[Outcomes of the Critical Pathway for Cooperative Follow-up on Patients with Postoperative Lung Cancer].

OBJECTIVES: We introduced the critical pathway (CP) for follow-up on patients with postoperative lung cancer to the staff of the Hyogo Prefectural Awaji Medical Center and regional medical institutions in Japan, in 2010. METHODS AND RESULTS: We raised awareness within our hospital and collaborating medical institutes and trained our staff on the CP before introducing it. From May 2013 through October 2023, lung cancer surgery was performed on 460 patients. Our CP was applied to 71.7% of these patients. Reasons for non-application included the high risk of recurrence due to advanced cancer stages( 39.2%) and the treatment for other types of cancer was needed in our hospital (26.2%). We reviewed the outcome of our CP. CONCLUSION: The high application rate was facilitated by preparatory actions, including training our hospital staff and collaborating medical institutions. An even higher application rate can be achieved by continuing to raise awareness and strengthening cooperation between concerned medical institutions that treat advanced lung cancer.

Occupational respiratory allergy to lettuce in lettuce farmers.

BACKGROUND: Lettuce-associated respiratory allergy has never been reported before. The aim of this study was to clarify the clinical condition of lettuce-associated respiratory allergy and to identify the lettuce antigen which induces allergic symptoms. METHODS: We distributed questionnaires to 1168 lettuce farmers and performed medical examinations in those who exhibited respiratory symptoms related to occupational exposure to lettuce. We analysed specific IgE-binding proteins in the sera of patients through immunoblotting analysis and determined molecular characterization of the IgE-binding bands using liquid chromatography-mass spectrometry. RESULTS: A total of 932 farmers (80%) responded to the questionnaire. Of those, 7% exhibited lettuce-associated respiratory symptoms, during harvesting and packaging. Thirteen patients were diagnosed with allergy to lettuce and agreed to undergo further examinations. The percentage of activated basophils in these patients was significantly higher compared with that reported in negative controls (P < .05). Lettuce-specific IgE (ImmunoCAP® ) and skin prick testing was positive in 46% and 62% of patients, respectively. Notably, occupational lettuce-allergic asthma was detected in one patient through specific bronchial provocation testing. The IgE-binding bands recognized in the sera of >50% of patients were identified as epidermis-specific secreted glycoprotein EP1-like (51 kDa). CONCLUSION: The present analysis identified a novel lettuce allergen. This allergen may have clinically useful applications, such as specific IgE testing and allergen-specific immunotherapy.

A case of eosinophilic pneumonia induced by lettuce.

A 56-year-old female lettuce farmer was admitted to the hospital with a low-grade fever, worsening cough, and dyspnoea. A blood test revealed eosinophilia and a high serum IgE concentration. The 3-year follow-up showed that her total IgE level increased in December, peaked in May, and suddenly decreased in August. This result was consistent with the lettuce harvest season. A chest x-ray taken on admission showed an infiltrative shadow in the upper lung field. Chest CT revealed patchy ground glass opacity on the upper lung field and thickening of the bronchial wall. The bronchoalveolar lavage fluid contained 8% eosinophils. She was treated with prednisolone, and her symptoms and radiological findings improved. The 37 kDa protein that reacted with the patient's sera was identified by immunoblot analysis.

A case of acute exacerbation of idiopathic pulmonary fibrosis after proton beam therapy for non-small cell lung cancer.

There have been no reports describing acute exacerbations of idiopathic pulmonary fibrosis after particle radiotherapy for non-small cell lung cancer. The present study describes the case of a 76-year-old Japanese man with squamous cell carcinoma of the lung that relapsed in the left upper lobe 1 year after right upper lobectomy. He had been treated with oral prednisolone 20 mg/day every 2 days for idiopathic pulmonary fibrosis, and the relapsed lung cancer was treated by proton beam therapy, which was expected to cause the least adverse effects on the idiopathic pulmonary fibrosis. Fifteen days after the initiation of proton beam therapy, the idiopathic pulmonary fibrosis exacerbated, centered on the left upper lobe, for which intensive steroid therapy was given. About 3 months later, the acute exacerbation of idiopathic pulmonary fibrosis had improved, and the relapsed lung cancer became undetectable. Clinicians should be aware that an acute exacerbation of idiopathic pulmonary fibrosis may occur even in proton beam therapy, although proton beam therapy appears to be an effective treatment option for patients with idiopathic pulmonary fibrosis.

Antigen-Specific IgG ameliorates allergic airway inflammation via Fcγ receptor IIB on dendritic cells.

BACKGROUND: There have been few reports on the role of Fc receptors (FcRs) and immunoglobulin G (IgG) in asthma. The purpose of this study is to clarify the role of inhibitory FcRs and antigen presenting cells (APCs) in pathogenesis of asthma and to evaluate antigen-transporting and presenting capacity by APCs in the tracheobronchial mucosa. METHODS: In FcγRIIB deficient (KO) and C57BL/6 (WT) mice, the effects of intratracheal instillation of antigen-specific IgG were analysed using the model with sensitization and airborne challenge with ovalbumin (OVA). Thoracic lymph nodes instilled with fluorescein-conjugated OVA were analysed by fluorescence microscopy. Moreover, we analysed the CD11c+ MHC class II+ cells which intaken fluorescein-conjugated OVA in thoracic lymph nodes by flow cytometry. Also, lung-derived CD11c+ APCs were analysed by flow cytometry. Effects of anti-OVA IgG1 on bone marrow dendritic cells (BMDCs) in vitro were also analysed. Moreover, in FcγRIIB KO mice intravenously transplanted dendritic cells (DCs) differentiated from BMDCs of WT mice, the effects of intratracheal instillation of anti-OVA IgG were evaluated by bronchoalveolar lavage (BAL). RESULTS: In WT mice, total cells and eosinophils in BAL fluid reduced after instillation with anti-OVA IgG1. Anti-OVA IgG1 suppressed airway inflammation in hyperresponsiveness and histology. In addition, the number of the fluorescein-conjugated OVA in CD11c+ MHC class II+ cells of thoracic lymph nodes with anti-OVA IgG1 instillation decreased compared with PBS. Also, MHC class II expression on lung-derived CD11c+ APCs with anti-OVA IgG1 instillation reduced. Moreover, in vitro, we showed that BMDCs with anti-OVA IgG1 significantly decreased the T cell proliferation. Finally, we demonstrated that the lacking effects of anti-OVA IgG1 on airway inflammation on FcγRIIB KO mice were restored with WT-derived BMDCs transplanted intravenously. CONCLUSION: Antigen-specific IgG ameliorates allergic airway inflammation via FcγRIIB on DCs.

Bortezomib potentially inhibits cellular growth of vascular endothelial cells through suppression of G2/M transition.

Bortezomib, a selective 26S proteasome inhibitor, has shown clinical benefits against refractory multiple myeloma. The indirect anti-angiogenic activity of bortezomib has been widely recognized; however, the growth-inhibitory mechanism of bortezomib on vascular endothelial cells remains unclear, especially on the cell cycle. Here, we showed that bortezomib (2 nM of the IC(50) value) potently inhibited the cellular growth of human umbilical vascular endothelial cells (HUVECs) via a vascular endothelial growth factor receptor (VEGFR)-independent mechanism resulting in the induction of apoptosis. Bortezomib significantly increased the vascular permeability of HUVECs, whereas a VEGFR-2 tyrosine kinase inhibitor decreased it. Interestingly, a cell cycle analysis using flow cytometry, the immunostaining of phospho-histone H3, and Giemsa staining revealed that bortezomib suppressed the G2/M transition of HUVECs, whereas the mitotic inhibitor paclitaxel induced M-phase accumulation. A further analysis of cell cycle-related proteins revealed that bortezomib increased the expression levels of cyclin B1, the cdc2/cyclin B complex, and the phosphorylation of all T14, Y15, and T161 residues on cdc2. Bortezomib also increased the ubiquitination of cyclin B1 and wee1, but inhibited the kinase activity of the cdc2/cyclin B complex. These protein modifications support the concept that bortezomib suppresses the G2/M transition, rather than causing M-phase arrest. In conclusion, we demonstrated that bortezomib potently inhibits cell growth by suppressing the G2/M transition, modifying G2/M-phase-related cycle regulators, and increasing the vascular permeability of vascular endothelial cells. Our findings reveal a cell cycle-related mode of action and strongly suggest that bortezomib exerts an additional unique vascular disrupting effect as a vascular targeting drug.

The transfer of maternal antigen-specific IgG regulates the development of allergic airway inflammation early in life in an FcRn-dependent manner.

Asthma is a chronic inflammatory airway disease characterized by airway hyperreactivity, increased mucus production, and reversible airway contraction. Asthma is a complex genetic trait caused by environmental factors in genetically predisposed individuals. The transportation of maternal antigen-specific IgG via amniotic fluid, placenta and breast milk plays an important role in passive immunity. First, to examine whether maternal passive immunity by the transportation of antigen-specific IgG via FcRn regulates allergic airway inflammation, ovalbumin-immunized FcRn(+/-) female mice were bred with FcRn(-/-) male mice to evaluate the degree of ovalbumin-induced allergic airway inflammation of FcRn(-/-) offspring. Maternal passive immunity regulated allergic airway inflammation in an FcRn-dependent manner. Second, to examine the role of maternal antigen-specific IgG1 injection into mothers, we intravenously injected ovalbumin-specific IgG1 into wild-type or FcRn(+/-) mice immediately after they gave birth. The offspring were sensitized and challenged with ovalbumin. Antigen-specific IgG1 administered to lactating mice reduced allergic airway inflammation in their offspring in an FcRn-dependent manner. Last, to exclude the factor of maternal passive immunity other than ovalbumin-specific IgG1, we administered ovalbumin-specific IgG1 orally to offspring after birth. Oral administration of ovalbumin-specific IgG1 to offspring during the lactating period prevented the development of allergic airway inflammation in an FcRn-dependent manner. These data show that the transfer of maternal antigen-specific IgG regulates the development of allergic airway inflammation early in life in an FcRn-dependent manner.

Sphingosine kinase 1 regulates mucin production via ERK phosphorylation.

Our previous report showed that inhibition of sphingosine kinase (SphK) ameliorates eosinophilic inflammation and mucin production in a mouse asthmatic model. To clarify the role of SphK in airway mucin production, we utilized the mouse asthmatic model and found that both SphK and MUC5AC expression were increased and co-localized in airway epithelium. Next we cultured normal human bronchial epithelial cells in an air-liquid interface and treated with IL-13 to induce their differentiation into goblet cells. We found that SphK1 and MUC5AC expression was increased by IL-13 treatment at both protein and mRNA levels, whereas SphK2 expression was not changed. N,N-dimethylsphingosine (DMS), a potent SphK inhibitor, decreased MUC5AC expression up-regulated by IL-13 treatment. Furthermore, DMS inhibited IL-13-induced ERK1/2 phosphorylation but neither p38 MAPK nor STAT6 phosphorylation. These results suggest that SphK1 is involved in MUC5AC production induced by IL-13 upstream of ERK1/2 phosphorylation, and independent of STAT6 phosphorylation.

[Pulmonary tumor thrombotic microangiopathy associated with cancer of unknown origin].

A nonsmoking, 52-year-old woman presented with a 4-month history of persistent dry cough. Chest X-ray film on admission showed small granular shadow in bilateral lung fields. Bronchoscopic biopsy did not yield a diagnosis. Two months later, she complained of dyspnea. Physical examination showed signs of pulmonary hypertension. Five days after the onset of dyspnea, she died of respiratory failure. An autopsy showed pulmonary embolism and swollen abdominal lymph nodes consisting of metastatic signet-ring cell carcinoma and poorly differentiated adenocarcinoma. There was also marked fibrocellular intimal proliferation and thrombus formation causing luminal stenosis in small pulmonary arterioles. Thrombi were organized by recanalization and included atypical cells. We diagnosed pulmonary tumor thrombotic microangiopathy (PTTM). In spite of various immunohistological staining procedure, we could not find out the primary lesion of this cancer. This case suggests that we should aggressively biopsy a large specimen of the lung to make a differential diagnosis of PTTM, because bronchoscopic biopsy is not enough to diagnose PTTM.

Rad9 is upregulated and plays protective roles in an acute lung injury model.

The Rad9-Hus1-Rad1 protein complex is believed to respond to DNA damage and play important roles in the cell cycle. We studied the role of Rad9 protein in alveolar epithelial cells in the pathogenesis of acute lung injury. In a mouse model of lung injury induced by bleomycin or lipopolysaccharide, Rad9 expression is increased in type II alveolar epithelial cells from the early stage of lung injury. A549 cells and mouse primary alveolar epithelial cells also upregulated Rad9 expression after exposure to bleomycin. Gene silencing of Rad9 using siRNA decreased the G2/M arrest in A549 cells induced by bleomycin and also decreased the survival of A549 cells following exposure to bleomycin and hydrogen peroxide. In conclusion, Rad9 is a signal in the earlier stage of epithelial cell cycle regulation and plays protective roles in alveolar epithelial cells in the pathogenesis of acute lung injury.

Non-small cell lung cancer: whole-body MR examination for M-stage assessment--utility for whole-body diffusion-weighted imaging compared with integrated FDG PET/CT.

PURPOSE: To prospectively and directly compare the capability of whole-body diffusion-weighted (DW) imaging, whole-body magnetic resonance (MR) imaging with and that without DW imaging, and integrated fluorine 18 fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) for M-stage assessment in non-small cell lung cancer (NSCLC) patients. MATERIALS AND METHODS: The institutional review board approved this study; informed consent was obtained from patients. A total of 203 NSCLC patients (109 men, 94 women; mean age, 72 years) prospectively underwent whole-body DW imaging, whole-body MR imaging, and FDG PET/CT. Final diagnosis of the M-stage in each patient was determined on the basis of results of all radiologic and follow-up examinations. Two chest radiologists and two nuclear medicine physicians independently assessed all examination results and used a five-point visual scoring system to evaluate the probability of metastases. Final diagnosis based on each of the methods was made by consensus of two readers. Receiver operating characteristic (ROC) analysis was used to compare the capability for M-stage assessment among whole-body DW imaging, whole-body MR imaging with and that without DW imaging, and PET/CT on a per-patient basis. Sensitivity, specificity, and accuracy were compared with the McNemar test. RESULTS: Area under ROC curve (A(z)) values of whole-body MR imaging with DW imaging (A(z) = 0.87, P = .04) and integrated FDG PET/CT (A(z) = 0.89, P = .02) were significantly larger than that of whole-body DW imaging (A(z) = 0.79). Specificity and accuracy of whole-body MR imaging with (specificity, P = .02; accuracy, P < .01) and that without DW imaging (specificity, P = .02; accuracy, P = .01) and integrated FDG PET/CT (specificity, P < .01; accuracy, P < .01) were significantly higher than those of whole-body DW imaging. CONCLUSION: Whole-body MR imaging with DW imaging can be used for M-stage assessment in NSCLC patients with accuracy as good as that of PET/CT.

An Open-Label, Multi-Institutional, Randomized Study to Evaluate the Additive Effect of a Leukotriene Receptor Antagonist on Cough Score in Patients with Cough-Variant Asthma Being Treated with Inhaled Corticosteroids.

Cough-variant asthma is one of the most common reasons for chronic cough. It is important to treat appropriately cough-variant asthma because 30% to 40% of cough-variant asthma becomes a typical asthma. However, little is known about the treatment of cough-variant asthma except for inhaled corticosteroid (ICS). The aim of this study was to validate the additive efficacy of a leukotriene receptor antagonist (LTRA) on cough score and respiratory function in patients with cough-variant asthma being treated with ICS. A total 28 patients were randomly assigned to either an ICS + LTRA group or an ICS group. There were statistically significant improvements in cough scores in the ICS + LTRA group from 0 weeks (6.7 ± 4.4) to 2 weeks (2.9 ± 3.2) (P < 0.05), 4 weeks (0.7 ± 1.1) (P < 0.001), and 8 weeks (0.8 ± 1.2) (P < 0.001). However similar improvements were not evident in the ICS group from 0 weeks (6.7 ± 4.4) to 2 weeks (5.6 ± 10.0) (P = 0.59), 4 weeks (4.6 ± 7.6) (P = 0.32), and 8 weeks (2.9 ± 5.2) (P = 0.08). On the other hand, no significant changes were evident in the forced expiratory volume in 1 s (FEV1) and FEV1/forced vital capacity (FVC). In conclusion, the LTRA was useful in improving cough in patients with cough-variant asthma, even though it appeared to be ineffective in improving respiratory function.

Neutrophil elastase inhibitor (sivelestat) attenuates subsequent ventilator-induced lung injury in mice.

Mechanical ventilation can paradoxically cause acute lung injury, which is termed ventilator-induced lung injury. Neutrophil recruitment and neutrophil elastase release play a central role in the pathogenesis of ventilator-induced lung injury including cell damage, extracellular matrix degradation and alveolar-capillary hyperpermeability. We therefore speculated that neutrophil elastase inhibition ameliorates ventilator-induced lung injury. Anesthetized C57/BL6 mice received mechanical ventilation with a high tidal volume (V(T); 20 ml/kg) for 4 h. The neutrophil elastase inhibitor (sivelestat, 100 mg/kg) or saline was given intraperitoneally (i.p.) 30 min before ventilation. Sivelestat completely inhibited both neutrophil elastase and myeloperoxidase activities that were increased by ventilation, and attenuated the histopathological degree of lung damage, neutrophil accumulation and lung water content, as well as the concentration of macrophage inflammatory protein (MIP)-2, interleukin (IL)-6 and tumor necrosis factor (TNF)-alpha in bronchoalveolar lavage fluid and serum. Moreover, mechanical ventilation increased the phosphorylation of c-Jun NH2-terminal kinase (JNK) and the expression of early growth response gene-1 (Egr-1) mRNA, and these increases were also recovered by sivelestat. The terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end-labeling (TUNEL) staining revealed apoptotic cells mainly in alveolar epithelial cells and their numbers corresponded to histological damage. These data suggested that sivelestat could protect against ventilator-induced lung injury by suppressing apoptotic responses through mechanical stress-induced cell signaling in addition to inhibiting neutrophil chemotaxis.

Postoperative lung function in lung cancer patients: comparative analysis of predictive capability of MRI, CT, and SPECT.

OBJECTIVE: The purpose of this study was to prospectively compare the utility of dynamic contrast-enhanced perfusion MRI in the prediction of postoperative lung function in patients with lung cancer with the utility of quantitative and qualitative assessment of CT and perfusion SPECT. SUBJECTS AND METHODS: One hundred fifty lung cancer patients (87 men, 63 women) underwent dynamic perfusion MRI, MDCT, perfusion SPECT, and measurement of preoperative and postoperative forced expiratory volume in the first second of expiration (FEV1) expressed as percentage of predicted value. Postoperative FEV1 was predicted with dynamic perfusion MRI by semiquantitative assessment of the perfusion of whole lungs and resected segments of lungs, with quantitative assessment of functional lung volume on CT with commercially available software, with qualitative assessment of CT on the basis of the number of segments of total and resected lung, and with perfusion SPECT by assessment of uptake of microaggregated albumin particles in whole lungs and resected segments of lungs. Correlation and limits of agreement between actual and predicted postoperative FEV1 values were statistically evaluated. RESULTS: Actual postoperative FEV1 had stronger correlation with postoperative FEV1 predicted from perfusion MRI (r = 0.87, p < 0.0001) and quantitative CT (r = 0.88, p < 0.0001) than with postoperative FEV1 predicted from qualitative CT (r = 0.83, p < 0.0001) and perfusion SPECT (r = 0.83, p < 0.0001). The limits of agreement between the actual postoperative FEV1 and postoperative FEV1 predicted from perfusion MRI (5.3% +/- 11.8% [mean +/- 2 SD]) were smaller than the values for postoperative FEV1 predicted from qualitative CT (6.8% +/- 14.4%) and perfusion SPECT (5.1% +/- 14.0%) and was almost equal to the value for postoperative FEV1 predicted from quantitative CT (5.0% +/- 11.6%). CONCLUSION: Dynamic perfusion MRI is more accurate in prediction of the postoperative lung function of patients with lung cancer than are qualitative CT and perfusion SPECT and may be at least as accurate as quantitative CT.

Coregistered ventilation and perfusion SPECT using krypton-81m and Tc-99m-labeled macroaggregated albumin with multislice CT utility for prediction of postoperative lung function in non-small cell lung cancer patients.

RATIONALE AND OBJECTIVE: Co-registered SPECT and CT imaging (SPECT-CT) has potential for more precise evaluation of regional pulmonary function and may be useful for prediction of postoperative lung function in non-small cell lung cancer (NSCLC) patients. The purpose of the present study was to prospectively assess the capability of co-registered SPECT-CT using krypton-81m (Kr-81m) and technetium-99m-labeled macroaggregated albumin (Tc-99m MAA) for prediction of postoperative lung function of NSCLC patients compared with SPECT and planar imaging. MATERIALS AND METHODS: Sixty consecutive patients considered candidates for lung resection underwent 16-slice CT, ventilation and perfusion scintigraphy with SPECT examinations, and preoperative and postoperative measurement of FEV(1)%. In each subject, SPECT and CT data were automatically fused by using commercially available software. Each postoperative FEV(1)% value was predicted from uptakes of Kr-81m and Tc-99m MAA within total and resected lungs. Then, reproducibility coefficients and the limits of agreement between actual and each predicted postoperative lung function were statistically assessed. RESULTS: Reproducibility coefficients of SPECT-CT (Kr-81m: 5.1%, Tc-99m MAA: 5.2%) were smaller than those of SPECT and planar image using Kr-81m (SPECT: 7.4%, planar image: 12.1%) and using Tc-99m MAA (SPECT: 7.2%, planar image: 11.8%). The limits of agreement for SPECT-CT (Kr-81m: 3.3 +/- 10.5%, Tc-99m MAA: 5.4 +/- 11.0%) were also smaller than that of SPECT and planar image and small enough for clinical purposes. CONCLUSIONS: Co-registered SPECT-CT using Kr-81m and Tc-99m MAA was able to more reproducibly and accurately predict postoperative lung function compared with SPECT and planar imaging.

Pemetrexed monotherapy for chemo-naïve elderly (aged ≥80) patients with non-squamous non-small cell lung cancer: results from combined analysis of two single arm phase II studies (HANSHIN002 and 003).

PURPOSE: The aim of this retrospective study was to evaluate via combined analysis the efficacy and safety of pemetrexed monotherapy for chemo-naïve elderly patients aged ≥80 with non-squamous non-small cell lung cancer (NSCLC). METHODS: We conducted a combined analysis from two phase II studies of pemetrexed for chemo-naïve elderly (aged ≥75) (n = 47) and performance status 2 (n = 28) patients with advanced non-squamous NSCLC. Population aged ≥80 (80+ Group) was compared to those aged 70-79 (70's Group). RESULTS: We analyzed a total of 66 patients (37 70s and 29 80+ Groups) after exclusion of 4 ineligible and 5 aged ≤69 patients. Overall response rate, disease control rate, median progression-free survival, and median overall survival of 70s vs. 80+ Groups were 13.5 vs. 13.8% [p = not significant (NS)], 67.6 vs. 58.6% (p = 0.608), 3.7 months vs. 4.2 months (p = 0.5588) and 18.5 vs. 13.5 months (p = 0.2621), respectively. Non-hematological and hematological toxicities ≥grade 3 of 70s vs. 80+ Groups were 24 vs. 35% (p = 0.4192) and 49 vs. 52% (p = NS), respectively. Dose reduction and/or delay due to toxicities of 70s vs. 80+ Groups was 19 vs. 28% (p = 0.7784). Febrile neutropenia and interstitial lung disease were not observed. Treatment-related death (bacterial pneumonia) was confirmed in one (3%) of 29 80+ Group patients. CONCLUSIONS: Pemetrexed monotherapy demonstrated similar efficacy and safety between aged ≥80 and aged 70-79 populations. It could be a therapeutic option in clinical practice for elderly non-squamous NSCLC patients aged ≥80 without indications of carboplatin-based combination regimens or docetaxel monotherapy.

Radiation pneumonitis following concurrent accelerated hyperfractionated radiotherapy and chemotherapy for limited-stage small-cell lung cancer: Dose-volume histogram analysis and comparison with conventional chemoradiation.

PURPOSE: The aim of this study was twofold: to determine whether the dose-volume metrics are valuable in predicting radiation pneumonitis (RP) in small-cell lung cancer (SCLC) patients treated with accelerated hyperfractionated radiotherapy and chemotherapy (AHFRT + CT); and to clarify how AHFRT influences the risk of RP in comparison to conventional once-daily radiotherapy and chemotherapy (QDRT + CT). METHODS AND MATERIALS: Study subjects were 43 patients with SCLC treated with AHFRT + CT. Radiotherapy was delivered at 1.5 Gy/fraction (fr) twice daily to 45 Gy/30 fr/3 weeks. We analyzed the relation between RP incidence and several dosimetric factors. We also compared this series data with our previously published data from lung cancer patients treated with QDRT + CT. RESULTS: Radiation pneumonitis Grades 1, 2, and 3 were observed in 28 patients, 7 patients, and 1 patient, respectively. Univariate analysis revealed that the percentage of lung volume receiving more than 15 Gy, 20 Gy, and 30 Gy (V15, V20, V30) and normal tissue complication probability were of predictive value for the development of RP. The 12-month cumulative incidences of RP greater than Grade 2 were 0%, 7.1%, 25%, and 42.9% in patients with a V20 of < or =20%, 21-25%, 26-30%, and > or =31%, respectively. These incidences were lower than that of our patients treated with QDRT + CT. CONCLUSIONS: Dosimetric factors are valuable in predicting RP in SCLC patients treated with AHFRT + CT. Regarding the incidence of RP, AHFRT appears to have some advantage over QDRT.

High resolution CT findings of pulmonary epithelioid hemangioendothelioma: unusual manifestations in 2 cases.

Pulmonary epithelioid hemangioendotheliomas (PEH), also known as intravascular sclerosing bronchoalveolar tumor, is a rare vascular tumor of the lung common among young women. Primitive lumena lined by single cells is the characteristic pathologic feature. The endothelial nature of these cells is confirmed by positive staining with factor VIII and CD34. PEH usually presents as single or multiple pulmonary nodules. The present report describes high resolution CT (HRCT) findings of 2 cases with unusual manifestations of PEH. One case was a 54-year-old woman with multiple pulmonary nodules with irregular thickening of both the bronchovascular bundles and perilobular structures, representing intensive lymphangitic spread on HRCT. The other was an 18-year-old woman who had multiple minute peripheral nodules in the lungs bilaterally. These HRCT findings demonstrated the presence of tumor nodules in the lymphatic spaces, which is quite an unusual histologic presentation for this tumor. Both cases also showed hepatic lesions on abdominal CT; the former showing hypoattenuating masses with coarse calcifications and the latter showing multiple tiny calcifications in the hepatic parenchyma. Recognition of these features in the appropriate clinical setting may allow the clinician and the pathologist to consider this rare tumor.

Weekly paclitaxel and carboplatin with concurrent radiation therapy in locally advanced non-small cell lung cancer: phase I study.

PURPOSE: The optimal dose of weekly paclitaxel in combination with carboplatin and concurrent radiation therapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC) is not well defined in Japan. The purpose of this study was to define the maximum-tolerated dose (MTD) of paclitaxel in this combination. MATERIALS AND METHODS: Treatment consisted of weekly paclitaxel plus carboplatin fixed AUC 2 and CRT for a total 60 Gy at 2 Gy/fraction/day 5 times weekly for 6 weeks. The dose of paclitaxel was 25 mg/m2 in the first cohort and escalated by 5 mg/m2 per cohort. RESULTS AND CONCLUSION: A total of 18 patients were enrolled and analyzed. The dose limiting toxicity of this study was considered to be pulmonary toxicity, and the MTD of it was determined to be 45 mg/m2 of paclitaxel in patients with NSCLC. Further evaluation of this regimen in a phase II trial is underway.

Predictive value of dose-volume histogram parameters for predicting radiation pneumonitis after concurrent chemoradiation for lung cancer.

PURPOSE: To clarify whether the percentage of pulmonary volume irradiated to >20 Gy (V20) is related to the incidence and grade of radiation pneumonitis (RP) in cases of lung cancer treated with concurrent chemoradiation. METHODS AND MATERIALS: The subjects comprised 71 patients with lung cancer who were treated with conventionally fractionated definitive concurrent chemoradiation. The chemotherapy agents were carboplatin or cisplatin combined with taxane for most patients. Radiotherapy was delivered at 1.8-2.0 Gy fractions once daily to a total of 48-66 Gy (median 60). We analyzed the relation between RP grade and V20. Univariate and multivariate analyses were performed to assess patient- and treatment-related factors, including age, gender, smoking history, pulmonary function (forced expiratory volume in 1 s), tumor location (upper lobe vs. middle/lower lobe), chemotherapy regimen (platinum + taxane vs. other), total dose, overall radiation periods in addition to V20. RESULTS: With a median follow-up of 7.5 months, an RP grade of 0, 1, 2, 3, and 5 was observed in 16, 35, 17, 1, and 2 patients, respectively; the corresponding mean V20 values were 20.1%, 22.0%, 26.3%, 27.0%, and 34.5%. The 6-month cumulative incidence of RP greater than Grade 2 was 8.7%, 18.3%, 51%, and 85% in patients with a V20 of or=31%, respectively (p <0.0001). According to both univariate and multivariate analyses, V20 was the only factor associated with RP of Grade 2 or greater. CONCLUSION: The incidence and grade of RP are significantly related to the V20 value. Thus, V20 appears to be a factor that can be used to predict RP after concurrent chemoradiation for lung cancer.