A phase I/II trial of pemetrexed plus radiotherapy in elderly patients with locally advanced non-small cell lung cancer.

Background Radiotherapy (RT) is an effective treatment for elderly patients with locally advanced non-small-cell lung cancer (NSCLC); however, no clinical trials have investigated combination RT with pemetrexed (PEM) in chemotherapy-naive patients ≥71 years old. We conducted a phase I/II study to evaluate the appropriate PEM dose, efficacy, and safety of PEM plus RT in elderly patients. Methods Patients ≥71 years with performance status (PS) scores of 0-2 who had pathologically confirmed stage IIIA/IIIB NSCLC received PEM (500 mg/m2 on day 1 of a 28-day cycle, 4 courses) and RT (a single 2 Gy daily fraction on 5 consecutive days weekly from day 1; 60 Gy total). The primary endpoint was the objective response rate (ORR); the secondary endpoints were progression-free survival (PFS), overall survival (OS), and adverse events (AEs). Results Forty-one patients with a median age of 79 years were enrolled; 31 were men. Eighteen patients had squamous cell carcinoma, 27 had stage IIIA disease, and 38 had PS scores 0-1. The ORR was 80.5%, while the median OS and PFS rates were 24.9 and 6.9 months, respectively. Two treatment-related deaths occurred owing to RT-related pneumonitis and severe infection, respectively. Common hematological AEs were leucopenia and neutropenia; common non-hematological AEs were anorexia and constipation. Three patients developed PEM-induced interstitial lung disease; however, most AEs were RT-related. Conclusions Combination PEM and RT shows promising efficacy but relatively severe RT-related toxicities. Therefore, this treatment should be prescribed to elderly patients with caution. Trial registration UMIN 000005036 .

[Amyloidoma Adjacent to the Thoracic Vertebral Body Developed into Systemic Amyloid Light-chain amyloidosis].

Amyloidoma is very rare case of amyloidosis, and seldom develop into systemic disease. We report a case of an 82-year-old man who was referred to our hospital because of an oppressive feeling in the upper chest. Chest computed tomography showed a tumor on thoracic vertebral body. Percutaneous needle biopsy showed pathological findings of AL amyloidosis. No obvious systemic finding was confirmed, and the tumor was diagnosed as amyloidoma. After a 1-year observation, heart amyloidosis was appeared, then 6 months later he died. The autopsy revealed amyloid deposit on thoracic vertebral body, heart, arterial walls, esophagus, kidney, thyroid gland, stomach and lung. Careful observation is suggested to be necessary for amyloidoma considering the possibility of the development into systemic amyloidosis.

Clinical efficacy of carbapenems on hospital-acquired pneumonia in accordance with the Japanese Respiratory Society Guidelines for management of HAP.

Hospital-acquired pneumonia (HAP) is the second most common cause of hospital-acquired infection and is the leading cause of death. In 2002, the Japanese Respiratory Society (JRS) published guidelines for the diagnosis and treatment of HAP (JRS GL 2002). In these guidelines, treatment with carbapenems is recommended for all disease types of HAP, excluding cases of mild or moderate pneumonia with no risk factors, and cases with early-onset ventilation-acquired pneumonia. To evaluate the efficacy of carbapenems on HAP in accordance with JRS GL 2002, we conducted a prospective study of HAP patients treated with carbapenems based on JRS GL 2002. The results of this study were also analyzed based on the revised guidelines published in June 2008 (JRS GL 2008), and the validity of the new guidelines was examined. Of the 33 subjects, 19 were judged as responders to the treatment, corresponding to a response rate of 57.6%. There were 3 deaths, corresponding to a mortality rate of 9.1%. The efficacy of carbapenems for the treatment of HAP based on JRS GL 2002 was confirmed. The severity rating system in JRS GL 2002 has a tendency to overestimate the severity of the cases and may lead to overtreatment in some cases. On the other hand, the severity rating system by JRS GL 2008 seemed to be more accurate and closely correlated with the efficacy of the treatment. It is suggested that JRS GL 2008 is more useful in clinical practice for accurately judging the severity of the disease and initiating appropriate subsequent antibiotic therapy.

[A case of IgG4-related disease with deterioration in pulmonary and pituitary involvements during a 10-year clinical course of inflammatory pseudotumor].

A 71-year-old man underwent pleural biopsy due to left pleural effusion and pleural thickening in August, 2001. An inflammatory pseudotumor (IPT) was diagnosed, and therefore systemic oral steroid therapy (prednisolone [PSL] 30 mg/day) was initiated. However, after tapering PSL to 7.5 mg/day, a complication of secondary central diabetes insipidus due to hypophysitis developed in 2008. As his pulmonary condition deteriorated over time and he began to experience exertional dyspnea, he was admitted to our hospital for re-evaluation of the disease in October, 2010. High-resolution CT (HRCT) revealed pulmonary involvements distributed in the interstitium and a high serum IgG4 level (240 mg/dl). Upon re-evaluating the pleural biopsy specimens of the first visit, we found lymphoplasmacytic-type IPT with approximately 10% IgG4-positive plasma cells in the affected areas. After increasing the PSL dose up to 0.6 mg/kg/day, his serum IgG4 levels decreased, his dyspnea improved, and the radiological findings of his pulmonary and pituitary involvements improved. This case was diagnosed as lymphoplasmacytic type IPT which appeared to be highly homologous with IgG4-related disease due to high serum levels of IgG4, pituitary involvements and the observed efficacy of PSL.

[Two cases of juvenile-onset and adult-onset recurrent respiratory papillomatosis].

We recently experienced one each of 2 types of recurrent respiratory papillomatosis (RRP). Case 1 (juvenile-onset type): A 30-year-old woman presenting with bloody sputum and large tumors with cavities on her chest Xray film, was referred to our hospital. She had been diagnosed with laryngeal papillomatosis when she was three years old. According to our bronchoscopical examination biopsy, she was diagnosed with squamous cell carcinoma of the lung in addition to papillomatosis of the trachea and bronchus. Although chemotherapy was performed, she died 2 years after the diagnosis of lung cancer without any distinct treatment efficacy. Case 2 (adult-onset type): A 43 year-old woman presenting with fever and dry cough visited our hospital. Chest CT revealed that there was narrowing of bilateral main bronchi and hilar lymphadenopathy. Bronchoscopic examination revealed diffuse papilloma distributed extensively from the trachea to bilateral main bronchi. However, she recovered spontaneously in 6 months and has remained stable without recurrence. Both cases were diagnosed with RRP based on the separation of HPV in case 1 and pathological findings of koilocytosis in case 2. Case 1 was complicated with squamous cell carcinoma of the lung in the clinical course, presumably due to occurrence of malignant conversion of papillomatosis. Since RRP is a rare but refractory disease, novel effective treatment is necessary.

[A case of lymphocytic interstitial pneumonia complicated with primary Sjögren's syndrome followed by chest CT scanning for thirteen years].

We encountered a rare case of lymphocytic interstitial pneumonia (LIP) complicated with primary Sjögren's syndrome (SjS), followed by chest CT scanning for a long period of time. A 54-year-old man with hemoptysis was admitted to our hospital in December, 2001. A diagnosis of SjS was made based on elevation of anti-SS-B/La antibody titer in serum in combination with diagnosis of keratoconjunctivitis sicca and xerostomia on a Schirmer test and a lip biopsy, respectively. Subsequent histopathological diagnosis by open lung biopsy showed LIP. Chest CT in September, 1995 at previous hospital revealed ground-glassed opacity (GGO), small nodules, thickened bronchovascular bundles and cyst formation in lungs. Chest CT was performed every year until 2008, when remarkable progression from thickened bronchovascular bundles accompanied by nodular opacities to an air-space consolidation in the right lower lobe was observed. Also, appearance of cyst formation in the right middle lobe, nodular lesions and GGO in the left lower lobe were noticed. Although the nodular opacities and GGO improved after an administration of corticosteroid (PSL 0.5 mg/kg/day), little improvement in the consolidations and cyst formation was demonstrated. In conclusion, it was suggested that differences among CT findings of LIP may be important for evaluating of efficacy of treatment by steroid agents for LIP associated with SjS.

[Clinical and pathological analysis of 10 cases of secondary pneumothorax due to angiosarcoma of the scalp].

Angiosarcoma of the scalp is a very rare disease. Secondary pneumothorax is known as a characteristic complication in this disease due to lung metastasis. In this study, 17 patients of angiosarcoma of the scalp, diagnosed at our hospital between 1996 and 2006, were analyzed. Secondary pneumothorax was observed in 10 of these patients, among which bilateral pneumothorax occurred in 5 relapse of pneumothorax occurred in 6 and pneumothorax with bloody pleural fluid occurred in 7 patients. Characteristic findings on chest CT were multiple thin-wall cavities and ground-glass attenuation around the cavity, located in bilateral subpleural lung fields. It is suggested that the subpleural thin-wall cavities cause pneumothorax. Although pleurosclerosis were performed in 5 patients and one of them had a subsequent partial resection of the lung, pneumothorax reocurred within a short period of time in all patients. The average survival time from the first pneumothorax episode was only 4.1 months. Secondary pneumothorax caused by this disease was intractable, resulting in an unfavorable outcome. It is necessary to develop a proper treatment strategy for secondary pneumothorax to create a favorable prognosis in this disease.

Polymerase chain reaction-based open reading frame typing (POT) method analysis for a methicillin-resistant Staphylococcus aureus (MRSA) outbreak through breast-feeding in the neonatal intensive care unit.

INTRODUCTION: The route of methicillin-resistant Staphylococcus aureus (MRSA) transmission in the neonatal intensive care unit (NICU) is not clearly explained. We investigate an MRSA outbreak involving five babies in the NICU. The molecular investigation using polymerase chain reaction-based open reading frame typing (POT) method was performed. PRESENTATION OF OUTBREAK: A MRSA outbreak occurred in a six-bed NICU affecting 5 babies. Within 13 days of the emergence of index case, all five babies including triplets and other two babies were found to colonize MRSA by the active surveillance culture. Environmental surveillance cultures revealed that the preserved breast milk provided by the triplets' mother was the only item in the NICU that was positive for MRSA. The mother had a bite wound on the nipples, and the breast milk was not pasteurized. The POT method revealed that MRSA strains detected from the triplets, the breast milk, and the other baby who was fed the triplets' mother's milk were genetically identical (POT index: 106-247-33). The all strains of MRSA carried Staphylococcal cassette chromosome mec (SCCmec) IV and had good susceptibility for the non-ß-lactam antimicrobial agents, suggesting the strains were community-acquired MRSA. CONCLUSIONS: The mother's milk contaminated with community-origin MRSA is serving as the reservoir of MRSA and one of the sources of MRSA outbreaks in the NICU. It is important to closely monitor the condition of the mothers of the children in the NICU. Pasteurization of breast milk should be considered when the skin on the nipple is broken.

The Platelet Count Can Predict In-hospital Death in HIV-negative Smear-positive Pulmonary Tuberculosis Inpatients.

Objective This retrospective cohort study investigated whether the three components of the blood cell count have prognostic implications in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis. Methods We reviewed patients who were treated by the isoniazid, rifampicin, pyrazinamide, and ethambutol regimen or by the isoniazid, rifampicin, and ethambutol regimen. The association between the patient data on admission and the survival outcome was evaluated. Results We reviewed 367 consecutive patients (male, 60.5%) with a median age of 72 [interquartile range (IQR), 54-82] years. While the white blood cell count did not differ between the two groups, (discharged alive: 7,000/µL; IQR, 5,500-9,300; died in hospital: 7,200/µL; IQR, 5,600-9,400; p=0.797), hemoglobin level (discharged alive: 11.5 g/dL; IQR, 10.0-13.1; died in hospital: 9.9 g/dL; IQR, 8.6-11.3; p<0.001) and the platelet count (discharged alive: 275,000/µL; IQR, 206,000-345,000; died in hospital: 149,000/µL; IQR, 93,000-236,000; p<0.001) were lower in patients who died in hospital. After dividing patients into hemoglobin- and platelet-based quantiles, the lower quantile class tended to show poorer survival (log-rank test for trend p<0.001 for both). A multi-variable Cox proportional hazards model revealed that hazard ratio for in-hospital death for every 1,000/µL increase of platelet count was 0.997 (95%CI, 0.995-0.999; p=0.010); the hazard ratio for the hemoglobin level was not significant. Conclusion A low platelet count was clearly related to a poor life prognosis in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis.

Metastatic brain mass caused by slow-growing small-cell lung cancer: differential vascular endothelial growth factor expression in primary and metastatic tumor.

Brain metastasis is a critical complication of small-cell lung cancer (SCLC), resulting in rare long-time survival. We report a case of a 72-year-old man who displayed a very unique clinical appearance, with a large metastatic brain tumor that grew much faster than primary SCLC. The brain tumor expressed high levels of vascular endothelial growth factor (VEGF) that was negative in primary lung tumor. The patient, who underwent brain surgery and chemotherapy against SCLC, has survived for > 2 years with a good performance status since initial brain symptoms occurred. Weak expression of VEGF in primary tumor might be associated with good prognosis. However, VEGF upregulation could occur after metastasis, resulting in aggressive tumor growth.

[A case of large cell carcinoma of the lung with rhabdoid phenotype].

A 37-year-old man was admitted to our hospital because of suspicion of the lung cancer in November 2003. Transbronchial tumor biopsy revealed a small number of tumor cells with rhabdoid features, which had eosinophilic cytoplasmic globules. However, a definitive histological diagnosis was not obtained. We considered that a diagnosis of lung malignant tumor was likely according to the findings of chest CT scan and pathology. Although radiotherapy reduced the tumor size, he started to have abdominal pain and tarry stool one month after radio therapy. Multiple small intestine metastases were detected by gastroenterological endoscopy. The patient died due to bleeding from these metastatic lesions in May 2004. Immunohistologic staining of the cervical lymph node showed that rhabdoid cells were positive for epithelial membrane antigen (EMA), vimentin, and anticytokeratin antibody (CAM5.2), but not for thyroid transcription factor-1 (TTF-1). From the autopsy findings and clinical course, he was finally diagnosed with large cell carcinoma of the lung with rhabdoid phenotype. Because of its aggressive clinical course, early diagnosis and decision on therapy would be very important for this disease.

[Effect of glycyrrhizin on anti-tuberculosis drug-induced hepatitis].

In cases in which hepatotoxicity developed during anti-tuberculosis chemotherapy, the rapid recovery of liver function is essential for the completion of the anti-tuberculosis chemotherapy protocol. Glycyrrhizin (Stronger Neo-Minophagen C: SNMC) is widely used in Japan for the treatment of patients with drug eruption or chronic hepatitis. However, a consensus on the clinical effects of glycyrrhizin for the treatment of anti-tuberculosis drug-induced hepatitis has not yet been reached. We studied 24 cases who showed abnormal liver function test results while undergoing anti-tuberculosis chemotherapy and who were treated with or without glycyrrhizin. We then compared recovery periods of liver function among both groups. The time required for liver function normalization in the patients who received glycyrrhizin (SNMC, 40 ml daily, intravenously) was 15.1 +/- 4.5 days and the time required for normalization in the non-glycyrrhizin group was 15.2 +/- 5.2 days. The difference was not significant and the fact indicated that glycyrrhizin is not useful for the treatment of anti-tuberculosis drug-induced hepatitis.

[A case of MPO-ANCA-related vasculitis with chronic alveolar hemorrhage].

It has been reported that alveolar hemorrhage caused by ANCA-associated vasculitis occurs in the seriously acute stage. However, we report a rare case of chronic alveolar hemorrhage in a 26-year-old woman who had been on maintenance hemodialysis because of rapidly progressive glomerulonephritis (RPGN) since the age of 17. On a regular checkup at her clinic, chest radiographs revealed diffuse micronodular opacities in both lung fields when she was 22 years of age, and anemia was identified at 24. Before the patient was referred to our hospital, the shadows on the radiographs remained almost unchanged, whereas the anemia, for reasons unknown, slowly deteriorated. She was referred to our hospital because of micronodular opacities detected on a chest radiogram in an annual health check at the age of 26. She was asymptomatic, but her laboratory data showed a normochromic anemia (hemoglobin 6.3 g/dl), and the serum level of MPO-ANCA was 195 EU. Bronchoalveolar lavage at bronchoscopy macroscopically revealed bloody fluids containing hemosiderin-laden macrophages. Histological examination of the biopsy specimen by video-assisted thoracoscopic lung biopsy revealed pauci-immune pulmonary capillaritis and alveolar hemorrhage. She was diagnosed as having MPO-ANCA-related vasculitis, especially microscopic polyangiitis preceding RPGN, and the clinical course suggesting alveolar hemorrhage was progressing slowly. The diagnosis was therefore "chronic alveolar hemorrhage". We emphasize that it is necessary to consider alveolar hemorrhage when a patient who has been on maintenance hemodialysis for RPGN has a combination of anemia and diffuse micronodular opacities, even if the condition is not accompanied with any respiratory symptoms.

Chemotherapy with carboplatin and paclitaxel after failure of primary chemotherapy for advanced thymic carcinoma. A report of three cases and review of the literature.

For patients with inoperable thymic carcinoma, multidrug chemotherapy containing cisplatin and an anthracycline is often used as first-line chemotherapy. A commonly applied regimen is cisplatin + doxorubicin + vincristine + cyclophosphamide (ADOC). There are relatively few reports on the use of carboplatin and paclitaxel as first-line chemotherapy for thymic carcinoma. In addition, little is known about its efficacy as second-line chemotherapy in patients with advanced thymic carcinoma. We here report on three patients with thymic carcinoma who were treated with carboplatin and paclitaxel as second-line chemotherapy after failure of ADOC. According to the Response Evaluation Criteria in Solid Tumors version 1.1, one patient achieved a partial response and two patients achieved stable disease. The median progression-free survival was 6.7 months and the median overall survival exceeded 3 years. Toxicities were well tolerated. Chemotherapy with carboplatin and paclitaxel appears to be effective as second-line chemotherapy for some persons with thymic carcinoma who fail ADOC.

Potential clinical benefit of the in situ hybridization method for the diagnosis of sepsis.

Despite the significant development of antibiotics, sepsis is still associated with high morbidity and mortality rates. The identification of pathologic organisms at an early stage of sepsis is critical to improve the outcome, but this is difficult to achieve with the conventional method of blood culture (BC). It has been demonstrated that the genes of pathogenic organisms surviving in neutrophils were detectable with in situ hybridization (ISH) and this method was useful for the accurate and rapid diagnosis of sepsis. In this study, we applied ISH to blood smears 60 patients with suspected sepsis. BC was also carried out using the same blood samples to investigate the diagnostic value of ISH. The number of positive results obtained by ISH was approximately four times higher than that obtained by BC (ISH, 25 [41.7%]; BC, 7 [11.7%]). The positive rate in the 21 patients given antibiotics was 61.9% by ISH (13 patients) and 4.7% by BC (1 patient). The antibiotic treatments targeting the organisms detected by either procedure showed a beneficial clinical outcome. Positive results by ISH were obtained earlier than those with BC (ISH, within 1 day; BC, several days). We conclude that ISH is a useful method for the rapid diagnosis of sepsis.