Phase I study of amrubicin plus cisplatin and concurrent accelerated hyperfractionated thoracic radiotherapy for limited-disease small cell lung cancer: protocol of ACIST study.

BACKGROUND: Etoposide plus cisplatin (EP) combined with concurrent accelerated hyperfractionated thoracic radiotherapy (AHTRT) is the standard treatment strategy for unresectable limited-disease (LD) small cell lung cancer (SCLC), which has remained unchanged for over two decades. Based on a previous study that confirmed the non-inferiority of amrubicin (AMR) plus cisplatin (AP) when compared with EP for extensive-disease (ED) SCLC, we have previously conducted a phase I study assessing AP with concurrent TRT (2 Gy/time, once daily, 50 Gy in total) for LD-SCLC therapy. Our findings revealed that AP with concurrent TRT could prolong overall survival to 39.5 months with manageable toxicities. Therefore, we plan to conduct a phase I study to investigate and determine the effect of AP combined with AHTRT, recommended dose (RD), maximum tolerated dose (MTD), and dose-limiting toxicity (DLT) of AP in patients with LD-SCLC. METHODS: Treatment-naive patients with LD-SCLC, age between 20 and 75 years, who had a performance status of 0 or 1 and adequate organ functions will be enrolled. For chemotherapy, cisplatin 60 mg/m2 /day (day 1) and AMR (day 1 to 3) will be administered with AHTRT (1.5 Gy/time, twice daily, 45 Gy in total). The initial AMR dose is set to 25 mg/m2 /day. RD and MTD will be determined by evaluating toxicities. DISCUSSION: Based on our previous study, the initial dose of AMR 25 mg/m2 is expected to be tolerated and acceptable. Here, we aim to determine whether treatment with AP and concurrent AHTRT would be an optimal choice with manageable toxicities for LD-SCLC.

Association of Genetic Polymorphisms With Afatinib-induced Diarrhoea.

BACKGROUND/AIM: Afatinib, a 2nd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used in treatment of non-small cell lung cancer (NSCLC), causes diarrhoea in over 90% of patients. The association of genetic background with diarrhoea is poorly understood. PATIENTS AND METHODS: We evaluated the roles of four single nucleotide polymorphisms (SNPs) in ATP binding cassette subfamily B member 1 (ABCB1) and ATP binding cassette subfamily G member 2 (ABCG2) genes-ABCB1 1236 C>T, 2677 G>T/A, and 3435 C>T, and ABCG2 421 C>A-on treatment-induced diarrhoea in 38 patients with NSCLC treated with afatinib. RESULTS: Diarrhoea occurred more frequently in patients with ABCB1 2677 T(A)/T(A) (14/16, 87.5%) than in patients with non-T(A)/T(A) alleles (8/22, 36.4%) (p=0.003). ABCB1 2677 T(A)/T(A) was significantly predictive of diarrhoea (p=0.002) by multivariable regression analysis. CONCLUSION: Afatinib-induced diarrhoea is associated with the SNP ABCB1 2677 T(A)/T(A).

Updated Survival Data for a Phase I/II Study of Carboplatin plus Nab-Paclitaxel and Concurrent Radiotherapy in Patients with Locally Advanced Non-Small Cell Lung Cancer.

LESSONS LEARNED: Updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy were collected. In the group of 58 patients who were enrolled at 14 institutions in Japan, the median overall survival was not reached and the 2-year overall survival rate was 66.1% (95% confidence interval, 52.1%-76.8%). Results reveal encouraging feasibility and activity for this regimen. BACKGROUND: We report the updated survival data for a phase I/II study of carboplatin plus nab-paclitaxel (nab-P/C) and concurrent radiotherapy (CRT) in patients with locally advanced non-small cell lung cancer (NSCLC). METHODS: Individuals between 20 and 74 years of age with unresectable NSCLC of stage IIIA or IIIB and a performance status of 0 or 1 were eligible for the study. Patients received weekly nab-paclitaxel at 50 mg/m2 for 6 weeks together with weekly carboplatin at an area under the curve (AUC) of 2 mg/ml/min and concurrent radiotherapy with 60 Gy in 30 fractions. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel (100 mg/m2 on days 1, 8, and 15) plus carboplatin (AUC of 6 on day 1). After the treatment, patients were observed off therapy. The primary endpoint of the phase II part of the study was progression-free survival (PFS). RESULTS: Between October 2014 and November 2016, 58 patients were enrolled at 14 institutions in Japan, with 56 of these individuals being evaluable for treatment efficacy and safety. At the median follow-up time of 26.0 months (range, 4.0-49.6 months), the median overall survival (OS) was not reached (95% confidence interval [CI], 25.3 months to not reached) and the 2-year OS rate was 66.1% (95% CI, 52.1%-76.8%). The median PFS was 11.8 months (95% CI, 8.2-21.0 months), and the 2-year PFS rate was 35.9% (95% CI, 23.1%-48.9%). Subgroup analysis according to tumor histology or patient age revealed no differences in median PFS or OS. Long-term follow-up of toxicities did not identify new safety signals, and no treatment-related deaths occurred during the study period. CONCLUSION: Concurrent chemoradiation with nab-P/C was safe and provided a long-term survival benefit for patients with locally advanced NSCLC.

Discontinuation due to immune-related adverse events is a possible predictive factor for immune checkpoint inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Immune-related adverse events (irAEs) should be anticipated with treatment by immune checkpoint inhibitors (ICIs). Although the relationship between irAEs and efficacy of ICI has been reported, it has not yet been clarified whether the benefit from ICI outweighs the low frequency of proceeding to subsequent therapies after discontinuation due to irAEs. METHODS: The study comprised 61 patients with non-small cell lung cancer who underwent treatment with ICIs (nivolumab or pembrolizumab monotherapy) at the Saga University Medical School Hospital from December 2015 to January 2018. Therapeutic effect and progression-free survival (PFS) were compared between the irAEs discontinuation group (AEg) and the group with discontinuation due to all causes other than irAEs (Non-AEg). RESULTS: A total of 30% patients(18/61) had therapy discontinued due to irAEs: 22.5% (9/40) with nivolumab and 42.9% (9/21) with pembrolizumab. The response rate was 50.0% in the AEg and 8.1% in the on-AEg (P = 0.001). The median PFS was significantly longer in the AEg (9.3 months; 95% CI 2.1-12.1) than in the non-AEg (1.9 months; 95% CI 0.9-3.6): HR 0.45 (95%CI 0.20-0.89; log-rank test P = 0.026). The prevalence of drug-induced interstitial lung disease (ILD) was 6.1% (3/49) in cases without interstitial pneumonia (IP) as the underlying disease, whereas it was 50% (6/12) in cases with IP (P = 0.001). CONCLUSION: Discontinuation of treatment with ICIs due to irAEs predict a good response to ICIs and favorable outcome since their anti-cancer effects continue even after discontinuation. However, the presence of IP as the underlying disease increases the risk of drug-related ILD onset.

Paraneoplastic Limbic Encephalitis Complicated with Small Cell Lung Cancer at the Time of Recurrence.

Paraneoplastic limbic encephalitis (PLE) is a rare neurologic disorder that can complicate various malignancies, including lung cancer. PLE is most frequently found the initial presentation of lung cancer. In this study, we reported the case of a 74-year-old Japanese woman who developed PLE after partial remission of small cell lung cancer (SCLC) by first-line systemic chemotherapy. Brain magnetic resonance imaging showed no metastatic tumor or cerebrovascular disease. Anti-glutamic acid decarboxylase (GAD) and anti-amphiphysin antibodies were detected in her serum. She was diagnosed as having PLE related to the recurrence of SCLC and received high-dose glucocorticoid, and sequentially systemic chemotherapy with amrubicin. Unfortunately, these treatments did not improve her disease progression and she died 4 months later. Although PLE rarely occurs at the time of SCLC recurrence, physicians should pay attention to PLE onset even after chemotherapy.

Mechanisms of acquired resistance to afatinib clarified with liquid biopsy.

Although mechanisms of acquired resistance to 1st and 3rd generation EGFR-TKI continue to be elucidated, there have been few clinical investigations into the mechanisms of acquired resistance to the 2nd generation EGFR-TKI afatinib. We analyzed data from 20 patients with advanced lung adenocarcinoma who acquired resistance to afatinib, including resistance during EGFR-TKI re-challenge. We examined EGFR T790M and C797S mutations, BRAF V600E mutation, and MET amplification with the MBP-QP method and with droplet digital PCR using ctDNA and re-biopsy samples obtained before and after afatinib treatment. Just before afatinib treatment, 15 of the 20 patients were T790M negative and five were positive. Among the T790M negative patients, 40.0% (6/15) became positive at the time of PD under afatinib. In patients positive for T790M, changes in T790M allele frequency were correlated with afatinib treatment efficacy. C797S was not detected in any patients just before afatinib treatment, but it appeared after treatment in three patients, although with very low allele frequency. Two of these three patients, although positive for both C797S and T790M, achieved PR to osimertinib. However, PFS of these patients was somewhat shorter than that of patients positive for T790M only. BRAF V600E was detected in one patient at PD under afatinib. MET amplification was not detected in this study. T790M is associated with acquired resistance to afatinib, as with 1st generation EGFR-TKI, but with somewhat lower frequency. The influence of C797S on resistance to afatinib is less than that of T790M, but C797S might cause shorter PFS under osimertinib.

Phase I/II study of carboplatin plus nab-paclitaxel and concurrent radiotherapy for patients with locally advanced non-small cell lung cancer.

OBJECTIVES: Chemoradiation regimens of greater efficacy are needed for patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: In a phase I study, escalating doses of weekly nab-paclitaxel (40 or 50 mg/m2) were administered along with weekly carboplatin at an area under the curve (AUC) of 2 mg mL-1 min and concurrent radiotherapy with 60 Gy in 30 fractions to patients with locally advanced NSCLC. This concurrent phase was followed by a consolidation phase consisting of two 3-week cycles of nab-paclitaxel plus carboplatin. In a phase II study, nab-paclitaxel was administered at the recommended dose (RD) together with carboplatin and radiation. RESULTS: In the phase I study, one of six patients experienced dose-limiting toxicity (leukopenia of grade 3 requiring a second consecutive skip in the administration of weekly chemotherapy) with nab-paclitaxel at 50 mg/m2, which was therefore determined to be the RD. Fifty-six patients treated at the RD were evaluable for safety and efficacy. Common toxicities of grade 3 or 4 in the concurrent phase included leukopenia (60.7%) and neutropenia (28.6%). No treatment-related deaths occurred during the study period. The objective response rate was 76.8% (95% confidence interval [CI], 64.2-85.9%), median progression-free survival was 11.8 months (60% CI, 10.6-16.2 months; 95% CI, 8.2-20.8 months), and median overall survival was not reached. CONCLUSION: Our results reveal encouraging feasibility and activity for concurrent chemoradiation with nab-paclitaxel at 50 mg/m2 and carboplatin at an AUC of 2 in patients with locally advanced NSCLC.

Primary Pulmonary Colloid Adenocarcinoma: How Can We Obtain a Precise Diagnosis?

A 76-year-old asymptomatic man was found to have a mass in the right lower lung field. Although the presence of a mucinous component in the majority of the tumor was shown by magnetic resonance imaging, the presence of cancer cells was suspected by contrast enhancement on computed tomography (CT) and based on the partial accumulation in the marginal regions of the tumor on fluorodeoxyglucose-positron emission tomography (FDG-PET). A transbronchial lung biopsy was non-diagnostic, but resection of the mass resulted in a diagnosis of colloid adenocarcinoma. The findings from combined contrast CT and FDG-PET may raise the suspicion of colloid adenocarcinoma and prompt the consideration of surgical resection.

Investigation of appropriate pre-analytical procedure for circulating free DNA from liquid biopsy.

Liquid biopsy with circulating free DNA (cfDNA) is a recommended alternative method of re-biopsy. Quality control with cfDNA is indispensable for precise examinations, and it is desirable to achieve high-quality cfDNA separation. We investigated two issues: the influence of pre-analytical procedures on cfDNA analysis performed as a routine procedure in a standard clinical laboratory, and the extent of deterioration of cfDNA quality due to long-term storage. Comparisons among blood collection tube types, storage temperatures, and periods of blood separation were performed in terms of cfDNA quantification, cfDNA size distribution, and detection of EGFR mutations. Quality of cfDNA was better with collection tubes containing 3.2% sodium citrate than with those containing EDTA 2K, and was maintained with storage at 4° C for up to 72 h after blood collection, equivalent to results with cell-stabilizing blood collection tubes. Analysis of cfDNA stored for 7 years showed that samples with low allele frequency (AF) deteriorated more readily than samples with high AF. Despite the same storage period and extraction method, AF of plasma stored for 7 years was remarkably lower than that of cfDNA. However, deterioration due to long-term plasma storage was overcome by changing the DNA extraction method from a silica membrane spin column to a cellulose magnetic beads system. These results can guide the establishment of standardized pre-analytical procedures for liquid biopsy with cfDNA.

Signet Ring Cell Carcinoma of Unknown Primary Complicated with Pulmonary Tumor Thrombotic Microangiopathy and Krukenberg Tumor.

Pulmonary tumor thrombotic microangiopathy (PTTM) is a rare disease that shows hypoxia with severe pulmonary hypertension related to malignant tumor. Diagnosis is difficult due to rapid clinical progression and the need to demonstrate pathological findings from lung biopsy. A 64-year-old woman visited our hospital with hypoxia and pulmonary hypertension. Diffuse granular shadows in the centrilobular area and ground-glass shadows in both lungs and left ovarian tumor were found on radiological imaging. PTTM was suspected, but pulmonary artery blood aspiration by right cardiac catheter failed to detect cancer cells. We could not obtain lung or ovary biopsies because of hypoxia or pulmonary hypertension. The patient died due to respiratory failure. Signet ring cell carcinoma of unknown primary, PTTM, and Krukenberg tumor were diagnosed on autopsy. Since early diagnosis facilitates adequate treatment, physicians should not miss the opportunity for biopsy in cases of suspected PTTM.

Current Status and Problems of T790M Detection, a Molecular Biomarker of Acquired Resistance to EGFR Tyrosine Kinase Inhibitors, with Liquid Biopsy and Re-biopsy.

BACKGROUND/AIM: The purpose of this study was to consider appropriate application of liquid and re-biopsy through analysis of current status in practice. PATIENTS AND METHODS: We performed a retrospective analysis of 22 patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer who exhibited 1st/2nd generation EGFR-tyrosine kinase inhibitors resistance. The cobas® method was used to detect T790M with re-biopsy and the mutation-biased PCR and quenched probe method was used with liquid biopsy. RESULTS: T790M detection rate was 52% with re-biopsy and 58% with liquid biopsy. The concordance between tissue and plasma was 58%. One patient who was T790M-positive with liquid biopsy showed heterogeneity among metastatic lesions in terms of osimertinib efficacy, as revealed by T790M detection with re-biopsy. CONCLUSION: Liquid biopsy reflects the whole body, whereas re-biopsy is useful for spatial diagnosis. Considering these characteristics, a combination of liquid and re-biopsy contribute to enhanced treatment.

Automated DNA extraction using cellulose magnetic beads can improve EGFR point mutation detection with liquid biopsy by efficiently recovering short and long DNA fragments.

The clinical utility of plasma DNA for detecting cancer-specific mutations has rapidly achieved recognition, but reliability has not been established because of relatively low mutation-detection rates compared with those from tissue re-biopsy. To address this shortcoming we examined efficiency, in terms of mutation detection, of an automated DNA extraction system that uses cellulose magnetic beads. A fully automated, highly sensitive point-mutation-detection method, mutation-biased PCR and quenching probe (MBP-QP) system, was used for this study. Plasma DNA was extracted from 61 plasma samples collected from patients with advanced non-small cell lung cancer. Extraction was performed manually with 200 µl plasma (200-M) by using a silica membrane spin column system or an automated system using 200 µl (200-A) or 1000 µl (1000-A) plasma. Median DNA yield quantified by real-time PCR was 4.4, 4.5, and 17.3 ng with the three methods, respectively. Sensitivity for detecting epidermal growth factor receptor (EGFR) L858R point mutation was 36.6%, 58.5%, and 77.5%, and specificity was 93.3%, 100%, and 96.7%, respectively. Concordance rates were 60.6%, 76.1%, and 85.7%. The size distribution of plasma DNA with automated extraction was bimodal with modes at about 170 bp and 5 Kb, and plasma DNA of both sizes included tumor-derived DNA. In this report, we demonstrate that automated DNA extraction using cellulose magnetic beads can improve mutation-detection rates with plasma DNA in association with two overall sizes of DNA fragments recovered by this DNA isolation system. Examining the biological characteristics of these fragments will be the subject of further investigation.

Sjögren Syndrome Complicated with Cystic Lung Disease and Pulmonary Amyloidosis.

A 72-year-old Japanese woman was noted to have multiple cystic lung shadows and infiltrates on chest radiography and computed tomography (CT). She complained of dryness of the mouth and eyes, but she did not have respiratory symptoms, such as cough, sputum production, and dyspnea. Her laboratory findings showed high titers of anti-SSA/Ro and anti-SSB/La antibodies. Surgical lung biopsy was performed and demonstrated pathologic findings of amyloid light-chain deposition and bronchiolitis with lymphocytic infiltration. Taken altogether, she was diagnosed as Sjögren syndrome with bronchiolitis and pulmonary amyloidosis. Since then, she has been carefully followed up without treatment. After 6 years, the cystic lung lesions on CT gradually enlarged and increased in number, but she remained to have no respiratory symptoms and no manifestations of lymphoma. Here, we report a rare case of Sjögren syndrome complicated with cystic lung disease and pulmonary amyloidosis.

A case of osimertinib-resistant lung adenocarcinoma responded effectively to alternating therapy.

We report a case of initial lung adenocarcinoma in which transformation to small cell lung carcinoma (SCLC) was observed after acquired resistance to the 3rd generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) osimertinib and alternating treatment between chemotherapy and osimertinib was effective. A 61-year-old woman with EGFR mutation positive stage IV lung adenocarcinoma was administered 1st generation EGFR-TKI for 8 months as the first line therapy, then chemotherapy and 2nd generation EGFR-TKI after progressive disease (PD). Four years after initial diagnosis, EGFR T790M was detected in a metastatic lesion of the right thoracic wall and osimertinib was prescribed. Although partial response (PR) was achieved, a new metastatic lesion appeared in the right pleurum near the diaphragm, in which SCLC characteristics were observed with elevation of pro-gastrin-releasing peptide (pro-GRP) at the time of PD under osimertinib. Osimertinib was discontinued and carboplatin plus irinotecan chemotherapy was chosen as the next treatment, leading to PR after 2 cycles. Subsequently, the right thoracic wall tumor harboring T790M and the right pleural tumor near the diaphragm showing transformation to SCLC exhibited opposite responses to therapy alternating between osimertinib and chemotherapy. It is concluded that extended disease control can be achieved by combining appropriate treatments according to the mechanisms of resistance inferred from precise genetic and pathological examination in real time.

Severity and predictive factors of adverse events in pemetrexed-containing chemotherapy for non-small cell lung cancer.

Pemetrexed is a key anticancer agent for treatment of advanced non-small cell lung cancer (NSCLC). Pemetrexed is generally well tolerated, but individual-patient differences exist in severity of adverse events. Our study aimed to characterize the adverse events of pemetrexed that result in discontinuation of chemotherapy and to identify risk factors associated with those adverse events. We retrospectively studied the incidence of adverse events in 257 patients with NSCLC who received pemetrexed (P) with or without bevacizumab (B) and/or carboplatin (C): P, PB, CP, or CPB. Patients whose chemotherapy was discontinued were divided into two groups according to adverse events and disease progression. Grade 2/3 nausea, fatigue with P and PB, and rash with CP and CPB occurred more frequent in the adverse events group than in the disease progression group. Multivariate analysis indicated that grade 2/3 nausea [odds ratio (OR) 9.94; 95% confidence interval (CI) 1.46-67.37; p = 0.01] and fatigue (OR 10.62; CI 1.60-70.20; p = 0.01) with P or PB, and rash (OR 6.12; CI 1.34-27.88; p = 0.01) with CP or CPB, were independent risk factors for discontinuation of chemotherapy. Administration of dexamethasone at doses less than 4 mg after the day of pemetrexed administration was associated with nausea following P or PB (OR 11.08; 95% CI 1.02-119.95; p = 0.04). Grade 2/3 nausea and fatigue with P or PB, and rash with CP or CPB, were associated with discontinuation of chemotherapy.

Plasma T790M and HGF as potential predictive markers for EGFR-TKI re-challenge.

Re-challenge with epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKI) has been suggested to potentially improve survival in certain populations of patients with advanced lung cancer, but predictive markers for the success of EGFR-TKI re-challenge have not been identified. The present study analyzed 16 re-challenges with EGFR-TKI undertaken in 12 patients with lung adenocarcinoma by investigating T790M and hepatocyte growth factor (HGF) in plasma coupled with clinical characteristics. EGFR mutations in plasma DNA were detected using the wild inhibiting PCR and quenched probe system for exon 19 deletions, and T790M and L858R were detected using the mutation-biased PCR and quenched probe system. HGF levels in the plasma were measured by enzyme-linked immunosorbent assay, and the ratio of HGF levels prior to re-challenge to those prior to the previous EGFR-TKI treatment was calculated. Two re-challenges demonstrated partial response, six remained as stable disease and eight had progressive disease (PD). A total of 4 of the 5 patients with a history of T790M positivity based on plasma DNA levels had PD. A total of 7 of the 8 patients who had ≥1.5-fold elevation of HGF prior to re-challenge with EGFR-TKI suffered PD. Elevation of the HGF ratio to ≥1.5 was significantly associated with poor response to EGFR-TKI re-challenge. Having no history of T790M and an HGF ratio <1.5 was significantly associated with a positive response to EGFR-TKI re-challenge. A combination of T790M detection and HGF quantification using plasma is a potentially useful assay system for predicting the effect of EGFR-TKI re-challenge. Future prospective studies are required to confirm the predictive validity of these markers.

SPARC is a possible predictive marker for albumin-bound paclitaxel in non-small-cell lung cancer.

OBJECTIVES: Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) produced good tumor response in cases with lung squamous cell carcinoma, one of the most difficult cancers to treat. Secreted protein acidic and rich in cysteine (SPARC) binds to albumin, suggesting that SPARC plays an important role in tumor uptake of nab-paclitaxel. There is as yet no predictive marker for cytotoxic agents against non-small-cell lung cancer (NSCLC), and hence we believed that SPARC expression might be associated with tumor response to nab-paclitaxel. PATIENTS AND METHODS: We studied stromal SPARC reactivity and its association with clinicopathological characteristics in 200 cases of NSCLC using a custom tissue microarray fabricated in our laboratory by immunohistochemical staining. We also investigated the relationship between stromal SPARC reactivity and tumor response to nab-paclitaxel using biopsy or surgical specimens obtained from advanced or recurrent lung cancer patients. RESULTS: High SPARC stromal reactivity (>50% of optical fields examined) was detected in 16.5% of cases and intermediate SPARC reactivity (10%-50%) in 56% of cases. High expression in cancer cells was rare (five cases). Stromal SPARC level was correlated with smoking index, squamous cell carcinoma, and vessel invasion. Furthermore, patients with high stromal SPARC reactivity in biopsy specimens such as transbronchial lung biopsy or surgical specimens tended to respond better to nab-paclitaxel. CONCLUSION: Stromal SPARC was detected by immunohistochemical staining in ∼70% of NSCLC cases, and good tumor response to nab-paclitaxel was correlated with high stromal SPARC reactivity. SPARC may be a useful predictive marker for selecting patients likely to respond favorably to nab-paclitaxel treatment.

Phase II trial of weekly nab-paclitaxel for previously treated advanced non-small cell lung cancer: Kumamoto thoracic oncology study group (KTOSG) trial 1301.

OBJECTIVES: We performed an open-label, multicenter, single-arm phase II study (UMIN ID 000010532) to prospectively evaluate the efficacy and safety of nab-paclitaxel for previously treated patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with advanced NSCLC who experienced failure of prior platinum-doublet chemotherapy received weekly nab-paclitaxel (100mg/m(2)) on days 1, 8, and 15 of a 21-day cycle until disease progression or the development of unacceptable toxicity. The primary end point of the study was objective response rate (ORR). RESULTS: Forty-one patients were enrolled between September 2013 and April 2015. The ORR was 31.7% (90% confidence interval, 19.3%-44.1%), which met the primary objective of the study. Median progression-free survival was 4.9 months (95% confidence interval, 2.4-7.4 months) and median overall survival was 13.0 (95% confidence interval, 8.0-18.0 months) months. The median number of treatment cycles was four (range, 1-17) over the entire study period, and the median dose intensity was 89.1mg/m(2) per week. Hematologic toxicities of grade 3 or 4 included neutropenia (19.5%) and leukopenia (17.1%), with no cases of febrile neutropenia being observed. Individual nonhematologic toxicities of grade 3 or higher occurred with a frequency of <5%. CONCLUSION: Weekly nab-paclitaxel was associated with acceptable toxicity and a favorable ORR in previously treated patients with advanced NSCLC. Our results justify the undertaking of a phase III trial comparing nab-paclitaxel with docetaxel in this patient population.

Coexistence of lung cancer and immunoglobulin G4-related lung disease in a nodule: a case report.

BACKGROUND: Immunoglobulin G4-related disease is characterized by infiltration of immunoglobulin G4-positive plasmacytes in various organs. The radiological findings of lung involvement of immunoglobulin G4-related disease include hilar and mediastinal lymphadenopathies, thickness of bronchovascular bundles, peribronchovascular consolidation, and lung nodules. Although a pathological approach is needed to diagnose immunoglobulin G4-related disease, it is ordinarily diagnosed by biopsy from one lesion even if there are multiple lesions. We reported a rare case of the coexistence of immunoglobulin G4-related disease and lung cancer in the same lung nodule. CASE PRESENTATION: A 72-year-old Japanese man visited our hospital for evaluation of a nodular shadow in the middle lobe of his right lung that was seen on chest radiograph and computed tomography scan. An abdominal computed tomography scan showed a tumefactive lesion in his anterior sacral spine. Blood examinations revealed high serum immunoglobulin G4 concentration at 346 mg/dl, renal dysfunction, and anemia. He underwent right upper lobectomy and regional lymph node dissection. Pathologic findings of the lung nodule showed lepidic pattern adenocarcinoma with infiltration of immunoglobulin G4-positive plasma cells and obliterative phlebitis. CONCLUSIONS: To date, there have been only few reports on the coexistence of immunoglobulin G4-related disease and lung cancer; here, we report such a rare case. Histologic examination should be considered in cases of suspicious immunoglobulin G4-related disease appearing in a lung nodule.