Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties.

Tumor-associated macrophages affect tumor progression and resistance to immune checkpoint therapy. Here, we identify the chemokine signal regulator FROUNT as a target to control tumor-associated macrophages. The low level FROUNT expression in patients with cancer correlates with better clinical outcomes. Frount-deficiency markedly reduces tumor progression and decreases macrophage tumor-promoting activity. FROUNT is highly expressed in macrophages, and its myeloid-specific deletion impairs tumor growth. Further, the anti-alcoholism drug disulfiram (DSF) acts as a potent inhibitor of FROUNT. DSF interferes with FROUNT-chemokine receptor interactions via direct binding to a specific site of the chemokine receptor-binding domain of FROUNT, leading to inhibition of macrophage responses. DSF monotherapy reduces tumor progression and decreases macrophage tumor-promoting activity, as seen in the case of Frount-deficiency. Moreover, co-treatment with DSF and an immune checkpoint antibody synergistically inhibits tumor growth. Thus, inhibition of FROUNT by DSF represents a promising strategy for macrophage-targeted cancer therapy.

Retrospective analysis of lung cancer patients treated with supportive care alone.

BACKGROUND: It is not uncommon for patients with lung cancer to receive supportive care alone. However, the clinical characteristics of these patients have not been fully studied. We conducted a retrospective study to identify the clinical characteristics of definitive lung cancer patients treated with supportive care alone. METHODS: We retrospectively analyzed the percentage of and reasons for definitive lung cancer patients treated with supportive care alone at a regional cancer center. We also investigated the histological diagnostic approaches, palliative therapy types, primary treatment locations after hospital consultation, and places of death. RESULTS: A total of 1,223 patients were histologically diagnosed as having lung cancer between 2011 and 2014. Of these, 160 (13%) patients were treated with supportive care alone. The primary reason for treatment with supportive care alone was a poor performance status (PS) in almost half of the patients. Overall, 40% of the patients received supportive care at home, and 17% were admitted to a palliative care unit (PCU). Death occurred at home for 17% of the patients and in the PCU for 42% of the patients. CONCLUSION: This study revealed that 13% of histologically proven lung cancer patients were treated with supportive care alone, mostly because of a poor PS. Only 40% of these patients received home care, suggesting the need for a more accessible home care system for patients and their families.

Successful Diagnosis of a Thymoma by Endobronchial Ultrasound-guided Transbronchial Needle Aspiration: A Report of Two Cases.

We herein report two cases of thymomas diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). In both cases, the tumor was adjacent to the central airway. Therefore, we attempted to perform EBUS-TBNA in order to obtain specimens for a histopathological examination, which resulted in a diagnosis of thymoma. In one case, surgical resection was conducted and the histological evaluation of the resected specimen confirmed thymoma type AB, consistent with the histology from the EBUS-TBNA specimen. As a safe and minimally invasive procedure, EBUS-TBNA may be considered for the diagnosis of mediastinal tumors, including thymoma.

Endobronchial ultrasound-guided transbronchial needle aspiration in a patient with pericardial mesothelioma.

Pericardial mesothelioma is a very rare pericardial tumor. Diagnosing pericardial disease can be challenging, and obtaining an antemortem diagnosis of pericardial mesothelioma is particularly difficult. We herein report the case of a 60-year-old man with pericardial mesothelioma diagnosed on endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). Chest computed tomography showed a mass surrounding the pericardium, and EBUS-TBNA of the right inferior paratracheal and subcarinal stations was consequently performed. No uptake was noted on (18)F-fluorodeoxy glucose positron emission tomography, other than in the pericardial mass. The results of histological and immunohistochemical examinations indicated the features of malignant mesothelioma. We therefore diagnosed the patient with pericardial mesothelioma, which was subsequently confirmed at autopsy.

Frequency of brain metastases in non-small-cell lung cancer, and their association with epidermal growth factor receptor mutations.

BACKGROUND: The brain is a frequent site of metastases from non-small-cell lung cancer (NSCLC). We analyzed the frequency of brain metastases (BMs) from NSCLC in the era of magnetic resonance images, and evaluated the correlation between epidermal growth factor receptor (EGFR) mutations and BMs among East Asian patients. METHODS: Frequency, number, and size of BMs, and survival of 1,127 NSCLC patients were retrospectively reviewed. Mutation status of EGFR was evaluated in all cases, and its association with BMs was statistically evaluated. RESULTS: EGFR mutations were found for 331 cases (29.4 %). BM was the cause of primary symptoms for 52 patients (4.6 %), and found before initiation of treatment for 102 other patients (9.1 %); In addition to these 154 patients, 107 patients (9.5 %) developed BMs, giving a total of 261 patients (23.2 %) who developed BMs from 1,127 with NSCLC. BM frequency was higher among EGFR-mutated cases (31.4 %) than EGFR-wild cases (19.7 %; odds ratio: 1.86; 95 % confidence interval (CI) 1.39-2.49; P < 0.001). BMs from EGFR-mutated NSCLC were small, but often became disseminated. EGFR mutations accounted for 39.9 % of BMs, but patient survival after BMs was significantly longer for EGFR-mutated cases than for EGFR-wild cases (hazard ratio: 2.23; 95 % CI 1.62-3.10; P < 0.001). CONCLUSIONS: Patients with EGFR-mutated NSCLC were more likely to develop BMs, but apparently also survived longer after BMs.

Endobronchial ultrasonography for positron emission tomography and computed tomography-negative lymph node staging in non-small cell lung cancer.

BACKGROUND: Integrated positron emission tomography (PET) with computed tomography (CT) is a useful modality to investigate lymph node metastases for non-small cell lung cancer, but is less sensitive for normal-sized lymph nodes. We sometimes encounter cases with radiologically normal lymph nodes and unsuspected mediastinal metastases detected by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). However, few studies have investigated staging in patients with radiologically normal mediastina, and the accuracy of EBUS-TBNA staging for radiologically normal mediastina and hila is unclear. METHODS: This study was a retrospective, single-institution review of a prospectively maintained database at Chiba Cancer Center between May 1, 2008, and September 1, 2013. We analyzed 113 non-small cell lung cancer patients with both CT-negative and PET/CT-negative lymph nodes (N0) in preoperative nodal staging performed by EBUS-TBNA. After preoperative staging was performed, patients with either N0 or N1 clinical staging underwent surgery. Final N factors were determined by mediastinal lymphadenectomy. RESULTS: In our study, the overall rate of N2 disease was 17.6% (20 of 113). For nodal staging by EBUS-TBNA, the sensitivity, specificity, negative predictive value, and diagnostic accuracy were 35.0% (7 of 20), 100% (93 of 93), 87.7% (93 of 106), and 88.4% (100 of 113), respectively. There were no severe complications from EBUS-TBNA staging. CONCLUSIONS: The overall rate of unsuspected N2 was not low. EBUS-TBNA was accurate and feasible for preoperative mediastinal nodal staging of non-small cell lung cancer with both CT-negative and PET/CT-negative lymph nodes. The sensitivity of EBUS-TBNA for radiologically normal mediastina and hila was low. Further investigations are required.

Pulmonary artery sarcoma diagnosed by endobronchial ultrasound-guided transbronchial needle aspiration.

Pulmonary artery sarcoma (PAS) is a rare tumor that is often detected at an advanced stage, when disease is so widespread that a radical surgical procedure is no longer indicated. Therefore, less invasive biopsy techniques are required to establish a definitive preoperative diagnosis. Endobronchial ultrasound (EBUS) is useful for producing real-time images of both lymph nodes and the interior of pulmonary arteries adjacent to the bronchi. We report a case with masslike lesions in the pulmonary artery that were observed by EBUS and from which tissue was obtained by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to establish a diagnosis of PAS.

ALK fusion gene positive lung cancer and 3 cases treated with an inhibitor for ALK kinase activity.

BACKGROUND: Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer accounts for 4-5% of non-small cell lung carcinoma. A clinical trial of the specific inhibitor of ALK fusion-type tyrosine kinase is currently under way. METHODS: ALK fusion gene products were analyzed immunohistochemically with the materials obtained by surgery or by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA). The echinoderm microtubule-associated protein-like 4(EML4)-ALK or kinesin family member 5B (KIF5B)-ALK translocation was confirmed by the reverse transcription polymerase chain reaction (RT-PCR) and fluorescence in situ hybridization (FISH). After eligibility criteria were met and informed consent was obtained, 3 patients were enrolled for the Pfizer Study of Crizotinib (PF02341066), Clinical Trial A8081001, conducted at Seoul National University. RESULTS: Out of 404 cases, there were 14 of EML4-ALK non-small cell carcinoma (NSCLC) and one KIF5B-ALK NSCLC case (8 men, 7 women; mean age, 61.9 years, range 48-82). Except for 2 light smokers, all patients were non-smokers. All cases were of adenocarcinoma with papillary or acinar subtypes. Three were of stage IA, 5 of stage IIIA, 1 of stage IIIB and 6 of stage IV. Ten patients underwent thoracotomy, 3 received chemotherapy and 2 only best supportive care (BSC). One BSC and 2 chemotherapy cases were enrolled for the clinical trial. Patients with advanced stages who received chemotherapy or best supportive care were younger (54.0±6.3) than those who were surgically treated (65.8±10.1) (p<0.05). The powerful effect of ALK inhibitor on EML4-ALK NSCLC was observed. Soon after its administration, almost all the multiple bone and lymph node metastases quickly disappeared. Nausea, diarrhea and the persistence of a light image were the main side effects, but they diminished within a few months. CONCLUSION: ALK-fusion gene was found in 3.7% (15/404) NSCLC cases and advanced disease with this fusion gene was correlated with younger generation. The ALK inhibitor presented in this study is effective in EML4-ALK NSCLC cases. A further study will be necessary to evaluate the clinical effectiveness of this drug.

Successful resection of schwannoma from an intercostal nerve causing bloody pleural effusion: report of a case.

We report a case of schwannoma arising from the 9th intercostal nerve, which caused a bloodstained pleural effusion. The patient, a 37-year-old woman, presented with left-sided back pain. A chest X-ray showed left pleural effusion, which was subsequently found to be bloodstained but without malignant cells. Chest magnetic resonance imaging showed a 76-mm tumor arising from the 9th intercostal nerve. The tumor and intercostal nerve were successfully resected. Histological examination revealed that the tumor comprised spindle cells with both Antoni types A and B patterns. There were necrotic changes and cystic degeneration, but no atypical or mitotic cells. Based on these findings, benign schwannoma was diagnosed. Schwannoma is rarely accompanied by bloody pleural effusion, which we assume was caused by partial tumor rupture. Magnetic resonance imaging proved very useful in localizing and characterizing the tumor in this case.

Detection of epithelial growth factor receptor mutations in cerebrospinal fluid from patients with lung adenocarcinoma suspected of neoplastic meningitis.

BACKGROUND: Neoplastic meningitis (NM) is a devastating neurological complication of cancer that needs to be diagnosed in the early stages of disease. Polymerase chain reaction detection of epithelial growth factor receptor (EGFR) mutations in cerebrospinal fluid (CSF), which are predictive markers for EGFR tyrosine kinase inhibitor therapy in lung cancer, might be important to diagnose and to treat NM in patients with lung cancer. In this study, we attempted to detect EGFR mutations in CSF and to compare EGFR status between CSF and primary or metastatic lesions in patients with lung adenocarcinoma suspected of NM. METHODS: Twenty-nine patients with lung adenocarcinoma suspected of having NM underwent lumbar puncture. EGFR status of CSF was analyzed by direct DNA sequencing. EGFR mutations of primary or metastatic lesions (lymph nodes and bones) were analyzed in 20 cases. RESULTS: EGFR mutations were detected in CSF of 13 (45%) of 29 patients. In 5 (31%) of 16 patients with negative CSF cytology, EGFR mutations were detected. In four patients, EGFR mutations were shown in CSF, but not in primary or metastatic lesions. Conversely, in two patients, EGFR mutations were shown in primary or metastatic lesions, but not in CSF despite positive CSF cytology. CONCLUSIONS: EGFR mutations, suggesting the existence of malignant cells, were detected in CSF, even in patients with non-small cell lung cancer with negative cytological results. EGFR mutations in CSF do not always reflect the same status as in primary or metastatic lesions.

Comparison of 21-gauge and 22-gauge aspiration needle during endobronchial ultrasound-guided transbronchial needle aspiration.

BACKGROUND AND OBJECTIVE: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has typically been performed using the 22 gauge (G) dedicated TBNA needle. Recently a new 21G TBNA needle has been introduced. The efficacy of using a larger gauge biopsy needle during EBUS-TBNA has not been reported. The purpose of this study was to compare the diagnostic yield and utility of 21G and 22G needles during EBUS-TBNA. METHODS: EBUS-TBNA was performed using both 21G and 22G needles. Cytological and histological findings were recorded for each samples obtained by an independent cytologist and pathologist. The cellularity and blood contamination were evaluated in the cytological samples. The quality of the histological core was evaluated by the amount of blood clots versus the actual tissue. Each factor was compared within two slides from the two different size needles. The diagnostic yield and the differences of the cytology and histology were analysed. RESULTS: The evaluation of 45 lesions by EBUS-TBNA revealed that tumour cells were equally detected by both 21G and 22G needles. Two patients of adenocarcinoma were histologically diagnosed only by the 21G needle. Although histological structure was better preserved in five lesions collected by the 21G needle, there was more blood contamination with the 21G needle (P < 0.0001). CONCLUSIONS: There were no differences in the diagnostic yield between the 21G and 22G needles during EBUS-TBNA. The preserved histological structure of the samples obtained by the 21G needle may be useful for the diagnosis of mediastinal and hilar adenopathy of unknown aetiology which may be a challenge with the 22G needle.

Restaging by endobronchial ultrasound-guided transbronchial needle aspiration in patients with inoperable advanced lung cancer.

We present two cases of inoperable advanced lung cancer in which the main lesions were mediastinal lymph nodes detected with positive positron emission tomography (PET). Drug therapy was very effective, and post-treatment PET results were negative. Restaging by endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed on the mediastinal lymph nodes with a short axis < or = 10 mm measured by computed tomography (CT). Cancer cells were detected, which helped determine the therapeutic strategy. Re-evaluation of mediastinal lymph nodes using EBUS-TBNA appears to be useful, even among patients with inoperable advanced lung cancer.

Successful treatment of lung cancer with gefitinib and EGFR mutation status determination using EBUS-TBNA samples in an extremely old patient.

We report a 90-year-old woman who had complained of bloody sputum and for whom a chest CT showed a nodular lesion on the right lower lobe. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) was performed and adenocarcinoma was revealed in both a subcarinal lymph node (#7) and in the primary lung tumor. Epidermal growth factor receptor (EGFR) gene mutation status was evaluated, and an exon 21 point mutation (L858R) was identified by direct sequencing. Two weeks after administration of gefitinib, the tumor size decreased and bloody sputum disappeared. The patient has remained in good condition for 6 months.

VEGF in patients with non-small cell lung cancer during combination chemotherapy of carboplatin and paclitaxel.

BACKGROUND: Vascular endothelial growth factor (VEGF) is a potent angiogenic factor related to tumor growth and metastasis. However, little is known about the clinical significance of circulating VEGF in cancer patients. PATIENTS AND METHODS: Eighteen patients with non-small cell lung cancer received chemotherapy using carboplatin and paclitaxel. Plasma levels of VEGF were analyzed at baseline and after 2 cycles of chemotherapy. RESULTS: Partial remission was observed in 3 patients (16.7%), stable disease in 10 patients (55.6%) and progressive disease in 5 patients (27.8%). Patients with partial remission or stable disease had significantly lower levels of plasma VEGF than did patients with progressive disease, both at baseline (p=0.0341) and after 2 cycles of chemotherapy (p=0.0265). There were no significant changes of plasma VEGF during chemotherapy. CONCLUSION: Pretreatment plasma levels of VEGF are a useful marker for predicting disease control by chemotherapy.

[A study on cases developed pulmonary tuberculosis after receiving gastrectomy].

OBJECTIVE: Patients who had undergone gastric resection are considered to be high risk of developing tuberculosis. We investigated the factors leading to pulmonary tuberculosis after gastrectomy. MATERIALS AND METHODS: We retrospectively examined 654 pulmonary tuberculosis patients discharged from Chiba-East National Hospital from January 1999 to December 2001. RESULTS: Fifty-five patients (31-84 years old, mean 63.5 +/- 12.5 years, 48 males and 7 females) had the history of gastric resection. The proportion of patients receiving gastrectomy among patients with pulmonary tuberculosis was 8.4 percent. The mean age of patients received gastric resection was 50.2 +/- 16.6 years, and the mean interval from gastrectomy to the development of pulmonary tuberculosis was 13.6 +/- 11.0 years. On admission to our hospital, 34 out of 55 cases were smear positive by sputum examination for acid-fast bacilli and 39 cases had cavitary lesions on chest X-ray. Gastrectomy was done due to carcinoma of the stomach in 31 cases, peptic ulcer in 21 cases, adenomatous polyp in two cases, and accidental injury in one case. Out of total 55 cases, 52 patients improved, but three cases died of pulmonary tuberculosis. None had the recurrence of carcinoma of the stomach. Body weight, Body mass index, Prognostic nutritional index (PNI; 10 x serum albumin concentration + 0.005 x peripheral lymphocyte count) which was proposed by Onodera, serum albumin level and serum total cholesterol level were lower in the gastrectomy group than in the non-gastrectomy group. The odds ratio of developing tuberculosis among gastrectomy patients compared with the appropriate controls in 30 to 59 year-old-men was 3.8. CONCLUSION: This study confirms that gastrectomy is one of the risk factors of developing tuberculosis in 30 to 59 year-old-men. However, whether gastrectomy in itself is a risk factor or whether it is secondarily associated with another risk factor such as underweight status and/or inadequate nutrition following surgery remains unclear.

[A study on pulmonary tuberculosis retreatment cases].

OBJECTIVE: To investigate the factors leading to the retreatment for tuberculosis. MATERIALS: Forty-seven retreatment cases with pulmonary tuberculosis, who were discharged from the National Chiba Higashi Hospital from 2000 to 2002. METHODS: Data on all retreatment cases were studied as to the condition of the original treatment and factors leading to the retreatment. RESULTS: Of the 47 cases, 33 cases received the original treatment in our hospital. Of the 33 cases, 24 cases were relapsed cases and 9 cases were defaulters. Most relapsed cases were male aged 50s and 12 cases (50%) were jobless. As the factors leading to retreatment, the delay in the negative conversion of sputum culture accounted for 11 cases (45.8%) out of 24 cases. No specific factors were found in three cases (12.5%). Among the defaulters, no bias was seen as to age and occupation of cases, but all the cases were male, and they defaulted during the maintenance phase of treatment at the out-patient department. CONSIDERATION: The delay in the negative conversion of sputum culture was the main factor relating to the relapse. Diabetes mellitus (DM) is one of the factors leading to the relapse, but many factors were observed in DM patients. Male cases aged 50s had many factors leading to the relapse. An intensive management for out-patients and involvement of welfare department aiming at the completion of treatment for the socially vulnerable groups might be necessary as the measure to prevent defaulting. CONCLUSION: The delay in the negative conversion of sputum culture was the main factor leading to relapse, and intensive management for out-patients aiming at the completion of treatment is necessary to prevent the defaulting.