A clustering approach to identify and characterize the asthma and chronic obstructive pulmonary disease overlap phenotype.

BACKGROUND: Asthma and chronic obstructive pulmonary disease (COPD) are heterogeneous diseases. The phenotypes that have clinical features of both asthma and COPD are still incompletely understood. OBJECTIVE: To clarify the best discriminators of the asthma-COPD overlap phenotype from asthma and COPD subgroups using a clustering approach. METHODS: This study assessed pathophysiological parameters, including mRNA expression levels of T helper cell-related transcription factors, namely TBX21 (Th1), GATA3 (Th2), RORC (Th17) and FOXP3 (Treg), in peripheral blood mononuclear cells in asthma patients (n=152) and in COPD patients (n=50). Clusters were determined using k-means clustering. Exacerbations of asthma and COPD were recorded during the 1-year follow-up period. RESULTS: The cluster analysis revealed four biological clusters: cluster 1, predominantly patients with COPD; cluster 2, patients with an asthma-COPD overlap phenotype; cluster 3, patients with non-atopic and late-onset asthma; and cluster 4, patients with early-onset atopic asthma. Hazard ratios for exacerbation were 2.5 (95% confidence interval [CI], 1.1-5.6) in cluster 1 and 2.3 (95% CI, 1.0-5.0) in cluster 2 compared with patients in other clusters. Cluster 2 was discriminated from other clusters by total serum IgE level ≥310 IU/mL, blood eosinophil counts ≥280 cells/µL, a higher ratio of TBX21/GATA3, FEV1 /FVC ratio <0.67 and smoking ≥10 pack-years with an area under the curve of 0.94 (95% CI, 0.90-0.98) in the receiver operating characteristic analysis. CONCLUSIONS AND CLINICAL RELEVANCE: The asthma-COPD overlap phenotype was characterized by peripheral blood eosinophilia and higher levels of IgE despite the Th2-low endotype.

Influence of ABCB1 and ABCG2 polymorphisms on the antiemetic efficacy in patients with cancer receiving cisplatin-based chemotherapy: a TRIPLE pharmacogenomics study.

Resistance to antiemetic treatment with 5-hydroxytryptamine-3 receptor antagonist is an issue. This study evaluated the potential roles of ABCB1 and ABCG2 polymorphisms in antiemetic treatment resistance in patients with cancer previously enrolled in a randomized controlled trial. A total of 156 patients were evaluated for their responses to antiemetic therapy and then subdivided into granisetron or palonosetron groups. The genotypes were evaluated for their association with antiemetic efficacy in each treatment groups. Additional risk factors associated with complete response (CR) were examined using a multivariate regression analysis. No significant associations were identified for genetic polymorphisms in the palonosetron group. In the granisetron group, patients with ABCB1 2677TT and 3435TT genotypes had higher proportion of CR. In addition to ABCB1 polymorphisms, gender and cisplatin dose were associated with granisetron response by univariate analysis. Multivariate logistic regression analysis revealed that the ABCB1 3435C>T polymorphism and cisplatin dose were significant predictors of CR.

Pim-2 kinase is an important target of treatment for tumor progression and bone loss in myeloma.

Pim-2 kinase is overexpressed in multiple myeloma (MM) cells to enhance their growth and survival, and regarded as a novel therapeutic target in MM. However, the impact of Pim-2 inhibition on bone disease in MM remains unknown. We demonstrated here that Pim-2 expression was also upregulated in bone marrow stromal cells and MC3T3-E1 preosteoblastic cells in the presence of cytokines known as the inhibitors of osteoblastogenesis in MM, including interleukin-3 (IL-3), IL-7, tumor necrosis factor-α, transforming growth factor-ß (TGF-ß) and activin A, as well as MM cell conditioned media. The enforced expression of Pim-2 abrogated in vitro osteoblastogenesis by BMP-2, which suggested Pim-2 as a negative regulator for osteoblastogenesis. Treatment with Pim-2 short-interference RNA as well as the Pim inhibitor SMI-16a successfully restored osteoblastogenesis suppressed by all the above inhibitory factors and MM cells. The SMI-16a treatment potentiated BMP-2-mediated anabolic signaling while suppressing TGF-ß signaling. Furthermore, treatment with the newly synthesized thiazolidine-2,4-dione congener, 12a-OH, as well as its prototypic SMI-16a effectively prevented bone destruction while suppressing MM tumor growth in MM animal models. Thus, Pim-2 may have a pivotal role in tumor progression and bone loss in MM, and Pim-2 inhibition may become an important therapeutic strategy to target the MM cell-bone marrow interaction.

Small molecule antibody targeting HLA class I inhibits myeloma cancer stem cells by repressing pluripotency-associated transcription factors.

Cancer stem cells have been proposed to be responsible for tumorigenesis and recurrence in various neoplastic diseases, including multiple myeloma (MM). We have previously reported that MM cells specifically express HLA class I at high levels and that single-chain Fv diabody against this molecule markedly induces MM cell death. Here we investigated the effect of a new diabody (C3B3) on cancer stem cell-like side population (SP) cells. SP fraction of MM cells highly expressed ABCG2 and exhibited resistance to chemotherapeutic agents; however, C3B3 induced cytotoxicity in both SP cells and main population (MP) cells to a similar extent. Moreover, C3B3 suppressed colony formation and tumorigenesis of SP cells in vitro and in vivo. Crosslinking of HLA class I by C3B3 mediated disruption of lipid rafts and actin aggregation, which led to inhibition of gene expression of ß-catenin and pluripotency-associated transcription factors such as Sox2, Oct3/4 and Nanog. Conversely, knockdown of Sox2 and Oct3/4 mRNA reduced the proportion of SP cells, suggesting that these factors are essential in maintenance of SP fraction in MM cells. Thus, our findings reveal that immunotherapeutic approach by engineered antibodies can overcome drug resistance, and provide a new basis for development of cancer stem cell-targeted therapy.

The relationship of changes in EORTC QLQ-C30 scores to ratings on the Subjective Significance Questionnaire in men with localized prostate cancer.

PURPOSE: To examine the relationship between changes in health-related quality-of-life (HRQOL) on the EORTC Quality of Life Questionnaire (QLQ-C30), and patients' perceptions of HRQOL changes as measured by the Subjective Significance Questionnaire (SSQ). PATIENTS AND METHODS: A total of 101 patients completed the QLQ-C30 on weeks 1, 4 and 7 of radical external-beam radiation therapy (RT) for localized cancer of the prostate. Patients rated their change in physical functioning, emotional functioning, social functioning, and overall/global quality of life (QOL) by completing a seven-category SSQ at weeks 4 and 7. The association between changes in the QLQ-C30 change and the corresponding SSQ ratings were determined by calculation of mean change scores for each SSQ category and by Spearman rank correlation coefficient analysis. RESULTS: Patients' completion of the QLQ-C30 and SSQ exceeded 95%. Statistically significant changes in fatigue, pain, appetite, diarrhea, and global QOL scores were detected during RT. For patients reporting 'a little' change in global QOL on the SSQ, absolute mean QLQ-C30 change scores ranged between 0 to 15 points with 12/16 mean change scores between 2.5 and 8.5 points. In the entire study sample, correlations between SSQ patient ratings and QLQ-C30 change scores were lower than previously reported, ranging between 0.15 and 0.24 for the four different domains, but were higher when QOL scores producing ceiling effects were omitted. CONCLUSION: The SSQ and QLQ-C30 may measure related concepts that could assist in the interpretation of changes in scores and in the calibration of the QLQ-C30. However, the nature of this relationship could not be elucidated in this data set because of a lack of variance in HRQOL scores in the study sample. Further investigation should be carried out in study samples with sufficient variance to allow more robust conclusions.

Midline lateralization thyroplasty for adductor spasmodic dysphonia.

Midline lateralization thyroplasty was successfully performed on a patient with adductor spasmodic dysphonia. The thyroid cartilage was incised at the midline, and a 3 x 2-mm perforation was made at the anterior commissure to widen it. The perforation was closed with a free composite graft taken from the upper edge of the thyroid ala, and the incised thyroid cartilage edges were kept separated 4 mm apart with silicone wedges. A part of the sternohyoid muscle was rotated to seal any leak from the perforation. The postoperative course was uneventful. The voice has been restored to normal, and there is no sign of recurrence of the symptom so far, as of 1 year 5 months postoperative. Although a longer follow-up is needed, this case indicates that midline type II thyroplasty could be a useful treatment for adductor spasmodic dysphonia.

Spontaneous cervical hematoma: a report of two cases.

Cervical hematomas are generally associated with trauma, surgery, and tumors. Although they are rare, they can be life-threatening because they put the patient at risk for great-vessel compression and upper airway obstruction. We describe two cases of spontaneous cervical hematoma--one in an 81-year-old man and the other in a 30-year-old woman. The man reported dysphonia, dysphagia, and neck swelling of 5 hours' duration. He had been taking 100 mg/day of aspirin for a cardiovascular condition. Examination revealed that the man had polycythemia vera. The woman was found to have neck ache, odynophagia, and cervical ecchymosis; portal hypertension, schistosomiasis, and blood dyscrasia were also found. Both patients denied trauma. A suspected diagnosis of cervical hematoma was confirmed by computed tomography, and treatment was instituted. The hematomas resolved in about 2 weeks. The treatment of cervical hematoma is controversial, although it is agreed that the evaluation of upper airway obstruction and its permeability is mandatory. Surgical treatment is generally reserved for complicated cases because of the risk of infection or bleeding.

Effect of filgrastim (G-CSF) during chemotherapy and abdomino-pelvic radiation therapy in patients with ovarian carcinoma.

PURPOSE: To evaluate the safety and effectiveness of filgrastim (granulocyte colony-stimulating factor, G-CSF) in reducing neutropenia and treatment interruptions during whole abdominal radiotherapy for ovarian cancer. METHODS AND MATERIALS: Sixteen patients with ovarian cancer treated with 2 to 6 courses of cisplatin-containing chemotherapy and abdomino-pelvic radiation therapy received filgrastim for neutrophil counts <2 x 10(9)/L. Endpoints for analysis included the ability to maintain the neutrophil count in the target range, number of treatment interruptions due to neutropenia, and toxicity attributed to filgrastim. RESULTS: Fourteen patients received a mean of 2.9 courses of filgrastim (each with a mean duration of 4.1 days), with no treatment interruptions due to neutropenia. The majority of neutrophil counts were maintained above the target range of 2 x 10(9)/L during treatment. Thrombocytopenia requiring treatment interruption was seen in six patients and necessitated platelet transfusions in one. Thrombocytopenia occurred at a mean abdominal radiation dose of 2207 cGy and in all but one patient was preceded by one or more episodes of neutropenia. In comparison with a control group of 31 patients treated without filgrastim there was no reduction in treatment interruptions. Four patients did not complete treatment because of persistent thrombocytopenia yet received a mean of 94% of the planned abdominal radiation dose and 69% of the planned pelvic dose. Filgrastim toxicity was limited to mild skeletal pains in six patients and a Grade 1 skin rash in two patients. CONCLUSIONS: Filgrastim is safe and effective in preventing neutropenia and reducing neutropenic treatment interruptions during abdominal radiotherapy in patients with ovarian cancer. However, there was no clear benefit to the use of filgrastim as thrombocytopenia became the dose-limiting toxicity resulting in a risk of treatment interruptions and early termination of radiotherapy.

Paradoxical vocal fold movement: a case report.

We present a case of one patient with respiratory stridor that was resolved by speech therapy. Paradoxical vocal fold movements were observed by flexible fiberoptic videolaryngoscopy in this patient during episodes of wheezing and dyspnea. Otherwise, normal vocal fold movement was observed in normal conditions of breathing (out of the crisis) and during phonation. Many different terms have been used to describe this entity in the literature, and it is crucial that clinicians recognize the subtle signs of functional stridor. Paradoxical vocal fold motion has to be considered as an important cause of respiratory disease. Its recognition and treatment are discussed in this report.

Actinomycosis of the larynx.

Actinomycosis is a disease characterized by a chronic suppurative and granulomatous process which tends to form multiple pyogenic draining sinus tracts. The most common site in which it occurs is the cervico-facial region, especially in the submandibular area. The exudates from the fistulous tracts usually contain yellow granules known as "sulfur granules," which can be considered as a hallmark of actinomycosis. We report a rare case of laryngeal actinomycosis which occurred in a 68-year-old male who had been irradiated 8 years before due to laryngeal carcinoma. During the admission, the patient was also diagnosed as being a myelodisplastic syndrome carrier. The patient was treated successfully with penicillin 10 million IU administered daily over 40 days. The etiologic agents, predisposing factors, diagnostic procedures, and available treatments are discussed, and the pertinent literature is reviewed herein.

Displacement of the ventricular fold following cordectomy.

In order to avoid radiation and its undesirable side effects, we have employed surgical techniques for treatment of early glottic cancer when the lesion is confined to one membranous cord (Fukuda, Saito, Sato, and Kitahara: J. Jpn. Bronchoesophagol. Soc. 30: 7-14, 1979; Fukuda and Saito: Otologica 26: 434-436, 1980; Fukuda, Kawaida, Ohki, Kawasaki, Kita, and Tatehara: J. Jpn. Bronchoesophagaol. Soc. 39: 139-144, 1988). Laser is one of the most popular techniques and it has been accepted as the first choice by many authors (Annyas, Overbeek, Escajadillo, and Hoeksema: Laryngoscope 94: 836-838, 1984; Mcguirt and Koufman: Arch. Otolaryngol. Head Neck Surg. 113: 501-505, 1987; Tsuji, Fukuda, Kawaskai, Kawaida, and Kanzaki: Keio J. Med. 38: 413-418, 1989). However, some cases are difficult to approach by direct laryngoscopy, requiring an external way to expose the lesion. In these cases, cordectomy by laryngofissure is the method of choice, but the function of the glottis could be improved by replacing the excised cord displacing the ventricular fold. This technique, designed by the authors, was carried out in 22 patients and the results from the viewpoint of phonodynamics, voice quality, and cure rate are discussed in this study. The results are encouraging and we believe that this method is a very reasonable alternative to the laser when such equipment is not available. We also believe that late side effects and oncogenic problems associated with radiation are important points to be considered, especially in patients of relatively younger age.

A clinical study on T1 glottic cancer treated by laser technique.

It is commonly accepted that radiotherapy is a first choice for treatment of T1 glottic cancer. However, side effects caused by irradiation are sometimes troublesome to a patient and to a physician. Among side effects, oncogenic problem and late radiation change are most undesirable and may become fatal. Hence, we avoid radiation therapy especially for younger aged patients. We prefer surgical therapy to radiotherapy for such a case. In our clinic, laser therapy has been employed. A laser beam is introduced through an operation microscope and a lesion can be microscopically vaporized. In this study, a survey of 40 patients with T1 glottic cancer submitted to laser surgery was reviewed. From those patients 25 were T1a and 15 were T1b. From our experience, laser vaporization is recommendable for T1 glottic cancer in younger aged patients. However, in order to obtain cure rate comparable to radiation therapy, the indication must be correctly designated.