Selumetinib in Japanese pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas: An open-label, phase I study.

Background: Plexiform neurofibromas (PN) are a manifestation of neurofibromatosis type 1 (NF1) that may cause morbidity and impact health-related quality of life (HRQoL). Selumetinib (ARRY-142886, AZD6244) is an orally available, selective, mitogen-activated protein kinase kinase 1/2 inhibitor approved for children with NF1 and symptomatic, inoperable PN in regions including the USA (aged ≥2 years), EU (≥3 years), and Japan (≥3 years). This open-label, single-arm, phase I study evaluated selumetinib in Japanese children with NF1 and symptomatic, inoperable PN. Methods: Eligible patients (aged 3-18 years) received oral selumetinib (25 mg/m2 twice daily) continuously in 28-day cycles in a fasted state. Primary objectives were safety and tolerability. Secondary objectives included pharmacokinetics, efficacy, PN-related morbidities, and HRQoL. Results: Twelve patients (median age 13.3 years) were enrolled, received ≥1 selumetinib dose (data cutoff: cycle 13 day 1) with median follow-up of 11.5 months. All patients had baseline PN-related morbidities, most commonly disfigurement (91.7%) and pain (58.3%). Most frequently reported any-grade adverse events were dermatologic and gastrointestinal. Objective response rate was 33.3%; median duration of response was not reached. Most patients (83.3%) had target PN volume reduction versus baseline. No patients reported worsening of PN-related morbidities. Selumetinib was rapidly absorbed with moderate-to-high inter-patient variability in maximum plasma concentration and area under the concentration-time curve from time 0-6 hours. Conclusions: Consistent with results of the phase II SPRINT trial, 25 mg/m2 selumetinib twice daily was well tolerated with a manageable safety profile in Japanese children with NF1 and symptomatic, inoperable PN.

Clinical Utility of Genomic Profiling Tests in Patients with Advanced Gastrointestinal Cancers.

BACKGROUND: Comprehensive analyses of cancer-related genomic alterations are expected to lead to increased availability of targeted therapies. However, in patients with gastrointestinal (GI) cancers, the utility of genomic profiling is unclear because of common non-druggable alterations and rapid disease progression that prevent a sufficient time period to seek targets. OBJECTIVE: The aim of this study was to determine the utility of genomic profiling tests in patients with GI cancers. METHODS: The subjects of this retrospective study were patients with GI cancers and patients with non-GI cancers who underwent tissue-based genomic profiling at a single institution from April 2017 to October 2020. The profile of gene alterations, frequency of tumor mutational burden-high (≥ 10 Muts/Mb), and accessibility of recommended molecular targeted therapy were compared between patients with GI cancers and patients with non-GI cancers. RESULTS: In all, 133 patients with GI cancers and 63 patients with non-GI cancers were included. The genomic profiles of GI cancers showed the highest frequencies of TP53, KRAS, and APC mutations and a significantly lower frequency of PIK3CA mutations than those of non-GI cancers. Tumor mutational burden-high was significantly less prevalent in GI cancers (4% vs 20%, p = 0.008). Twenty-nine patients with GI cancers (40%) and 35 patients with non-GI cancers (56%) were recommended for targeted therapies based on the findings. Among them, seven patients each with GI cancers and non-GI cancers received the recommended therapy on their genomic findings, which showed similar treatment accessibility between the GI and non-GI cancer groups (10% vs 11%, p = 0.791). HER2-targeted and BRAF-targeted therapies were the primary treatments administered to patients with GI cancers. CONCLUSIONS: Although their genomic profiles revealed fewer druggable sites, patients with GI cancers accessed targeted therapies similarly to patients with non-GI cancers. The utility of genomic profile testing in patients with GI cancers was highlighted to determine if patients can receive specific treatments, such as HER2-targeted and BRAF-targeted therapies.

A Case of Guillain-Barré Syndrome and Stevens-Johnson Syndrome/Toxic Epidermal Necrosis Overlap After Pembrolizumab Treatment.

A 76-year-old man was admitted to our hospital with Guillain-Barré syndrome (GBS), presenting with facial palsy, dysarthria, and dysphagia as Grade 3 immune-related adverse events (irAEs) due to pembrolizumab administration for Stage IV lung adenocarcinoma. Although prednisolone (1 mg/kg) was started for GBS due to the irAE, dark erythema and skin eruptions appeared on the patient's torso. Then erosion was observed on 18% of the body surface area and skin biopsy was performed. Finally, the patient was diagnosed with Stevens-Johnson syndrome/toxic epidermal necrosis overlap. Intravenous immunoglobulin therapy was started, and the skin symptoms improved, with the erosion becoming epithelial. He died of aspiration pneumonia related to GBS, although his neurological symptoms had improved after steroid and intravenous immunoglobulin therapy. This is the first reported case of pembrolizumab-induced GBS and Stevens-Johnson syndrome/toxic epidermal necrosis overlap. It is necessary to be careful that the possibility of other severe irAEs may occur simultaneously.

A case of hyperprogressive disease following atezolizumab therapy for pulmonary pleomorphic carcinoma with epidermal growth factor receptor mutation.

A 66-year old man with non-smoking history was diagnosed with pulmonary pleomorphic carcinoma of the right lower lobe. The carcinoma metastasized to the brain, lungs, pleura, and mediastinal lymph nodes. It was positive for epidermal growth factor receptor (EGFR) L858R mutation, and tumor cells highly expressed programmed death-ligand 1(PD-L1). Atezolizumab was initiated as the fourth treatment. After three days, he developed cardiac tamponade and immediately underwent pericardial drainage. Computed tomography showed bilateral ground-glass opacity (GGO), significant worsening of multiple lung metastases, and increased size of metastatic lesions. Newly developed metastasis was noted in the lung, and the patient's respiratory condition rapidly deteriorated. He died of respiratory failure on day 13 after atezolizumab administration. The autopsy showed widespread metastasis in all lobes of the bilateral lungs, cardiac tamponade due to carcinomatous pericarditis, carcinomatous lymphangiopathy, and multiple lung metastases, which were thought to be comprehensively the cause of death. These symptoms suggested hyperprogressive disease (HPD). Hence, we report the first case of HPD following atezolizumab therapy for pulmonary pleomorphic carcinoma with EGFR mutation.

Homeless Patients with Lung Cancer in Metropolitan Tokyo.

Background Homeless persons are those who carry out their activities of daily living in city parks and other facilities. Little is known about homeless patients with lung cancer in Japan. Therefore, we characterized the clinical features and outcomes of homeless people in metropolitan Tokyo. Methods Between January 2014 and August 2018, 2,068 homeless patients were admitted to the homeless patient care unit at Tokyo Saiseikai Central Hospital. Of these, 13 patients were treated for primary lung cancer. We retrospectively analyzed the patients' clinical characteristics, including their age, gender, treatment, and outcome, obtained from the hospital's electronic medical records. Results A total of 13 patients were treated for lung cancer. The median age was 66.2 (range, 51-77) years old. Twelve patients (92.3%) were smokers. All of the patients were men and had advanced lung cancer. Of these, four patients had adenocarcinoma, four had squamous carcinoma, and four had other histologies. Ten patients received chemotherapy, and 3 received chemoradiotherapy (carboplatin, n=8; cisplatin, n=2, immune check point inhibitor, n=2; other, n=1). Of the patients on first-line treatment, 58% discontinued treatment, with 71% doing so willfully. The median overall survival was 7.5 (1-44) months. During the study, nine patients died in the hospital, and four were lost to follow up. Conclusion It is difficult for homeless patients to continue chemotherapy, and they often quit therapy willfully. Therefore, it is necessary to develop an education and health insurance support system to ensure treatment continuity in a good social environment.

A Case of Intravascular Diffuse Large B-Cell Lymphoma Initially Suspected as Interstitial Pneumonia Associated With Systemic Scleroderma.

Intravascular large B-cell lymphoma (IVLBCL) is a rare form of diffuse LBCL. The patient was a 71-year-old female admitted to our hospital with hypoxia. On admission, chest computed tomography revealed a ground-glass opacity. Interstitial pneumonia associated with systemic scleroderma was suspected because of positive anti-centromere antibody. Thereafter, steroid pulse therapy and plasma exchange were performed. Although ground-glass opacity improved, bilateral pleural effusion appeared, so we performed a random skin biopsy because of her elevated serum lactate dehydrogenase and soluble interleukin-2 receptor levels. The patient was diagnosed with IVLBCL with symptoms improving after 6 cycles of rituximab plus chemotherapy treatment.

A case report of aspergillosis accompanied by saccular bronchodilation after bronchial thermoplasty in a 19-year-old woman.

BACKGROUND: Fungal infections are rarely reported as a complication of bronchial thermoplasty (BT) in patients without immunosuppressive comorbidity. CASE PRESENTATION: A 19-year-old woman college student was admitted to our hospital owing to uncontrolled severe asthma despite using the maximum dose of steroid inhalation. She experienced asthmatic attacks more frequently while cheerleading, which is an extracurricular activity. She received BT because she wanted to continue cheerleading. After the second BT session, she developed more sputum and cough. During the third session, white secretion and saccular bronchodilation appeared in the left lower bronchus. Aspergillus fumigatus was detected in the culture of the bronchial lavage sample, and saccular bronchodilation in the affected bronchus was observed on computed tomography (CT). Five months after the start of oral itraconazole, her subjective symptoms as well as her CT findings improved. Her asthma condition improved enough for the patient to continue cheerleading without exacerbation. CONCLUSIONS: It is necessary to consider the possibility of respiratory tract infections including fungal infections after BT. Detailed observations of the entire bronchus and sample collection for microbial culture are highly recommended.

Lung Adenocarcinoma with Lynch Syndrome and the Response to Nivolumab.

Lynch syndrome is caused by mutations in mismatch repair genes that lead to microsatellite instability (MSI). An increased number of mutation-associated neoantigens have been observed in patients with high-frequency MSI (MSI-H) cancer; in addition, membranous programmed death ligand-1 (PD-L1) tends to be expressed at higher levels in MSI-H cancers than in microsatellite-stable cancers. MSI-H cancer patients are therefore considered to be susceptible to immune checkpoint blockade. We herein report for the first time a case of lung adenocarcinoma with Lynch syndrome and the response to nivolumab.

Improvement in the survival of patients with stage IV non-small-cell lung cancer: Experience in a single institutional 1995-2017.

OBJECTIVES: In the past two decades several antineoplastic agents have been approved for the treatment of advanced non-small-cell lung cancer (NSCLC), and the management of these patients has drastically changed. However, there is limited information regarding the impact of these advances on patient survival in clinical practice. MATERIALS AND METHODS: We analyzed the survival of patients with stage IV NSCLC who received any treatment in the Cancer Institute Hospital of the Japanese Foundation for Cancer Research (JFCR) between January 1, 1995 and March 1, 2017. A total of 1,547 consecutive patients were included in this case series. In this analysis, five diagnostic periods were evaluated: 1995-1999 (period A), 2000-2004 (period B), 2005-2009 (period C), 2010-2014 (period D), and 2015-2017 (period E). We compared overall survival (OS) between the periods before and after propensity score matching (PSM) and in patients with EGFR mutation, with ALK fusion gene, or without driver mutation. RESULTS: In the past two decades the OS of patients with stage IV NSCLC improved. The median OSs for periods A, B, C, D, and E were 9.0, 11.0, 13.7, 17.9 months, and not reached, respectively. After PSM with known baseline characteristics, the trend of improvement in OS was similar. However, the OS of patients with EGFR mutation or ALK fusion gene did not improve between periods, despite the availability of several tyrosine kinase inhibitors in Japan. The OS of patients without a driver mutation was slightly longer in the period E. CONCLUSION: The introduction of new classes of drugs has significantly improved the survival of patients with stage IV NSCLC. However, the approval of similar types of drugs may not be associated with further improvement in survival.

Efficacy of bevacizumab and erlotinib combination for leptomeningeal carcinomatosis after failure of erlotinib.

In patients with non-small-cell lung cancer harboring an epithelial growth factor receptor (EGFR) active mutation, central nervous system progression after a response to EGFR tyrosine kinase inhibitors is frequent. Central nervous system metastasis, especially leptomeningeal carcinomatosis (LMC), is a serious complication and no standard treatment has been established for LMC. Here, we report two cases in which the addition of bevacizumab to erlotinib enhanced the efficacy against LMC; as a result, radiographic abnormalities decreased markedly and symptoms were well controlled. This combination treatment may be useful to treat LMC in patients with EGFR-positive non-small-cell lung cancer.

Factors influencing sustainable efficacy of smoking cessation treatment with varenicline beyond nine months.

Pharmacological therapies play an important role in the success of interventions for smoking cessation; however, long-term follow-up studies with analysis of influencing factors are scarce. We examined the sustainable effects of smoking cessation therapy with varenicline, beyond nine months as well as the factors influencing effectiveness. Our sample consisted of 193 patients (126 men [68.2%], 67 women [31.8%], aged 26 to 85 years) who underwent varenicline therapy at the Nagoya University Hospital between January 2009 and October 2013. We examined their clinical records and also conducted a mail survey and evaluated success rates of smoking cessation therapy beyond nine months. Overall, 95.8% (185/193) of the patients had at least one complication. The response rate of questionnaires at the end of smoking cessation was 61.6% (119/193). The smoking cessation rate continued to decline for one year and leveled off afterwards. Smoking cessation rates tended to correlate with an increasing number of outpatient visits. Logistic regression analysis showed that two factors, young age and high Beck Depression Inventory-II (BDI-II) scores, were inversely correlated with success rates of smoking cessation. From the results of this study, aggressive intervention would needed for younger patients or patients with higher BDI-II scores.

Extension of the Calvert formula to patients with severe renal insufficiency.

PURPOSE: The Calvert formula was derived from the study among patients with glomerular filtration rates (GFRs) of 33-135 ml/min, and it remains unclear whether the formula can be used to calculate optimal and safe dosages of carboplatin in patients with severe renal insufficiency. We evaluated the utility of this formula in patients with severe renal insufficiency. METHODS: For pharmacokinetic analysis, we studied nine adult Japanese patients with advanced cancer who had an estimated GFR of lower than 30 ml/min/1.73 m(2), as calculated by the Japanese equation for estimating GFR, or who were receiving hemodialysis. The dose of carboplatin was calculated with the Calvert formula, in which GFR was measured by inulin clearance or was assumed to be 0 in patients requiring hemodialysis. Hemodialysis was started 23 h after the end of carboplatin infusion. RESULTS: Although there was a significant correlation between the estimated and measured carboplatin clearance, the estimated clearance was consistently higher than the measured clearance [mean prediction error ± standard deviation = 41.0 ± 26.3 %] in all seven patients with renal insufficiency (GFR, median 21.4, range 7.8-31.4 ml/min) and in the two hemodialysis patients. Actual areas under the concentration-time curve (AUC) (mg/ml min) were 5.4, 5.7, 6.2, and 9.0 for the four patients with a target AUC (mg/ml min) of 5; 5.7, 6.2, and 7.1 for the three patients with a target AUC (mg/ml min) of 4; and 5.1 and 8.7 for the two hemodialysis patients with a target AUC (mg/ml min) of 5. The measured clearance of carboplatin ranged from 23.0 to 51.3 ml/min in the seven patients not receiving hemodialysis. The pre-hemodialysis carboplatin clearance in the hemodialysis patients was 20.5 and 11.1 ml/min, respectively. CONCLUSION: For adult patients with severe renal insufficiency, the Calvert formula causes carboplatin overdosing by overestimating the carboplatin clearance.

EGFR Mutation Impact on Definitive Concurrent Chemoradiation Therapy for Inoperable Stage III Adenocarcinoma.

BACKGROUND: Concurrent chemoradiation therapy (CRT) is the current standard of care for patients with locally advanced lung adenocarcinoma; however, little has been reported about the impact of epidermal growth factor receptor (EGFR) mutation on CRT efficacy. METHODS: From 2006 to 2013, we retrospectively screened 104 unresectable stage III adenocarcinoma patients who were examined for EGFR mutation status and received definitive concurrent CRT consisting of platinum doublet chemotherapy in first-line setting and compared the clinical outcomes and recurrence patterns according to mutation status. RESULTS: Among 104 patients, EGFR mutation was detected in 29 (28%). The overall response rate did not differ between EGFR-mutant and wild-type patients (72.4% versus 72.0%, p = 0.607). The median progression-free survival in concurrent CRT was significantly shorter in EGFR-mutant patients than in wild-type patients (9.8 [95% confidence interval, CI: 7.6-19.0] versus 16.5 [95% CI: 11.8-19.9] months, p = 0.041). The 2-year recurrence-free survival rate was 7.7% and 28.1% in EGFR-mutant and wild-type patients, respectively (p = 0.028). Distant metastases were more frequently identified as the first recurrence site in EGFR-mutant patients than in wild-type patients (76% versus 40%, p = 0.001). The brain was the most often affected site in EGFR-mutant patients (35%). However, locoregional recurrence was less common in EGFR-mutant patients than in the wild-type population (14% versus 35%, p = 0.027). Overall survival was similar between EGFR-mutant and wild-type patients (51.1 [95% CI: 28.2-70.2] versus 42.9 [95% CI: 35.3 to not available] months, p = 0.637). Among the EGFR wild-type population who were examined for Kras mutation, Kras-mutant patients had significantly worse overall survival than Kras wild-type patients (21.6 versus 49.8 months, p = 0.024). CONCLUSION: Concurrent CRT resulted in shorter progression-free survival in EGFR-mutant stage III adenocarcinoma patients than in wild-type patients, mainly because of distant metastasis relapse, regardless of better local control. Because of these distinct biological features, a different strategy, including EGFR-tyrosine kinase inhibitors for EGFR-mutant locally advanced adenocarcinoma patients receiving definitive CRT may be needed.

Anaplastic lymphoma kinase gene rearrangements in patients with advanced-stage non-small-cell lung cancer: CT characteristics and response to chemotherapy.

Few articles have been published on the imaging findings of anaplastic lymphoma kinase (ALK)-positive non-small-cell lung cancer (NSCLC). To investigate the radiological findings of ALK-positive NSCLC in the advanced stage, CT scans were examined. In addition, the response to chemotherapy was evaluated. Of the 36 patients with ALK-rearranged NSCLC, a mass and a nodule were identified in 17 (47.2%) and 16 (44.4%), respectively, indicating that more than 40% had a small-sized tumor. Overall, 31 (86.1%) patients had lymphadenopathy, seven (19.4%) had extranodal lymph node invasion, and three (8.3%) had lymphangitis. A pleural effusion was seen in 15 patients (41.7%). All but one patient had no ground-glass opacity (GGO) lesions, indicating that most ALK-positive tumors showed a solid growth pattern without GGO on CT. Twenty were evaluable for response to chemotherapy; 10 (50.0%) had a partial response (PR), nine (45.0%) had stable disease (SD), and one (5.0%) had progressive disease (PD) with first-line chemotherapy. With second-line chemotherapy, five (26.3%) had PR, 11 (57.9%) had SD, and three (15.8%) had PD. The five patients with PR were all treated by using crizotinib. Time to progression was 8.2 months with first-line chemotherapy, and 6.0 months with second-line chemotherapy. Advanced-stage ALK-positive tumors have a relatively aggressive phenotype, which cannot be inferred from the size of the tumor alone. ALK-positive patients have a good response to first-line cytotoxic drugs and to crizotinib as second-line therapy, but a relatively poor response to cytotoxic drugs as second-line therapy.

Association between severe toxicity of nilotinib and UGT1A1 polymorphisms in Japanese patients with chronic myelogenous leukemia.

BACKGROUND: Nilotinib is a BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myelogenous leukemia (CML). The UDP-glucuronosyltransferase 1A1 (UGT1A1) polymorphism UGT1A1*28 (*28)/*28 has been linked to an increased risk of hyperbilirubinemia in patients with CML who receive nilotinib. Beside *28, UGT1A1*6 (*6) is another important variant allele in Japanese patients because it is associated with adverse events of irinotecan, metabolized by UGT1A1. We retrospectively investigated the association between severe toxicity of nilotinib and UGT1A1 polymorphisms (*6 and*28) in Japanese patients with CML. PATIENTS AND METHODS: Eight patients with cytogenetically confirmed CML who were receiving nilotinib were studied to explore the association of UGT1A1 polymorphisms with severe nilotinib-related toxicity. Genotyping analyses were determined for *6 and *28. RESULTS: All 3 patients with the *6/*6 or *6/*28 genotype had severe toxicity, including QT interval prolongation (grade 3), elevated lipase levels (grade 3) plus hyperbilirubinemia (grade 2), and anemia (grade 3) plus hepatic cyst hemorrhage (grade 2) in 1 patient each. Among the 5 patients with the *6/*1 or *1/*1 genotype, 1 had elevated lipase levels (grade 3) and another had severe pain in the lower extremities (grade 3). CONCLUSION: These findings suggest that UGT1A1 polymorphisms are important determinants of severe toxicity of nilotinib in Japanese patients.

Genetic polymorphisms associated with oxaliplatin-induced peripheral neurotoxicity in Japanese patients with colorectal cancer.

OBJECTIVE: Pharmacogenomic associations between severe oxaliplatininduced chronic peripheral neurotoxicity (OXCPN) (Grade 2 lasting for > 7 days or Grade 3) and 9 single nucleotide polymorphisms (SNPs) in 8 genes (TAC1, FOXC1, ITGA1, ACYP2, DLEU7, BTG4, CAMK2N1, and FARS2) were reported by the genomewide association study (GWAS) in Korean patients. The present study was designed to explore reliable predictors of OXCPN and thereby improve the management of metastatic colorectal cancer (CRC). METHODS: We retrospectively investigated pharmacogenomic characteristics of OXCPN in 70 Japanese patients with CRC who received oxaliplatin-based chemotherapy and updated the results of our previous analysis of ERCC1 (C118T, rs11615 and C8092A, rs3212986) and GSTP1 (Ile105Val, rs1695) polymorphisms. RESULTS: Univariate analysis suggested potential associations of severe OXCPN with rs843748 in ACYP2 and rs17140129 in FARS2, as well as with the absence of diabetes mellitus (DM) (p = 0.056, 0.072, and 0.029, respectively). There was no association between severe OXCPN and any of the 7 other SNPs. Multiple logistic regression analysis showed that an increased risk of severe OXCPN was related to rs17140129 and the absence of DM (p = 0.034 and 0.030, respectively). On updated analysis, polymorphisms of ERCC1 (C118T, rs11615) and rs10486003 in TAC1 were associated with time to the onset of Grade 1 OXCPN (p = 0.024 and 0.049, respectively). CONCLUSIONS: Severe OXCPN is significantly related to rs17140129, found in the GWAS of Korean patients, in Japanese patients. Patients without DM are more likely to have OXCPN. The association between ERCC1 polymorphism and time to the onset of OXCPN was significant on updated analysis.

Association between bevacizumab-related hypertension and vascular endothelial growth factor (VEGF) gene polymorphisms in Japanese patients with metastatic colorectal cancer.

PURPOSE: Bevacizumab, a monoclonal antibody that binds to VEGF, has a well-known toxic effect of hypertension. We studied possible associations between bevacizumab-related hypertension and gene polymorphisms to assure safer cancer therapy. METHODS: We retrospectively studied 60 Japanese patients with metastatic colorectal cancer who had received bevacizumab-based chemotherapy. Genotypes were determined for five well-known functional single-nucleotide polymorphism of the VEGF gene at positions C-2578A, T-1498C, G-1154A, G-634C, and C936T. Hypertension was graded according to CTCAE v4.0 on the basis of home blood pressure. RESULTS: The VEGF-2578 C/C and -1498 T/T genotypes were associated with significantly less hypertension during the first 2 months of bevacizumab-based chemotherapy (p = 0.004, p = 0.025, respectively). During the treatment period as a whole, the VEGF-2578 C/C and 936 C/C genotypes were associated with less hypertension (p = 0.031, p = 0.043, respectively). Preexisting hypertension was not associated with bevacizumab-related hypertension. CONCLUSIONS: This study demonstrated a significant relation between a lower incidence of grade 2 or higher bevacizumab-related hypertension and the VEGF-2578 C/C genotype for the entire treatment period in Japanese patients with metastatic colorectal cancer. This genotype might be useful for ensuring safer treatment of patients who receive bevacizumab-based chemotherapy.

Febrile complications after endobronchial ultrasound-guided transbronchial needle aspiration for intra-pulmonary mass lesions of lung cancer--a series of 3 cases.

Recent case reports have shown that endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for mediastinal lesions is sometimes accompanied by severe infectious complications. Here, we report 3 cases with refractory febrile complications following EBUS-TBNA for intra-pulmonary large mass lesion of lung cancer (squamous cell carcinoma, n=2; adenocarcinoma, n=1). After the EBUS-TBNA, all cases showed prolonged fever and systemic inflammation despite receiving a sufficient dose of broad-spectrum antibiotics. The presence of a low-density area inside the masses upon CT examination, suggesting necrosis, may be a predictive sign of febrile complications associated with EBUS-TBNA.

Pivotal role of epithelial cell adhesion molecule in the survival of lung cancer cells.

Epithelial cell adhesion molecule (EpCAM) is overexpressed in a wide variety of human cancers including lung cancer, and its contribution to increased proliferation through upregulation of cell cycle accelerators such as cyclins A and E has been well established in breast and gastric cancers. Nevertheless, very little is known about its role in supporting the survival of cancer cells. In addition, the functional role of EpCAM in the pathogenesis of lung cancer remains to be explored. In this study, we show that RNAi-mediated knockdown of EpCAM suppresses proliferation and clonogenic growth of three EpCAM-expressing lung cancer cell lines (H3255, H358, and HCC827), but does not induce cell cycle arrest in any of these. In addition, EpCAM knockdown inhibits invasion in the highly invasive H358 but not in less invasive H3255 cells in a Transwell assay. Of note, the EpCAM knockdown induces massive apoptosis in the three cell lines as well as in another EpCAM-expressing lung cancer cell line, HCC2279, but to a much lesser extent in a cdk4/hTERT immortalized normal human bronchial epithelial cell line, HBEC4, suggesting that EpCAM could be a therapeutic target for lung cancer. Finally, EpCAM knockdown partially restores contact inhibition in HCC827, in association with p27(Kip1) upregulation. These results indicate that EpCAM could contribute substantially to the pathogenesis of lung cancer, especially cancer cell survival, and suggest that EpCAM targeted therapy for lung cancer may have potential.

Pharmacokinetic analysis of carboplatin in patients with cancer who are undergoing hemodialysis.

PURPOSE: To examine the safety of carboplatin-based chemotherapy and the applicability of the Calvert formula in patients with cancer who are undergoing hemodialysis. METHODS: We treated two patients who were undergoing hemodialysis and received carboplatin-based chemotherapy to treat non-small-cell lung cancer or ovarian cancer. The dose of carboplatin was calculated by the Calvert formula. Glomerular filtration rate was considered to be 0, and the target area under the plasma concentration versus time curve (AUC) was 4 (carboplatin dose, 100 mg) for patient 1 and 5 (125 mg) for patient 2. Carboplatin was administered as a 1-h intravenous infusion on day 1. Hemodialysis was performed for 3 or 4 h, starting 24 h after the infusion of carboplatin had begun. Heparinized blood samples were collected during the first cycle of chemotherapy. RESULTS: The AUCs in patients 1 and 2 were 4.7 and 6.1 (mg/ml min), which were about 20% higher than the target values (4 and 5 mg/ml min, respectively). In the absence of hemodialysis, the hypothetical AUCs were 6.2 and 7.6 (mg/ml min), respectively. The pre-dialysis body clearances of carboplatin were 16.1 and 16.5 ml/min, with elimination half-lives of 17.5 and 13.8 h, respectively. CONCLUSION: By performing hemodialysis 24 h after the start of chemotherapy, we obtained reproducible and robust AUC data. Use of the Calvert formula allowed carboplatin-based chemotherapy to be performed safely. Our results suggest that the non-renal clearance of carboplatin is lower in Japanese patients than in non-Asian patients.