Assessment of exposure risk of irinotecan and its active metabolite, SN-38, through perspiration during chemotherapy.

BACKGROUND: Irinotecan (CPT-11) is the key drug used in chemotherapy for many malignant tumors. CPT-11 has cholinergic activity and induces perspiration during intravenous administration. In this study, concentrations of CPT-11 and its active metabolite, SN-38, released during perspiration were measured and risk of exposure of these drugs was assessed. METHOD: Beads of sweat were collected using a dropper from four patients undergoing a chemotherapy regimen involving intravenous administration of CPT-11. The concentrations of CPT-11 and SN-38 in sweat were measured using liquid chromatography tandem mass spectrometry. RESULT: Chemotherapy regimens were capecitabine and irinotecan plus bevacizumab (n = 1), CPT-11 monotherapy (n = 1), and oxaliplatin-irinotecan-leucovorin-5-fluorouracil (n = 2). Uridine diphosphate-glucuronosyltransferase 1A1 phenotypes were *6 homo-type (n = 1), *6 hetero-type (n = 1), and wild type (n = 2). CPT-11 dose was 292.3 ± 75.5 mg/body weight (mean ± standard deviation). CPT-11 was detected in sweat secreted by all the four patients, and its mean (±standard deviation) concentration was 252.6 (±111.9) ng/ml. SN-38 was detected in only one of the patients who received oxaliplatin-irinotecan-leucovorin-5-fluorouracil treatment and who had the wild-type uridine diphosphate-glucuronosyltransferase 1A1 phenotype at a concentration of 74.37 ng/ml. CONCLUSION: CPT-11 and SN-38 are detected in sweat released during intravenous CPT-11 administration. Beads of sweat or linen clothes that absorb the sweat might be the source of CPT-11 and SN-38 exposure.

Afatinib plus bevacizumab combination after acquired resistance to EGFR tyrosine kinase inhibitors in EGFR-mutant non-small cell lung cancer: Multicenter, single-arm, phase 2 trial (ABC Study).

BACKGROUND: Preclinical studies suggested that the addition of bevacizumab could overcome acquired resistance (AR) to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The aim of this study was to evaluate the clinical efficacy and safety of a combination of afatinib and bevacizumab after AR. METHODS: Patients with EGFR-mutant non-small cell lung cancer after AR were enrolled during any line of therapy. Afatinib was prescribed at 30 mg, and 15 mg/kg bevacizumab was administered every 3 weeks until progression. RESULTS: Between October 2014 and May 2017, 32 eligible patients were evaluated. The mutation subtypes were Del-19 (20 [63%]), L858R (11 [34%]), and L861Q (1 [3%]). T790M was detected in 14 patients (44%). The median number of prior regimens was 4 (range, 1-10). Six patients obtained a partial response, and 23 had stable disease; this resulted in an objective response rate (ORR) of 18.8% (95% confidence interval [CI], 7.2%-36.4%) and a disease control rate of 90.7% (95% CI, 75.0%-98.0%). The median progression-free survival (PFS) was 6.3 months (95% CI, 3.9-8.7 months). The ORRs and median PFS times of T790M+ and T790M- patients were 14.3% and 22.2%, respectively, and 6.3 and 7.1 months, respectively; those of Del-19 and L858R patients were 20.0% and 11.1%, respectively, and 6.3 and 5.1 months, respectively. Grade 3 or higher adverse events (incidence ≥ 10%) included paronychia (25%), hypertension (41%), and proteinuria (19%). There were no treatment-related deaths, interstitial lung disease, or bevacizumab-associated severe bleeding. CONCLUSIONS: Afatinib plus bevacizumab demonstrated clinical efficacy and safety after AR to EGFR TKIs and could be a therapeutic salvage option for T790M- populations.

Standard-dose osimertinib for refractory leptomeningeal metastases in T790M-positive EGFR-mutant non-small cell lung cancer.

BACKGROUND: Osimertinib demonstrated promising efficacy for refractory leptomeningeal metastases (LM) in preclinical data and a clinical study at 160 mg, but there is limited data for the standard 80 mg dose. METHODS: T790M-positive patients with suspected LM after classical epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) failure were enroled. RESULTS: We investigated 13 patients (5 definitive and 8 possible LM cases). In two of the five definitive cases with T790M in and outside the central nervous system (CNS), osimertinib was effective for both lesions, with cerebrospinal fluid (CSF) clearance of cancer cells and sensitive/T790M mutations. In three definitive cases with extra-CNS T790M without CSF T790M, cancer cells and sensitive mutations in the CSF persisted after osimertinib initiation. The median progression-free survival of all 13 patients was 7.2 months. Osimertinib was generally well-tolerated despite poor performance status, but interstitial lung disease (grade 2) was confirmed in one patient. Based on 25 samples from 13 patients, the osimertinib CSF penetration rate was 2.5±0.3%. CONCLUSIONS: Osimertinib 80 mg is a useful therapeutic option for refractory LM after classical EGFR-TKI failure. It appears more effective in CSF T790M-positive cases.

An LC-MS/MS Method for Absolute Quantification of Nivolumab in Human Plasma: Application to Clinical Therapeutic Drug Monitoring.

BACKGROUND: Nivolumab is a fully humanized IgG4 monoclonal antibody that targets the programmed death-1 (PD-1) receptor, disrupting PD-1-mediated signaling and restoring antitumor immunity. The objective of this study was to develop a nivolumab quantification method using liquid chromatography-tandem mass spectrometry (LC-MS/MS) and to evaluate its application in clinical therapeutic drug monitoring. METHODS: Nivolumab was purified from human plasma using rProtein A resin and then digested with trypsin. The ASGITFSNSGMHWVR peptide (multiple reaction monitoring transition: m/z 550.6→661.4) was detected as a surrogate peptide of nivolumab by triple quadrupole mass spectrometry. Plasma samples (126) were collected from 14 patients with non-small cell lung cancer who were undergoing clinical dosing regimen with nivolumab. The pharmacokinetic data were analyzed using Phoenix NLME software (Version 7.0, Certara, St. Louis, MO) based on a previously reported population pharmacokinetics (PPK) model of nivolumab. RESULTS: Nivolumab was selectively detected in human plasma and the linear range was 5-200 mcg/mL (R = 0.99). The accuracy and intraday and interday imprecision were within ±15% of the quality control values of 5 (lower limit of quantification), 10 (low), 80 (medium), and 160 (high) mcg/mL. The nivolumab concentrations measured using LC-MS/MS were consistent with those of previously reported PPK models, and the pharmacokinetic parameters could be adequately predicted from a single trough concentration using a Bayesian approach. CONCLUSIONS: An absolute quantification method for nivolumab using LC-MS/MS was successfully developed and validated. Combined with PPK analysis, this method should be useful for the therapeutic drug monitoring of nivolumab in clinical practice.

Validation of the digital PCR system in tyrosine kinase inhibitor-resistant EGFR mutant non-small-cell lung cancer.

The aim of this study was to compare the accuracy of the QuantStudio 3D Digital polymerase chain reaction (dPCR) system and a PCR-based next generation sequencing (NGS) system for detecting a secondary mutation in the epidermal growth factor receptor (EGFR) gene T790M in non-small cell lung cancer (NSCLC) patients previously diagnosed with EGFR-activating mutations. Twenty-five patients with NSCLC previously treated with EGFR-TKIs were examined. The patients were treated daily with either erlotinib or gefitinib. New biopsies, followed by DNA sequencing on an Ion Torrent systems using the Ion Torrent AmpliSeq Cancer Hotspot Panel and dPCR were performed. A comparison of NGS, sensitive PCR, and dPCR revealed that the sensitivities of NGS and dPCR were similar in this study. As well, T790M was detected in as low as about 5% of mutant allelic frequencies, which represented 5% of the total reads on site mapped reads in NGS and greater than 5% of the dPCR reads, which represented mutant and wild type copies. The strategy in which NGS sequencing is followed by revealed acquired mutation with dPCR may be a reasonable one. We demonstrated the utility of combining NGS and dPCR as a tool for monitoring T790M. NGS and dPCR with formalin-fixed paraffin-embedded (FFPE) specimens might become a standard genomic test for exploring acquired resistance to targeted molecular medicines.

Next-generation sequencing of tyrosine kinase inhibitor-resistant non-small-cell lung cancers in patients harboring epidermal growth factor-activating mutations.

BACKGROUND: The aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer. METHODS: Fifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2. RESULTS: All 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0%) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7%) exhibiting TP53 P72R mutations, 5 cases (33.3%) of KDR Q472H, and 2 cases (13.3%) of KIT M541L. CONCLUSIONS: Here, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.

CT-guided fine-needle aspiration and core needle biopsies of pulmonary lesions: a single-center experience with 750 biopsies in Japan.

OBJECTIVE: CT-guided lung biopsy is a well-established diagnostic method for pulmonary lesions. The aim of our study was to evaluate the diagnostic outcomes and safety profile of conventional CT-guided lung biopsies. MATERIALS AND METHODS: We retrospectively analyzed the results of CT-guided lung biopsies for 750 patients to determine the diagnostic accuracy, complication rates, and independent risk factors for diagnostic failure and severe pneumothorax. RESULTS: Diagnostic accuracy was 92.9%. Independent risk factors for diagnostic failure were malignant lesions (odds ratio [OR], 4.20; 95% CI, 1.66-14.1; p = 0.001), lesions in the lower lobe (OR, 2.01; 95% CI, 1.17-3.47; p = 0.011), lesions 2.0 cm or smaller (OR, 2.87; 95% CI, 1.59-5.48; p < 0.001), and the presence of pneumothorax during the procedure (OR, 2.18; 95% CI, 1.27-3.78; p = 0.004). Pneumothorax requiring drainage occurred in 7% of patients. Independent risk factors for pneumothorax requiring drainage were age of 73 years or older (OR, 2.19; 95% CI, 1.21-4.05; p = 0.009), the presence of emphysema (OR, 4.29; 95% CI, 2.05-8.82; p < 0.001), benign lesions (OR, 2.33; 95% CI, 1.20-4.40; p = 0.012), supine positioning of the patient (OR, 2.61; 95% CI, 1.44-4.84; p = 0.001), and length from the pleura to the lesion of 1.5 cm or greater (OR, 3.08; 95% CI, 1.63-6.17; p < 0.001). CONCLUSION: CT-guided lung biopsy has a high diagnostic accuracy. Complication rates were acceptable and comparable to those of previous studies.

[Comparison of garenoxacin and levofloxacin for the prophylaxis of febrile neutropenia].

Placebo-controlled randomized trials have demonstrated that prophylactic levofloxacin (LVFX) significantly reduced the incidence of febrile neutropenia (FN) in patients receiving chemotherapy for advanced solid tumors. Garenoxacin (GRNX) has been reported to be more effective than LVFX against gram-positive bacteria especially Streptococcus pneumoniae. Against this background we conducted a study to compare the efficacy and safety of GRNX with that of LVFX for the prophylaxis of FN. We retrospectively analyzed 127 patients at high risk for FN who were administered GRNX or LVFX for the prophylaxis of FN that occurred during chemotherapy for advanced solid tumors. Our primary outcome of interest was the incidence of febrile episodes. Secondary outcomes included evidence of bacterial infection and infection focus when febrile episodes were observed; adverse drug reactions and mortality were also evaluated. Febrile episodes were observed in 2 patients administered GRNX and 7 patients administered LVFX (p=0.044). Definitive pathogenic bacteria and infection focus could not be identified in any patient with febrile episodes and all cases of fever resolved simultaneously with the recovery from neutropenia. We observed 4 cases of rashes and 3 cases of liver dysfunction in the GRNX group and 2 cases of rashes and 2 cases of liver dysfunctions were observed in the LVFX group(not statistically significant in both the groups). No severe adverse effects or deaths were associated with either of these drugs. These results suggest that GRNX is useful for the prophylaxis of FN.

Rebiopsy of non-small cell lung cancer patients with acquired resistance to epidermal growth factor receptor-tyrosine kinase inhibitor: Comparison between T790M mutation-positive and mutation-negative populations.

BACKGROUND: The secondary epidermal growth factor receptor (EGFR) mutation Thr790Met (T790M) accounts for approximately half of acquired resistances to EGFR-tyrosine kinase inhibitor (TKI). Recent reports have demonstrated that the emergence of T790M predicts a favorable prognosis and indolent progression. However, rebiopsy to confirm T790M status can be challenging due to limited tissue availability and procedural feasibility, and little is known regarding the differences among patients with or without T790M mutation. METHODS: The study investigated 78 EGFR-mutant patients who had undergone rebiopsy after TKI failure. The peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp method was used in EGFR mutational analyses. Various patient characteristics and postprogression survivals (PPSs) after initial TKI failure were retrospectively compared in patients with and without T790M. RESULTS: The T790M mutation was identified in 4 (17%) of 24 central nervous system lesions, and in 22 (41%) of 54 other lesions (P = .0417). No other characteristics had a statistical association with T790M prevalence. Median PPS was 31.4 months in 26 patients with T790M, and 11.4 months in 52 patients without T790M (P = .0017). In the multivariate analysis, statistically significant factors for longer PPS included T790M-positive, good performance status, and no carcinomatous meningitis. CONCLUSIONS: The emergence of T790M in central nervous system lesions was rare, compared with other lesions. Patients with T790M after TKI failure appear to have better prognoses than those without T790M. TKI rechallenge or continuous administration beyond progression may be effective after initial TKI failure.

Clinical features and outcome of acute exacerbation of interstitial pneumonia: collagen vascular diseases-related versus idiopathic.

BACKGROUND: Relatively little is known about acute exacerbation (AE) of interstitial pneumonia associated with collagen vascular diseases (CVD-IPs). OBJECTIVES: This study was aimed at clarifying clinical characteristics and outcome in AE of CVD-IPs, compared with those of idiopathic interstitial pneumonias (IIPs). METHODS: We retrospectively reviewed 112 admission cases with suspected AE of CVD-IPs or IIPs during 2003-2009. IIPs were diagnosed with idiopathic pulmonary fibrosis (IPF) or non-IPF, mostly based on radiologic findings. Of these, 15 AEs of CVD-IPs (6 rheumatoid arthritis, 6 dermatomyositis and 3 systemic sclerosis) and 47 AEs of IIPs (13 IPF and 34 non-IPF) were included. RESULTS: The clinical characteristics in AE of CVD-IPs were similar to those of IIPs, except for younger age (63.3 ± 6.8 vs. 73.8 ± 9.1 years; p = 0.0001) and higher PaO(2)/FiO(2) at the onset of AE (205 ± 81.2 vs. 145 ± 53.8 mm Hg; p = 0.002) in the former. Dermatomyositis-related interstitial pneumonia (IP) showed a relatively indolent onset and was often associated with worsening control of the underlying disease, whereas AE of other CVD-IPs resembled that of IIPs. 90-day mortality of 33% in AE of CVD-IPs was similar to that of IIPs (44%; p = 0.44) or non-IPF (34%; p = 0.94), but was significantly better than that of IPF (69%; p = 0.04). CONCLUSION: Clinical features and outcome in AE of CVD-IPs were similar, if not identical, to those of IIPs, having a significant impact on the clinical course. AE of advanced IPF with typical radiologic features seems to have higher mortality compared with other forms of IP.

[Cisplatin administration for outpatients with short hydration of less than four hours].

BACKGROUND: The administration of cisplatin (CDDP)-containing regimens for outpatients has been popularized with the development of supportive care such as antiemetics. Currently, the number of chemotherapies available for outpatients has increased for many kinds of cancer, and administration with a shorter duration is desirable even in CDDP-containing regimens. METHODS: Between January 2008 and October 2011, we retrospectively evaluated 22 outpatients who received B 50mg/m² of cisplatin with a short hydration of within 4 hours. We instructed the patients to drink water(1, 000mL/day) on days 2 and 3 instead of receiving a drip infusion. The first course of chemotherapy was usually introduced on admission, and subsequent courses were administered in outpatient clinics. RESULTS: Thirteen cases of lung cancer, eight with gastric cancer, and one with esophageal cancer, were retrospectively evaluated. Thirteen CDDP+S-1 regimens, four CDDP+gemcitabine regimens, and five other types of regimens were administered. The median dose of CDDP was 60mg/m² (range, 50-75mg/m²), the median amount of drip infusion was 1, 600 mL (range, 1, 350-2, 000mL), and the median duration of drip infusion was 4 hours (range 3-4 hours). The decision to use antiemetics and diuretics was made on a case-by-case basis. The average creatinine level before the initiation of a CDDP-containing regimen was 0. 778±0. 212mg/dL, and the lebel four weeks after completion of the regimen was 0. 847±0. 200mg/dL. Among these 22 patients, 20 completed cisplatin-containing regimens. However, cisplatin was reduced in one patient due to renal dysfunction, and the cisplatin regimen was interrupted in one patient due to intolerable nausea and vomiting. CONCLUSIONS: CDDP administration at doses of 50-60mg/m² for outpatients was suggested to be safe with optimal patient selection, a total duration of administration of less than four hours, and with 2, 000 mL of hydration on day 1 and without drip infusion from day 2.

Erlotinib for pretreated squamous cell carcinoma of the lung in Japanese patients.

OBJECTIVE: Erlotinib has demonstrated survival benefit in patients with not only adenocarcinoma but also squamous cell carcinoma. Epidermal growth factor receptor-tyrosine kinase inhibitors are more effective in Asian populations, including the Japanese than in western populations. However, a higher incidence of interstitial lung disease has been reported as a fatal adverse event in the Japanese population. There is little data on erlotinib for Japanese patients with pretreated squamous cell carcinoma. METHODS: Between January 2004 and October 2010, we retrospectively evaluated the efficacy and toxicity of erlotinib administered as the first epidermal growth factor receptor-tyrosine kinase inhibitors for 41 Japanese patients with pretreated squamous cell carcinoma. Patients with pre-existing interstitial lung disease were carefully excluded by several examinations including high-resolution computed tomography. RESULTS: The response rate and disease control rate were 9.7% [95% confidence interval: 2.7-23.1%) and 43.9% (95% confidence interval: 28.5-60.2%], respectively. Median time to treatment failure and overall survival were 2.2 months (95% confidence interval: 1.0-2.8 months) and 11.0 months (95% confidence interval: 5.7-15.7 months), respectively. Interstitial lung disease (Grade 5) was observed in one (2.4%) patient. Patients with Grade 0-1 skin rashes vs. patients with Grades 2-3 exhibited disease control rates of 28 vs. 83% (P = 0.0017), and median time to treatment failure of 1.2 months vs. 3.4 months (P = 0.0099). CONCLUSIONS: Erlotinib has moderate efficacy for pretreated squamous cell carcinoma in Japanese patients. A higher grade of skin rash was associated with clinical benefit. Careful exclusion of pre-existing interstitial lung disease can minimize the occurrence of interstitial lung disease.

[Direct low-dose fentanyl patch (2.1mg) introduction for opioid naïve outpatients with cancer pain].

BACKGROUND: The administration of opioids to outpatients with cancer pain can be difficult because the constant dose modification and treatments of side effects involved are occasionally impossible. Therefore, more effective and safer drugs with better patients compliance are needed to complete a successful opioid introduction. Compared with other opioids, low-dose fentanyl has been suggested to produce milder side effects such as nausea, constipation, and somnolence. Further more, compliance can be improved because the drug is a patch,administered transdermally. METHODS: Between July 2008 and December 2009, we investigated the safety and analgesic effect of a fentanyl patch (2.1 mg) as a direct opioid introduction for 36 outpatients with cancer pain without titrations of other opioids. RESULTS: Side effects of constipation, nausea, somnolence, and dizziness were observed in 17 (47%), 6 (17%), 4 (11%), and 3 (8%) patients, respectively, and no respiratory suppression was observed. Regarding the analgesic effect, 23 (64%) patients reported improvement on pain scales one week after the initiation of the fentanyl patch. CONCLUSIONS: Opioid introduction to opioid-naÏve outpatients with cancer pain using the low-dose fentanyl patch (2.1 mg) may be effective.

Genetic polymorphisms in the endothelial nitric oxide synthase gene correlate with overall survival in advanced non-small-cell lung cancer patients treated with platinum-based doublet chemotherapy.

BACKGROUND: Nitric oxide (NO) is a free radical that is involved in carcinogenesis. Endothelial NO, synthesized from L-arginine by endothelial NO synthase (eNOS), inhibits apoptosis and promotes angiogenesis, tumor cell proliferation and metastasis. The aim of this study was to evaluate the influence of polymorphisms in the eNOS gene on prognosis of patients with advanced stage non-small-cell lung cancer (NSCLC). METHODS: Unresectable, chemotherapy naïve stage III or IV NSCLC patients who were treated with standard platinum-containing doublet regimens were analyzed. All individuals were genotyped for the single-nucleotide polymorphism G894T in exon 7 of the eNOS gene and for a variable number of tandem repeats (VNTR) polymorphism in intron 4 that results in a rare smaller allele (a) and a common larger allele (b), to investigate the association between these polymorphisms and clinical outcomes. The primary endpoint was correlation with overall survival. RESULTS: From October 2004 to December 2007, 108 patients (male/female, 66/42; Stage IIIA/IIIB/IV, 6/30/72) aged 29-77 years (median 63) with good performance status were consecutively enrolled in this study. Using Kaplan-Meier estimates, we showed that 5-year overall survival was significantly increased in patients carrying the VNTR a-allele compared with VNTR b/b patients (P = 0.015). In multivariate Cox proportional hazard analysis, the VNTR polymorphism was an independent prognostic factor for survival. CONCLUSIONS: The results support the role of the VNTR polymorphism in intron 4 as a marker for survival in patients with advanced stage NSCLC who are candidates for standard chemotherapy.

[Two cases of effective S-1 monotherapy for patients with metastatic adenocarcinoma of the lung after multiple previous chemotherapies].

Case one was a 76-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases (cT4N0M1, stage IV, mucinous BAC)in June, 2004. Starting in July, 2004, she received various modalities of chemotherapy( cisplatin+vinorelbine, gefitinib, pemetrexed, gemcitabine, docetaxel, paclitaxel). S-1 monotherapy given to her starting April, 2006 achieved a partial response(PR)as a seventh-line treatment. Case two was a 60-year-old woman. She was diagnosed as having lung adenocarcinoma with multiple metastases(cT4N3M1, stage IV)in October, 2004. That month, her chemotherapy began. After various treatments(cisplatin+vinorelbine, docetaxel, gefitinib), S-1 monotherapy was initiated in February, 2007 as the fourth-line treatment; as a result, PR was achieved. Even though chemotherapies were performed in succession, in the condition of good general status, salvage chemotherapy can be affected by the rotation of drugs. In such cases, S-1 monotherapy can be a reasonable choice from the standpoint of feasibility and effectiveness.

[A case of cavitating pneumococcal pneumonia developed during the treatment with etanercept for rheumatoid arthritis].

A 54-year-old woman who had been treated for rheumatoid arthritis (RA) with the anti-TNF-alpha drug, etanercept, was referred to our department on 27 April 2006 because of dyspnea and shock. Chest X-ray and computed tomography on admission indicated bilateral pneumonia which was proved to be caused by Streptococcus pneumoniae with positive blood culture results. The patient had recovered from multiple organ failure with intensive treatments such as NIPPV and cardiovascular support with cathecolamines, however, the left upper lobe of her lung had developed a large cavity that had been producing viable pneumococci on sputum culture for more than one month. As the development of lung necrosis and subsequent formation of a cavity is rare in patients with pneumococcal pneumonia, this case should be noted in terms of the relevance of both the fulminating pathogenecity of Streptococcus pneumoniae and the anti TNF-alpha drug treatment.

[An autopsy case of racemose hemangioma of bronchial arteries associated with neovascularization from the chest wall after ligation and frequent embolizations].

We report an autopsied 33 year old pregnant woman with racemose hemangioma of the bronchial arteries. She was first given a diagnosis of racemose hemangioma of the bronchial arteries at age 19 and underwent surgical ligation. Nevertheless, she had to be admitted to the hospital for bronchial artery embolizations every time hemoptysis recurred. In her 21st gestational week, she was admitted to our hospital because of her 9th recurrent massive hemoptysis and dyspnea. Bronchial artery embolizations were repeatedly performed under intubation to ventilate the healthy left lung separately. We succeeded in temporarily stopping the hemoptysis, but her case was complicated by bacterial pneumonia and septic shock. Her baby was born dead on day 11 and she died on day 12. The autopsy revealed abnormal convoluted and dilated arteries branching from the right intercostal and subclavian arteries and intruding into the lung parenchyma through adhesion caused by her previous thoracostomy. The connections of these abnormal arteries with pulmonary arteries and veins, which had been shown by angiography, were confirmed by autopsy. The autopsy findings suggest that temporal surgical procedures with thoracostomy in this condition can induce abnormal neovascularization via pleural adhesion.

Sleeve lobectomy for lung adenocarcinoma treated with neoadjuvant afatinib.

Afatinib, the second-generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI), has been postulated to be associated with improved inhibition of EGFR-dependent tumor growth compared with first-generation EGFR-TKIs for advanced non-small cell lung cancer (NSCLC). We present a case of lung adenocarcinoma (cT3N0M0) treated with neoadjuvant afatinib and sleeve lobectomy. Because of the location of the tumor, reduced FEV1 value, and the presence of EGFR mutation, the patient was planned to be prescribed afatinib (30 mg daily) for 3 weeks as neoadjuvant therapy and underwent sleeve lobectomy to avoid pneumonectomy as much as possible. Although the patient presented with grade 3 diarrhea and dose reduction of afatinib to 20 mg daily was needed, several image findings showed a partial response of the tumor on Day 20. Oral administration of afatinib was discontinued on Day 22. A right upper sleeve lobectomy combined with partial resection of lower lobe was performed after oral administration of afatinib on Day 24. The patient's postoperative course was uneventful and she has been free of recurrence for 26 months. This strategy could reduce the risk of pneumonectomy with acceptable side effects. The treatment, clinical course and pathological findings of the patient are discussed.

Docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte-colony stimulating factor for pretreated non-small cell lung cancer.

PURPOSE: The aim of our study was to evaluate the efficacy and safety of docetaxel plus ramucirumab with primary prophylactic pegylated (PEG)-granulocyte-colony stimulating factor (G-CSF) for pretreated non-small cell lung cancer (NSCLC). RESULTS: Sixty-one pretreated NSCLC patients underwent docetaxel plus ramucirumab. Primary prophylactic PEG-G-CSF was performed in 52 (85%) patients (prophylactic group). No febrile neutropenia (FN) (0%) was confirmed in 52 prophylactic group patients, whereas FN was observed in 3 (33%) of 9 non-prophylactic group patients. Among prophylactic group, median lines of prior therapy was 2 (range, 1-9). Median cycles of docetaxel plus ramucirumab was 3 (range, 1-25) (9 and 3 cases moved to ramucirumab and docetaxel monotherapies, respectively). Response rate and disease control rate were 30.8% and 73.1%, respectively. Median progression-free survival was 4.5 (95% confidence interval [CI], 3.0-6.6) months. Median overall survival was 11.4 (95% CI, 8.0-13.9) months. Six (11.5%) patients had grade 3/4 neutropenia. Observed grade 3 (incidence ≥10%) adverse event (AE) was oral mucositis (13.5%). There were no grade 4/5 non-hematological AEs. CONCLUSIONS: Our study demonstrated the efficacy and safety of docetaxel plus ramucirumab with PEG-G-CSF in clinical practice. Primary prophylactic PEG-G-CSF could markedly reduce incidence of FN. METHODS: We retrospectively reviewed medical records of pretreated NSCLC cases who had received docetaxel plus ramucirumab in our departments.

Does afatinib plus bevacizumab combination therapy induce positive conversion of T790M in previously-negative patients?

Third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are markedly effective for T790M-positive patients. To confer their clinical benefit to more patients, a novel therapy to induce positive conversion in T790M-negative patients may be possible. We retrospectively reviewed medical records of patients who had received rebiopsy after completion of ABC-study: a prospective phase II study of Afatinib plus Bevacizumab Combination (ABC)-therapy after acquired resistance to EGFR-TKI. Between October 2014 and September 2016, 32 eligible patients were enrolled in ABC-study at our institutes. Eighteen patients were T790M-negative and 14 were T790M-positive before ABC-therapy. Rebiopsy was performed on 13 T790M-negative and 5 T790M-positive patients after progression of ABC-therapy. In 8 (62%) of 13 T790M-negative patients, T790M status changed from negative to positive after ABC-therapy. Seven of these 8 patients underwent osimertinib therapy. The response rate and median time to treatment failure were 86% and 12.2 months, respectively. There were no adverse events ≥grade 3, nor any treatment-related deaths. On the other hand, T790M remained positive after ABC-therapy in all 5 previous T790M-positive patients. ABC-therapy could induce positive conversion of T790M even in previously-negative patients. We hypothesize that ABC-therapy could provoke "clonal selection", which purifies T790M-positive cancer cells in heterogeneous tumors. Further studies are warranted to confirm this phenomena.