Primary Cytomegalovirus Pneumonia Successfully Treated with Corticosteroid Therapy and Valganciclovir.

Cytomegalovirus infection is typically asymptomatic in immunocompetent individuals. A 26-year-old woman was admitted to our hospital with a fever and breathlessness. Chest computed tomography (CT) revealed bilateral diffuse reticulation and nodules. Laboratory investigations showed atypical lymphocytosis and increased transaminases. She was treated with corticosteroid pulse therapy because of acute lung injury, and her clinical condition improved. Based on the presence of cytomegalovirus antibodies, antigen, and polymerase chain reaction findings, she was diagnosed with primary cytomegalovirus pneumonia and treated with valganciclovir. Primary cytomegalovirus pneumonia is very rare in immunocompetent individuals. The efficacy of corticosteroid and valganciclovir against cytomegalovirus pneumonia in this patient is noteworthy.

Fixation rate of fiducial gold markers in each segmental bronchus for stereotactic body radiotherapy.

BACKGROUND: In real-time tumor-tracking radiotherapy for lung tumors, placement of fiducials, such as a gold marker (GM), is necessary. However, transbronchially placed GMs often drop out spontaneously. Therefore, we aimed to clarify the fixation rate of GMs in each segmental bronchus. METHODS: In this study, we examined the fixation rates of 791 GMs placed in 235 patients (259 procedures), from November 2011 to November 2020, at a single facility. The relationship between the elapsed time and the fixation rate was assessed using the Kaplan-Meier method. Moreover, we measured the distance between the GM and the chest wall (DMC), as confirmed using planning computed tomography, and analyzed the relationship of this distance with the fixation rate. RESULTS: Overall, 28.8% of GMs dropped out within 10 days of placement. The fixation rate of GMs in the bronchi was significantly lower in the upper lobe than in the other lobes, in both lungs (right, p < 0.01; left, p = 0.05). Moreover, in the left upper lobe, the fixation rate of GMs was significantly lower in B1+2 than in B3 (p = 0.0181). In addition, the group with a short DMC had a significantly higher GM fixation rate. (p < 0.01). CONCLUSIONS: The fixation rate of GMs was lower in the upper lobes than in the lower lobes. Additionally, the fixation rate was lower in B1+2 than in B3. Shorter DMCs were associated with higher GM fixation rates.

Two cases of trastuzumab deruxtecan-induced interstitial lung disease in advanced breast cancer.

Trastuzumab deruxtecan (T-DXd) frequently induces interstitial lung disease (ILD) more than other anti-human epidermal growth factor receptor 2 therapies. We diagnosed two cases of ILD induced by T-DXd in patients with advanced breast cancer. The first case is that of a 57-year-old Japanese woman who complained of dyspnoea and fever after 4 cycles of T-DXd. Chest computed tomography (CT) showed diffuse consolidation and a reticular shadow. The second case was that of a 72-year-old Japanese woman who complained of dyspnoea after 3 cycles of T-DXd. Chest CT showed a reticular shadow predominantly in the left lung. Both patients were treated with corticosteroids, including pulse methylprednisolone; however, their general condition weakened due to ILD, long-term corticosteroid therapy and breast cancer progression. Subsequently, the patients were unable to continue chemotherapy for breast cancer. To the best of our knowledge, this is the first report in a real-world clinical setting.

Low-dose oestrogen-progestin associated pulmonary infarction mimicking pneumonia and pleurisy.

A 28-year-old woman with a history of treatment with a low-dose oestrogen-progestin (LEP) formulation presented to our hospital due to right chest pain. She had just been discharged from another hospital for pneumonia and pleurisy which had improved with antibiotics. Contrast-enhanced computed tomography (CT) revealed bilateral pulmonary emboli corresponding to the peripheral consolidations. The pulmonary emboli indicated that the peripheral consolidation was due to pulmonary infarction (PI). No aetiological factors were identified except for the history of LEP therapy. Although the typical CT images of PI are consolidations in the peripheral area, these finding are non-specific for PI. This case of PI was misdiagnosed as infection because of response to antibiotics and similar CT findings. Therefore, careful evaluation of the patient history and clinical findings are imperative for accurate diagnosis. Venous thromboembolism can occur frequently around 3 months after the start of LEP treatment.

Granulomatous-lymphocytic Interstitial Lung Disease Associated with Good's Syndrome That Responded to Immunoglobulin Therapy.

Good's syndrome is associated with thymoma and acquired immunodeficiency. A 54-year-old man visited our hospital with a complaint of cough. Chest imaging revealed diffuse nodular shadows and anterior mediastinal mass. Hypogammaglobulinemia and a decreased B lymphocyte count were found by a laboratory evaluation. The lung nodules markedly regressed after immunoglobulin therapy. The mediastinal mass and remaining nodule were surgically resected and diagnosed as a type AB thymoma and a necrotizing epithelioid granuloma with T lymphocyte-dominant alveolitis, respectively. The overall appearances of these lesions were mostly in line with the spectrum of granulomatous-lymphocytic interstitial lung disease associated with Good's syndrome.

Idiopathic Pulmonary Hemosiderosis Associated with Emphysematous Change in an Adult Who Underwent Lung Transplantation.

Idiopathic pulmonary hemosiderosis is characterized by repeated alveolar hemorrhaging. We herein report a 52-year-old Japanese woman who had shortness of breath, diffuse small nodules, thin-walled cysts, and bronchiolectasis. A surgical lung biopsy revealed peribronchial hemosiderosis, centrilobular emphysema, and fragile elastic fibers of the alveolar septa and small vessels. She ultimately underwent living-donor lung transplantation five years after the first visit.

Airway-centered Interstitial Fibrosis Involving Smooth Muscle Hyperplasia with Severe Pulmonary Hypertension.

In the 2013 updated classification of the American Thoracic Society/European Respiratory Society, airway-centered interstitial fibrosis (ACIF) is included as a bronchiolocentric pattern of interstitial pneumonia (IP) among idiopathic IPs. We encountered a case of severe pulmonary hypertension (PH) with chronic IP. The patient initially presented with shortness of breath and often lost consciousness due to PH, and seven years after his first visit, he ultimately died. An autopsy revealed ACIF and usual IP. In particular, the ACIF comprised non-atypical smooth muscle hyperplasia, and pulmonary hypertensive vascular degeneration was detected. This case may represent a new pathological feature of ACIF.

Photo-degradation products of pramipexole.

Two pyrrolidine compounds (1 and 2) were isolated from photo-degradation of Bi-Sifrol tablets. Compound 1 was esterified to p-bromophenacyl ester as single-crystal, and then the structure was elucidated by single-crystal X-ray study. Compound 2 was determined by 2D NMR and mass spectra. Otherwise, we established that the photo-degradation of pramipexole was smoothly carried out in the methanol solution, and elucidate the degradation mechanism.

Initial findings and progression of lung adenocarcinoma on serial computed tomography scans.

OBJECTIVE: To study the initial findings of lung adenocarcinoma revealed by computed tomography (CT) scanning and observe tumor progression and elucidate appropriate follow-up schedule of tumor diagnosis via CT findings of suspected lung adenocarcinoma. METHOD: We studied 59 patients who had undergone CT scanning twice or more at intervals of 3 months or longer before surgery. We evaluated the initial CT findings as well as all subsequent changes. The rate of tumor growth was estimated by tumor volume doubling time, using the original method of Schwartz. The histological classifications were evaluated according to the criteria of Noguchi et al (Cancer 1995;75:2844-2852). RESULT: The initial appearances of lung adenocarcinoma were divided into 4 types: (1) ground-glass opacity-like lesions, (2) bubble-like appearance, (3) small nodules, and (4) scar-like lesions. Ground-glass opacity-like lesions tended to increase in size over the years, with solid parts appearing in some lesions during follow-up examinations. Bubble-like appearance displayed characteristic CT findings and tended to increase over the years from the time of initial diagnosis, and we therefore tended to consider them as old inflammatory lesions. Small nodules tended to increase in size over the months more rapidly than in other types. Scar-like lesions tended to exist mainly in the lungs already damaged by lung fibrosis and/or emphysema and therefore were difficult to detect on initial CT scans. CONCLUSION: We categorized 4 types of initial findings of lung adenocarcinomas detected by CT. We determined that each type of lesion had its own unique characteristic growth patterns and required varying follow-up periods.

[Case of pulmonary aspergillosis associated with inappropriate antidiuretic hormone syndrome caused by voriconazole therapy].

A 75-year-old man presented with hemoptysis. Consolidation was identified in the left lower lobe around multiple bullae. He was found to have chronic necrotizing pulmonary aspergillosis based on a high titer of aspergillus antigen and positive antibody. He was treated with 400 mg/day voriconazole. However, liver dysfunction and hyponatremia developed at 21 days after beginning administration of voriconazole. Serum sodium levels were 122 mEq/l. but urinary sodium showed a high level of 135 mEq/l. The serum sodium level improved 10 days after voriconazole was discontinued. Serum levels of voriconazole on day 15 were high at 18 microg/ml (safe effective serum level: 1.5 to 4.5 microg/ml). An analysis of genetic polymorphism showed a mutation of cytochrome P450 (CYP2C19*2 G681A). We report the first case of a voriconazole-induced syndrome of inappropriate antidiuretic hormone caused by a polymorphism mutation of cytochrome P450.

[Usefulness of FDG-PET for the diagnosis of postoperative recurrence of lung cancer].

No standardized postoperative follow-up strategy has been established for lung cancer patients, although CT and tumor markers are often employed. We conducted a retrospective study evaluating fluoro-2-deoxyglucose positron emission tomography (FDG-PET) for the diagnosis of postoperative recurrence of lung cancer. We evaluated 28 patients with suspected postoperative recurrence of lung cancer, who underwent FDG-PET between July 2004 and November 2005. Of these, 15 showed positive PET finings. Recurrence of lung cancer cases confirmed in 14 of these and the remaining case showed a postoperative scar. Thirteen patients with no findings on PET scan have demonstrated no evidence of recurrence during follow-up periods between 10 to 23 months. The negative predictive value was therefore 100%. FDG-PET in addition to chest CT and tumor markers for the diagnosis of the postoperative recurrence of lung cancer is considered to be beneficial in terms of avoiding excessive radiation exposure and limiting medical costs, but further evaluation in more patients is necessary.

Design, synthesis, and biological evaluation of the combinatorial library with a new spirodiketopiperazine scaffold. Discovery of novel potent and selective low-molecular-weight CCR5 antagonists.

We previously reported the discovery of several spirodiketopiperazine derivatives as potent CCR5 antagonists with anti-HIV activity. Herein, we describe in detail the identification of these lead compounds using a combinatorial chemistry approach. A novel spirodiketopiperazine scaffold was designed on the basis of the concept of the privileged structure of G-protein-coupled receptors (GPCRs). This new framework was obtained in acceptable yield with high purity from the readily prepared isonitrile resin through the Ugi reaction, sequential transformations, and cyclative cleavage. By measuring the inhibitory activity of each compound in the initial library against the intracellular calcium mobilization stimulated by MIP-1alpha, several compounds were found to show modest but selective CCR5 antagonistic activity. After the rapid evaluation of these hit compounds, several single-digit nanomolar, low-molecular-weight CCR5 antagonists that can potently block the infectivity and replication of laboratory and clinical strains of HIV as well as those of highly drug-resistant HIV variants with minimal cytotoxicity have been identified.

Synthesis of 8,9-leukotriene A4 by murine 8-lipoxygenase.

Arachidonate 8-lipoxygenase was identified in phorbol ester induced mouse skin. We expressed the enzyme in an Escherichia coli system using pET-15b carrying an N-terminal histidine-tag sequence. The enzyme, purified by nickel-nitrilotriacetate affinity chromatography, showed specific activity of about 0.1 micromol/min/mg of protein with arachidonic acid as a substrate. When metabolites of arachidonic acid were reduced and analyzed by reverse-phase HPLC, 8-hydroxy derivative was a major product as measured by absorbance at 235 nm. In addition, three polar compounds (I, II, and III) were detected by measuring absorbance at 270 nm. These compounds were also produced when the enzyme was incubated with 8-hydroperoxyeicosa-5,9,11,14-tetraenoic acid. Neither heat-inactivated enzyme nor mutated enzyme produced these compounds, suggesting that they are enzymatically generated. Ultraviolet spectra of these compounds showed typical triplet peaks around 270 nm, indicating that they have a triene structure. Molecular weight of these compounds was determined to be 336 by liquid chromatography-mass spectrometry, indicating that they carry two hydroxyl groups. Compounds I and III were generated even under anaerobic condition, indicating that oxygenation reaction was not required for their generation from 8-hydroperoxyeicosa-5,9,11,14-tetraenoic acid. By analogy to the reactions of 5-lipoxygenase pathway where leukotriene A4 is generated, it is suggested that 8-hydroperoxyeicosa-5,9,11,14-tetraenoic acid is converted by the 8-lipoxygenase to 8,9-epoxyeicosa-5,10,12,14-tetraenoic acid which degrades to compounds I and III by non-enzymatic reaction. In contrast, compound II was not generated under anaerobic condition, indicating that it was produced by oxygenation reaction. Taken together, 8-lipoxygenase catalyzes both dehydration reaction to yield 8,9-epoxy derivative and oxygenation reaction presumably at 15-position of 8-hydroperoxyeicosa-5,9,11,14-tetraenoic acid.

Genomewide cDNA microarray screening of genes related to benefits and toxicities of platinum-based chemotherapy in patients with advanced lung cancer.

The authors conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with the outcome of chemotherapy. Forty-seven patients were studied, and all except 3 received platinum-based chemotherapy. The expression levels of 1176 genes in transbronchial biopsy specimens of tumors that were obtained before chemotherapy were analyzed using the Atlas Human Cancer 1.2 Array. Multivariate regression analysis revealed that 3 genes were each independent factors related to tumor resistance to chemotherapy and patient survival (P < 0.01). Among various chemotherapy-related toxicities, 1, 3, 3, 1, and 1 genes were also revealed to be independent factors that were correlated with neutropenia, anemia, diarrhea, infection, and increased serum creatinine respectively (P < 0.01). It is concluded that not only the benefits but also the toxicities of chemotherapy can be predicted by cDNA microarray using tumor specimens obtained before chemotherapy.

A new function of isonitrile as an inhibitor of the Pdr5p multidrug ABC transporter in Saccharomyces cerevisiae.

Pdr5p in Saccharomyces cerevisiae is a functional homologue of mammalian P-glycoprotein implicated in multidrug resistance (MDR). In order to obtain useful inhibitors to overcome MDR in clinical tumors, screening of Pdr5p inhibitors has been carried out. We isolated a fungal strain producing Pdr5p inhibitors using our original assay system, and it was classified as Trichoderma sp. P24-3. The purified inhibitor was identified as isonitrile, 3-(3'-isocyano-cyclopent-2'-enylidene)-propionic acid, a compound whose carboxyl residue is essential for the inhibitory activity. A non-toxic concentration of the isonitrile (41.5 microg/ml, 255 microM) inhibited Pdr5p-mediated efflux of cycloheximide or cerulenin in Pdr5p-overexpressing cells. In addition, addition of the isonitrile led to accumulation of rhodamine 6G, a substrate of Pdr5p, in the Pdr5p-overexpressing cells. The inhibitory profiles of the isonitrile against S1360 mutants (S1360A and S1360F) of Pdr5p were different from those of FK506 and enniatin. The isonitrile did not influence PDR5 gene expression and the amount of Pdr5 protein, nor did it inhibit the function of Snq2p, a homologue of Pdr5p. Interestingly, the isonitrile inhibited the function of Cdr1p and Cdr2p, Pdr5p homologues in pathogenic yeast Candida albicans. Thus, it was found that the isonitrile shows a different inhibitory spectrum from that of FK506 and enniatin as a potent inhibitor for Pdr5p, Cdr1p, and Cdr2p.

Enniatin has a new function as an inhibitor of Pdr5p, one of the ABC transporters in Saccharomyces cerevisiae.

Pdr5p is one of the major multidrug efflux pumps whose overexpression confers multidrug resistance (MDR) in Saccharomyces cerevisiae. By using our original assay system, a fungal strain producing inhibitors for Pdr5p was obtained and classified as Fusarium sp. Y-53. The purified inhibitors were identified as ionophore antibiotics, enniatin B, B1, and D, respectively. A non-toxic concentration of each enniatin (5 microg/ml, approximately 7.8 microM) strongly inhibited a Pdr5p-mediated efflux of cycloheximide or cerulenin in Pdr5p-overexpressing cells. The enniatins accumulated a fluorescent dye rhodamine 123, a substrate of Pdr5p, into yeast cells. The mode of Pdr5p inhibition of enniatin was competitive against FK506, and its inhibitory activity was more potent with less toxicity than that of FK506. The enniatins showed similar inhibitory profile as FK506 against S1360 mutants (S1360A and S1360F) of Pdr5p. The enniatins did not inhibit the function of Snq2p, a homologue of Pdr5p. Thus, it was found that enniatins are potent and specific inhibitors for Pdr5p, with less toxicities than that of FK506.

Genomic-wide cDNA microarray screening to correlate gene expression profile with chemoresistance in patients with advanced lung cancer.

We conducted a study using cDNA microarray analysis to determine whether expression levels of genes in tumors were correlated with tumor response to chemotherapy. Between September 2000 and December 2001, 47 patients were registered in the study. Eighteen patients had small cell lung cancer (SCLC), and others had non-small cell lung cancer (NSCLC). All patients except three received platinum-based chemotherapy. Sixteen of the 18 patients with SCLC (89%) and 13 of the 29 patients with NSCLC (45%) responded to chemotherapy, respectively. Transbroncheal biopsy specimens of tumors were obtained before chemotherapy. The expression levels of 1176 genes in tumor specimens were analyzed using the Atlas Human Cancer 1.2 Array. When we analyzed the data for correlations between gene expression levels and tumor response to chemotherapy, there was a significant increase in the expression of nine genes in non-responders compared with responders to chemotherapy (p< 0.01). Multivariate regression analysis revealed that allogenic inflammatory factor, HLA-DR antigen associated invariant subunit and MHC class II HLA-DR-beta precursor were independent chemo-resistant factors (p<0.0001). When we analyzed the differences in gene expression levels between patients with SCLC and NSCLC, expression levels of one or more resistant genes were increased in comparison with the mean expression of control house keeping genes in five of 18 SCLC patients and 19 of 29 NSCLC patients, respectively (p=0.012). In conclusion, some chemo-resistant genes were detected in the tumor tissue of lung cancer patients using cDNA microarray analysis. A prospective study is required to confirm whether expression levels of these genes reflect chemosensitivity.

Prognostic impact of survivin, cyclin D1, integrin beta1, and VEGF in patients with small adenocarcinoma of stage I lung cancer.

The purpose of this study was to investigate the impact of survivin, cyclin D1, integrin beta1, and vascular endothelial growth factor (VEGF) in tumor on survival of patients with small adenocarcinoma of the lung. Seventy-two patients with pathologic stage I resected tumors <2 cm in diameter were entered into the study. Each patient underwent curative surgical resection for lung cancer between July 1992 and November 1999. The resected tumors were subjected to immunostaining for each gene. Thirty-five, 26, 6, and 16 patients had tumors with >10% survivin-, >20% cyclin D1-, >10% integrin beta1-, and >10% VEGF-positive cells, respectively. When the survival of 72 patients was compared according to each gene expression, the overall survival of patients with positive expression of survivin, cyclin D1, and integrin [beta]1 was significantly worse than that of individuals whose tumors had negative expression of each gene. By multivariate analysis controlling for each gene expression, no gene expression was an independent marker of poor prognosis, however, the overall survival of the complex gene expression (2 or more gene-positive) group (n = 35) was significantly worse than that of 0 or 1 gene-positive group (n = 37; log-rank test, P = 0.0011; Wilcoxon test, P = 0.0011). When the association between survival and pathologic factors, including lymphatic invasion, venous invasion, type of bronchioalveolar carcinoma, and complex gene positive expression was analyzed, only complex gene-positive expression was found to be a significant independent factor (hazard ratio = 0.085, P = 0.0299). It can be concluded that multiple increased expression of oncogene is a poor prognostic factor in patients with small adenocarcinoma of the lung.

High expression of integrin beta1 and p53 is a greater poor prognostic factor than clinical stage in small-cell lung cancer.

The purpose of this study was to investigate the possible association between expression of integrin beta1 and p53 and survival in patients with small-cell lung cancer (SCLC). One hundred four patients with SCLC who had received an initial course of a full-dose of combination chemotherapy between February 1989 and July 1999 were entered in the study. Transbronchial biopsy specimens of tumors obtained before chemotherapy were subjected to immunostaining for integrin beta1 and p53. Twenty-eight and 58 patients could not be evaluated for integrin beta1 and p53 immunostaining, respectively, because the tissue samples had been crushed during the biopsy. Fifty-four patients had tumors with less than or equal to 25% integrin beta1-positive cells and 22 patients had tumors with more than 25% integrin beta1-positive cells, whereas 19 and 27 patients had tumors with less than or equal to 50% and more than 50% p53-positive cells, respectively. By comparison, the overall survival of patients with high expression of integrin beta1 and p53 were significantly worse than those of individuals whose tumors had low expression (log-rank test, p = 0.046 and p = 0.0067, respectively). Moreover, the overall survival of patients with high expression of either integrin beta1 or p53 (n = 42) was significantly worse than that of other patients without high expression of integrin beta1 and p53 (n = 38; log-rank test, p = 0.0003; Wilcoxon test, p = 0.0026). The association between survival and prognostic factors, including gender, age, performance status, clinical stage, and integrin beta1/p53 expression was examined by the Cox proportional hazards model; only integrin beta1/p53 expression was found to be a significant independent factor (hazard ratio = 0.394, p = 0.0005). In conclusion, the high expression of integrin beta1 and p53 in tumor cells is a greater poor prognostic factor than clinical stage in patients with SCLC.

Acute and late effects on induction of allodynia by acromelic acid, a mushroom poison related structurally to kainic acid.

1. Ingestion of a poisonous mushroom Clitocybe acromelalga is known to cause severe tactile pain (allodynia) in the extremities for a month and acromelic acid (ACRO), a kainate analogue isolated from the mushroom, produces selective damage of interneurons of the rat lower spinal cord when injected either systemically or intrathecally. Since ACRO has two isomers, ACRO-A and ACRO-B, here we examined their acute and late effects on induction of allodynia. 2. Intrathecal administration of ACRO-A and ACRO-B provoked marked allodynia by the first stimulus 5 min after injection, which lasted over the 50-min experimental period. Dose-dependency of the acute effect of ACRO-A on induction of allodynia showed a bell-shaped pattern from 50 ag x kg(-1) to 0.5 pg x kg(-1) and the maximum effect was observed at 50 fg x kg(-1). On the other hand, ACRO-B induced allodynia in a dose-dependent manner from 50 pg x kg(-1) to 50 ng x kg(-1). 3. N-methyl-d-aspartate (NMDA) receptor antagonists and Joro spider toxin, a Ca(2+)-permeable AMPA receptor antagonist, inhibited the allodynia induced by ACRO-A, but not by ACRO-B. However, other AMPA/kainate antagonists did not affect the allodynia induced by ACRO. 4. Whereas no neuronal damage was observed in the spinal cord in ACRO-A-treated mice, induction of allodynia by ACRO-A (50 fg x kg(-1)) and ACRO-B (50 ng x kg(-1)) was selectively lost 1 week after i.t. injection of a sublethal dose of ACRO-A (50 ng x kg(-1)) or ACRO-B (250 ng x kg(-1)). Higher doses of ACRO-A, however, could evoke allodynia dose-dependently from 50 pg x kg(-1) to 500 ng x kg(-1) in the ACRO-A-treated mice. The allodynia induced by ACRO-A (500 ng x kg(-1)) was not inhibited by Joro spider toxin or NMDA receptor antagonists. These properties of the late allodynia induced by ACRO-A were quite similar to those of the acute allodynia induced by ACRO-B. 5. ACRO-A could increase [Ca(2+)](i) in the deeper laminae, rather than in the superficial laminae, of the spinal cord. This increase was not blocked by the AMPA-preferring antagonist GYKI52466 and Joro spider toxin. 6. Taken together, these results demonstrate the stereospecificity of ACRO for the induction of allodynia and suggest the presence of a receptor specific to ACRO.