Masakazu Yoshioka

Expression of constitutively activated EGFRvIII in non-small cell lung cancer.

The epidermal growth factor receptor (EGFR) variant type III (variously called EGFRvlll, de2–7 EGFR or ΔGFR) has an in‐frame deletion of the extracellular domain and is found in numerous types of human tumors. Since EGFRvlll has been reported to be tumorspecific and has oncogenic potential, it is being investigated as a potential therapeutic target. Because the cell‐specific expression of EGFRvlll in lung has not been well documented, we examined the expression of EGFRvlll in 76 non‐small cell lung cancers (NSCLCs) and 10 non‐neoplastic lung tissues by immunohistochemistry using a new monoclonal antibody specific for this variant receptor. We found a higher incidence (30 of 76, 39%) of enhanced EGFRvlll expression in NSCLC than previously described. Interestingly, the presence of EGFRvlll was also observed in several normal tissue components of lung (e.g., normal bronchial epithelium). Given the high prevalence of EGFRvlll in NSCLC, a newly developed phospho‐specific (activated) EGFR antibody was employed for immunohistochemical analysis that permitted visualization of activated EGFR and/or EGFRvlll in tumors. This study presents evidence, for the first time, that EGFRvlll expressed in human tumors is phosphorylated and hence activated. Our results suggest that the sustained activation of EGFRvlll is implicated in the pathogenesis of NSCLC and thus EGFRvlll is a potential therapeutic target in this challenging disease. (Cancer Sci 2003; 94: 50–56)

Loss of alveolar basement membrane type IV collagen α3, α4, and α5 chains in bronchioloalveolar carcinoma of the lung

Type IV collagen, the major component of basement membrane (BM), is composed of six genetically distinct α(IV) chains. This study investigated for the first time the expression of these six α(IV) chains immunohistochemically, using α(IV) chain‐specific monoclonal antibodies, in normal lung and in small (less than 2 cm in diameter) adenocarcinoma of the lung with a bronchioloalveolar growth pattern at the periphery. Small adenocarcinomas were histopathologically classified into three subtypes: bronchioloalveolar carcinoma (BAC) without collapse, BAC with collapse, and adenocarcinoma with bronchioloalveolar features. In normal lung, alveolar BM was composed of α1(IV)/α2(IV) chains and α3(IV)/α4(IV)/α5(IV) chains. In non‐collapsed areas of BAC, alveolar BM was composed of linear α1(IV)/α2(IV) chains and discontinuous α3(IV)/α4(IV)/α5(IV) chains. In collapsed areas of BAC, alveolar BM was composed of linear and thick α1(IV)/α2(IV) chains only, because of the complete loss of α3(IV)/α4(IV)/α5(IV) chains. In invasive areas of adenocarcinoma with bronchioloalveolar features, α1(IV)/α2(IV) chains around the cancer cell nests were disrupted, in addition to the complete loss of α3(IV)/α4(IV)/α5(IV) chains. In conclusion, during the process of stromal invasion of lung adenocarcinoma, type IV collagen of alveolar BM is remodelled from the complete type, composed of α1(IV)/α2(IV)/α3(IV)/α4(IV)/α5(IV) chains, to the incomplete type, composed of only α1(IV)/α2(IV) chains, before the disruption of α1(IV)/α2(IV) chains. These findings may help to clarify the molecular mechanisms of cancer invasion. Copyright

Fibroproliferative changes on high-resolution CT in the acute respiratory distress syndrome predict mortality and ventilator dependency: a prospective observational cohort study

Objectives To examine whether the extent of fibroproliferative changes on high-resolution CT (HRCT) scan influences prognosis, ventilator dependency and the associated outcomes in patients with early acute respiratory distress syndrome (ARDS). Design A prospective observational cohort study. Setting Intensive care unit in a teaching hospital. Participants 85 patients with ARDS who met American-European Consensus Conference Criteria and eligible criteria. Interventions HRCT scans were performed and prospectively evaluated by two independent observers on the day of diagnosis and graded into six findings according to the extent of fibroproliferation. An overall HRCT score was obtained by previously published method. Primary and secondary outcomes The primary outcome was 60-day mortality. Secondary outcomes included the number of ventilator-free days, organ failure-free days, the incidence of barotraumas and the occurrence of ventilator-associated pneumonia. Results Higher HRCT scores were associated with statistically significant decreases in organ failure-free days as well as ventilator-free days. Multivariate Cox proportional hazards model showed that the HRCT score remained an independent risk factor for mortality (HR 1.20; 95% CI 1.06 to 1.36; p=0.005). Multivariate analysis also revealed that the CT score had predictive value for ventilator weaning within 28 days (OR 0.63; 95% CI 0.48 to 0.82; p=0.0006) as well as for an incidence of barotraumas (OR 1.61; 95% CI 1.08 to 2.38; p=0.018) and for an occurrence of ventilator-associated pneumonia (OR 1.46; 95% CI 1.13 to 1.89; p=0.004). A HRCT score <210 enabled prediction of 60-day survival with 71% sensitivity and 72% specificity and of ventilator-weaning within 28 days with 75% sensitivity and 76% specificity. Conclusions Pulmonary fibroproliferation assessed by HRCT in patients with early ARDS predicts increased mortality with an increased susceptibility to multiple organ failure, including ventilator dependency and its associated outcomes.

Successful Polymyxin B Hemoperfusion Treatment Associated With Serial Reduction of Serum Anti-CADM-140/MDA5 Antibody Levels in Rapidly Progressive Interstitial Lung Disease With Amyopathic Dermatomyositis

Clinically amyopathic dermatomyositis (CADM), a subtype of dermatomyositis with subtle or no muscle involvement, is occasionally accompanied by fatal, rapidly progressive interstitial lung disease (RP-ILD) that is resistant to aggressive immunosuppressive therapy. The presence of anti-CADM-140/MDA5 antibodies is diagnostic for patients with dermatomyositis (particularly CADM) and is known to be strongly associated with the pathogenesis, disease activity, and mortality of RP-ILD. Polymyxin-B direct hemoperfusion (PMX-DHP), originally developed for the removal of endotoxin, has been demonstrated to be effective for treating various types of acute respiratory failure. We describe a patient with amyopathic dermatomyositis who developed RP-ILD characterized by elevated anti-CADM-140/MDA5 autoantibodies, was resistant to combined steroid and immunosuppressant therapy, and was treated successfully with PMX-DHP. To our knowledge, this is the first case to indicate a serial reduction of anti-CADM-140/MDA5 autoantibodies, associated with clinical improvement, following PMX-DHP. Early intervention using PMX-DHP may improve the prognosis of RP-ILD accompanied by CADM.

Primary leiomyosarcoma of the thyroid gland.

A primary leiomyosarcoma of the thyroid gland in a 72 year old Japanese woman is described. This is the second case reported in the English literature. The patient presented with a 7 month history of a gradually expanding tumor in the right neck. The surgical specimen taken by thyroid lobectomy revealed a relatively well demarcated tumor, 2X2X3 cm in size, confined to the right lobe. Histologically, the tumor showed a classical leiomyosarcomatous appearance of interlacing fascicles of spindle‐shaped cells with occasional blunt‐ended nuclei and a high frequency of mitotic figures. lmmunohistochemistry of the tumor cells clearly showed smooth muscle differentiation; the cells were positive for desmin, muscle‐specific action and vimentin and negative for cytokeratin, epithelial membrane antigen, carcinoembrionic antigen, thyroglobulin and calcitonin. The patient was free of disease for 3 years and 11 months without further treatment when evidence of multiple bone metastases appeared on bone scintigraphy. She died of pneumonia 4 years and 3 months after the lobectomy.

Microscopic-Sized “Microthymoma” in Patients With Myasthenia Gravis

BACKGROUND In 2005, Cheuk et al reported two patients with microscopic-sized thymomas and proposed the term microthymoma to distinguish it from the nodular hyperplasia of thymic epithelium, so-called microscopic thymoma. Here, we present microthymomas that were found in 196 patients with myasthenia gravis (MG) who had undergone thymectomy. MATERIALS AND METHODS Thymic tissues in 196 patients with MG who underwent thymectomy or thymothymomectomy were examined. Of these patients, 73 patients had thymoma indicated by CT before surgery, and the other 123 patients had no mediastinal tumors. From the resected thymic tissues, an average of 14 hematoxylin-eosin-stained sections (range, 4 to 55 sections) were prepared for microscopic examination. The histologic type of the thymoma was classified according to the World Health Organization (WHO) classification. RESULTS From the 196 patients, we found three microthymomas in 3 patients (1.5%). While these three tumors could not be seen grossly in pathology section, they were found microscopically (range, 2 to 4 mm). The histologic subtype according to the WHO classification system was B1 in one patient and B2 in two patients. CONCLUSION Microthymoma was found in 3 of 196 patients (1.5%) with MG. Microthymoma might exist in thymus of patients with MG, even in patients who have no thymoma indicated by CT.

DOES NEOADJUVANT CHEMOTHERAPY FOR CARCINOMA IN THE THORACIC ESOPHAGUS INCREASE POSTOPERATIVE MORBIDITY

OBJECTIVES The aims of this study were to examine whether neoadjuvant chemotherapy for a carcinoma in the thoracic esophagus increased the incidence of postoperative complications, and which clinicopathological factors may affect postoperative complications after esophagectomy. SUBJECTS AND METHODS One hundred and forty-four patients who underwent neoadjuvant chemotherapy followed by esophagectomy for a carcinoma in the thoracic esophagus were reviewed in a retrospective study. Ninety-six patients received neoadjuvant chemotherapy and 48 did not. The postoperative complications were grouped either general complications (Complications A) or surgery-related complications (Complications B). Complications A consisted of pulmonary, cardiac, hepatic, renal, and neurological complications, and catheter sepsis. Complications B consisted of a gastrointestinal tract leak, gastrointestinal tract necrosis, an intrathoracic or intraabdominal abscess, hemorrhage, ileus, and vocal cord palsy. In these two categories of complications, 17 factors obtained from subjects were compared between patients with complications and those without by univariate and multivariate analyses. RESULTS The patient characteristics did not differ between patients who received neoadjuvant chemotherapy and those without. The preoperative serum albumin level was higher in patients without complication than in those with complication in both two categories of complications (Complications A: p = 0.001, Complications B: p = 0.05). The proportion of patients who received neoadjuvant chemotherapy did not differ between patients with complication and those without complication in either category of complications. Multivariate analysis showed that preoperative Onoderas Prognostic Nutritional Index was the only factor reducing the incidence of complications A (p = 0.02, Odds ratio: 0.63). CONCLUSION Neoadjuvant chemotherapy was well tolerated and was not associated with any increased morbidity or mortality after esophagectomy for a carcinoma in the thoracic esophagus.

Preoperative in vitro chemosensitivity test of esophageal cancer with endoscopic specimens

Background. From January 1990 to June 1991, the authors tested in vitro chemosensitivity before surgery with endoscopic biopsy specimens from 23 patients with intrathoracic esophageal cancer.

Efficacy of Azithromycin for Treatment of Acute Exacerbation of Chronic Fibrosing Interstitial Pneumonia: A Prospective, Open-Label Study with Historical Controls

Background: Acute exacerbation of chronic fibrosing interstitial pneumonia (AE-CFIP) is an often fatal condition with no established treatment. Recently, macrolides were found to be beneficial in cases of acute lung injury. Objectives: To examine the clinical effectiveness and safety of intravenous azithromycin in patients hospitalized for AE-CFIP. Methods: A prospective, open-label study with historical controls was conducted. Twenty consecutive patients with AE-CFIP received azithromycin. They were compared with a historical cohort treated with fluoroquinolone (n = 56). All patients received high-dose steroid pulse therapy. The primary end point was mortality at 60 days. The secondary end point was safety of intravenous azithromycin in patients with AE-CFIP. Inverse probability of treatment weighting (IPTW) using the propensity score was performed to investigate the relationship between azithromycin use and survival time. Results: Mortality was significantly lower in the patients treated with azithromycin than in those treated with fluoroquinolone (mortality rate at 60 days: 20 vs. 69.6%, p < 0.001; median survival time: not reached vs. 29.5 days, p < 0.001). The IPTW adjusted hazard of mortality at 60 days in patients receiving azithromycin was 0.17 (95% CI 0.05-0.61). No serious adverse events were observed. Conclusions: Azithromycin was associated with improved outcomes in patients with AE-CFIP. Further studies are needed to verify this finding (Clinical trial JMA-IIA00095).

Hermansky–Pudlak syndrome type 4 with interstitial pneumonia

Hermansky–Pudlak syndrome (HPS) is an autosomal recessive disorder characterized by oculocutaneous albinism, bleeding tendency, and lysosomal accumulation of ceroid-like material, with occasional development of interstitial pneumonia (IP). Nine genetically distinct subtypes of HPS are known in humans; IP develops primarily in types 1 and 4. Most reported cases of HPS with IP are type 1, and there are no published reports of type 4 in Japanese individuals. A 58-year-old man with congenital oculocutaneous albinism and progressive dyspnea for 1 month was admitted to our hospital. We administered high-dose corticosteroids on the basis of a diagnosis of acute exacerbation of interstitial pneumonia. Respiratory symptoms and the findings of high-resolution computed tomography (CT) showed improvement. He was diagnosed with HPS type 4 with interstitial pneumonia on the basis of gene analysis. He has been receiving pirfenidone for 1 year and his condition is stable. This is the first report on the use of pirfenidone for HPS with IP caused by a novel mutation in the HPS4 gene. We conclude that HPS should be suspected in patients with albinism and interstitial pneumonia. High-dose corticosteroid treatment may be useful in cases of acute exacerbation of interstitial pneumonia due to HPS-4, and pirfenidone may be useful and well tolerated in patients with HPS-4.