-tip diathermic knife during semirigid pleuroscopy.

BACKGROUND: The biopsy size obtained with standard flexible forceps (SFF) during semirigid pleuroscopy is often insufficient for pathological examination. An insulated-tip diathermic knife (IT knife) allows safe resection of a larger lesion during gastrointestinal endoscopy. We sought to validate an electrocautery pleural biopsy technique using the IT knife during semirigid pleuroscopy. We compared the diagnosis of specimens obtained using the IT knife and SFF in 20 subjects with unexplained pleural effusion, and reviewed pleuroscopic parameters such as complications, procedure time, and diameter of the specimens. METHODS: After injecting saline with lidocaine and epinephrine below the affected pleura, the lesion was incised in a circular shape with full thickness by manipulating the IT knife. RESULTS: Diagnostic yields from specimens obtained with the IT knife and SFF were 85% (17 of 20 cases) and 60% (12 of 20 cases), respectively. The IT knife biopsy was superior to SFF in 8 of 20 patients (malignant pleural mesothelioma in three, nonspecific inflammation in two, metastatic breast cancer in one, and tuberculosis in one). These pleural lesions revealed thickened, smooth abnormal appearances. The overall diagnostic yield for both IT knife and SFF was 100%. Median time of the procedure, from first pleural injection to specimen removal, was 21 min (range 12-92 min), and median diameter of specimen was 13 mm (range 6-23 mm). There were no severe complications during the procedure. CONCLUSIONS: Electrocautery biopsy using the IT knife during semirigid pleuroscopy has great potential for diagnosing smooth abnormal pleura which are difficult to biopsy with SFF.

Phase I/II study of docetaxel and S-1 in patients with previously treated non-small cell lung cancer.

INTRODUCTION: The aim of this study was to determine and evaluate the recommended dose of docetaxel in combination with a novel oral 5-fluorouracil analogue S-1 and evaluate the efficacy and safety in patients with previously treated non-small cell lung cancer. METHODS: In phase I, patients with previously treated non-small cell lung cancer were treated with docetaxel (starting dose 40 mg/m) intravenously on day 1 and oral administration of S-1 at a fixed dose of 80 mg/m on days 1 to14 every 3 weeks. The recommended dose was the dose level preceding the maximum tolerated dose; once determined, patients were enrolled in phase II. RESULTS: The recommended dose of docetaxel was 40 mg/m in combination with S-1 80 mg/m/d. Of 30 patients enrolled in phase II part, 29 patients were eligible and analyzed. No complete response and 7 (24.1%) partial responses were observed, for an overall response rate of 24.1% (95% confidence interval, 10.3-43.5%). Median overall survival was 11.8 months. The 1-year survival rate was 42%. The grade 3 to 4 hematologic toxicities were neutropenia (34.5%), leukopenia (20.6%), and anemia (10.3%). The grade 3 to 4 nonhematological toxicities included fever 2 (6.9%), diarrhea 1 (3.4%), stomatitis 1 (3.4%), cerebral infarction 1 (3.4%), and pneumonitis 1 (3.4%). There was one treatment-related death due to relapse of drug induced pneumonitis. CONCLUSIONS: This combination chemotherapy is highly active and well tolerated in previously treated patients with non-small cell lung cancer. These results are encouraging and warrant additional investigation.

Clinical experience with autofluorescence imaging system in patients with lung cancers and precancerous lesions.

BACKGROUND: It is important to detect preinvasive bronchial lesions before they become invasive cancer, because detection of early cancer is expected to lead to a cure. Autofluorescence bronchoscopy is a useful device in the detection of preinvasive and cancerous lesions. Recently, a new autofluorescence bronchoscopic system, autofluorescence imaging (AFI) system, has been developed. OBJECTIVES: We evaluated the efficacy of AFI in the diagnosis of precancerous and cancerous lesions. METHODS: A total of 31 patients underwent both conventional white-light bronchoscopy (WLB) and AFI from January 2002 to September 2004. We evaluated autofluorescence findings using a four-point scale: AFI-I, II, III, and B. The findings in WLB were evaluated on a three-point scale: WLB-I, II, and III. Abnormal areas by WLB and AFI were biopsied for histopathological examinations. RESULTS: A total of 64 lesions were evaluated. When the AFI-III finding was regarded as positive in AFI and WLB-III as positive in WLB, sensitivity for severe dysplasia or worse was 94.7% with AFI and 73.7% with WLB, respectively. CONCLUSIONS: AFI is an effective system for the detection of precancerous and cancerous lesions.

High-dose-rate brachytherapy for small-sized peripherally located lung cancer.

BACKGROUND: The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with (192)Ir radioactive source. RESULTS: A (192)Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 x 5 Gy to 2 x 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%. CONCLUSION: Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.

Vacuolar protein sorting receptor in Schizosaccharomyces pombe.

The mechanism by which soluble proteins, such as carboxypeptidase Y, reach the vacuole in Saccharomyces cerevisiae is very similar to the mechanism of lysosomal protein sorting in mammalian cells. Vps10p is a receptor for transport of soluble vacuolar proteins in S. cerevisiae. vps10(+), a gene encoding a homologue of S. cerevisiae PEP1/VPS10, has been identified and deleted from the fission yeast Schizosaccharomyces pombe. Deletion of the vps10(+) gene resulted in missorting and secretion of Sch. pombe vacuolar carboxypeptidase Cpy1p, indicating that it is required for targeting Cpy1p to the vacuole. Sch. pombe Vps10p (SpVps10p) is a type I transmembrane protein and its C-terminal cytoplasmic tail domain is essential for Cpy1p transport to the vacuole. Cells expressing green fluorescent protein-tagged SpVps10p produced a punctate pattern of fluorescence, indicating that SpVps10p was largely localized in the Golgi compartment. In addition, Sch. pombe vps26(+), vps29(+) and vps35(+), encoding homologues of the S. cerevisiae retromer components VPS26, VPS29 and VPS35, were identified and deleted. Fluorescence microscopy demonstrated that SpVps10p mislocalized to the vacuolar membrane in these mutants. These results indicate that the vps26(+), vps29(+) and vps35(+) gene products are required for retrograde transport of SpVps10p from the prevacuolar compartment back to the Golgi in Sch. pombe cells.

Improved diagnostic efficacy by rapid cytology test in fluoroscopy-guided bronchoscopy.

BACKGROUND: Fluoroscopy-guided bronchoscopy is a safe and routine method used to obtain a histologic or cytologic specimen of peripheral lung nodules, but it has low sensitivity in diagnosing malignant tumors. Although feedback from rapid cytology tests are expected to improve diagnostic rates, the value of the routine use of rapid cytology tests has not been established. MATERIALS AND METHODS: We prospectively studied 657 patients with suspected peripheral malignant lung lesions on chest computed tomography who underwent fluoroscopy-guided bronchoscopy between January 2002 and December 2004. Rapid on-site cytopathologic examinations (ROSE) were performed during bronchoscopic examinations. The additional approach to the lesions was performed immediately after conventional bronchoscopic examinations when ROSE was not considered diagnostic. RESULTS: There were 528 patients diagnosed as having malignant lesions. In 477 of these patients (90.3%), final malignant diagnosis was established by the initial bronchoscopy. Among these, 84 patients (15.9%) were diagnosed only with the additional feedback from ROSE. Of 240 peripheral lesions < or =2 cm, 174 were found to be malignant. Without ROSE, 110 (63.2%) of peripheral malignant lesions were diagnosed by bronchoscopy. The integration of ROSE enabled us to diagnose an additional 40 patients (23.0%) by bronchoscopy. ROSE improved diagnostic yield independent of the site and histology of the lesions and experience of the operators. CONCLUSION: ROSE increased the diagnostic yield of bronchoscopy from 74.4% to 90.3% and therefore is an effective reinforcement in bronchoscopic diagnosis of peripheral pulmonary malignancies. The use of ROSE in routine bronchoscopy should be encouraged.

Usefulness of ultrathin bronchoscopy in diagnosis of lung cancer.

Although ultrathin bronchoscopes are suggested to have comparable abilities to conventional bronchoscopes in diagnosing peripheral lung lesions, how to introduce ultrathin bronchoscopes into bronchoscopic examination is still to be determined. In our first study, 35 patients with peripheral lung lesions underwent ultrathin followed by conventional bronchoscopy to compare their diagnostic abilities. The diagnostic rate was 54.3% in conventional bronchoscopy alone, 60.0% in ultrathin bronchoscopy alone, and 62.8% in the combination of the two. In the next study, we introduced a rapid cytology test of the material obtained in conventional bronchoscopy. When malignant cells were not detected in the material by the rapid cytology, ultrathin bronchoscopy was immediately conducted. Thirty-two patients with negative rapid cytology were enrolled in this study. Ultrathin bronchoscopy resulted in diagnostic materials in 59.3% of these cases. Ultrathin bronchoscopes showed better access to the lesions than a brush or a curette introduced through conventional bronchoscopes. We conclude that ultrathin bronchoscopes have a comparable ability to conventional ones in diagnosing peripheral lung cancer even when used alone, and become a good complement to conventional ones by introducing the rapid cytology test.