Factors related to fixedness after transbronchial fiducial marker placement for image-guided proton therapy: A retrospective study.

BACKGROUND: The usefulness of transbronchially inserted gold fiducial markers has been reported in radiation therapy and proton therapy for mobile lesions, such as lung tumors. However, there is occasional dropout of inserted markers. This retrospective study investigated the factors related to dropout of markers inserted for image-guided proton therapy (IGPT). METHODS: Between June 2013 and October 2021, 535 markers were inserted in 171 patients with lung tumors. We investigated whether marker dropout was affected by the location of marker insertion, distance between the marker and the chest wall (DMC), and difference in forced expiratory volume in 1 s (FEV1)/forced vital capacity (FVC). Marker dropout from the time of planning computed tomography (CT) to follow-up CT was also evaluated. RESULTS: Of the 535 inserted markers, 417 were confirmed on planning CT and 356 on follow-up CT after IGPT. Multivariate analysis revealed that marker insertion into the upper lobe and FEV1/FVC ≥70% were factors associated with total marker dropout. Marker dropout between planning CT and follow-up CT was associated with DMC, FEV1/FVC ≥70%, and planning CT performed within 4 days of marker insertion. CONCLUSIONS: Marker dropout can be minimized by inserting markers more peripherally, by considering the planned insertion location, and FEV1/FVC. Additionally, planning CT should be scheduled at least 5 days after marker insertion.

Mycobacterium avium complex lung disease in a patient treated with an immune checkpoint inhibitor: A case report.

Immune checkpoint inhibitors (ICIs) are becoming widely used for the treatment of various types of cancer. However, characteristic side effects, which are referred to as immune-related adverse events, may appear, and they have important clinical implications for the management of patients treated with ICIs. The development of mycobacterial infections has also been reported, but they have mostly been seen in cases with tuberculosis, and only a few cases involved non-tuberculous mycobacteriosis. We herein present the case of an 82-year-old man who was treated with nivolumab for gastric cancer. After the 22nd course of the treatment, the patient experienced loss of appetite for 1 week, and infiltration shadows were observed in the lower lobe of the left lung. Treatment for bacterial pneumonia was ineffective, and the lung field shadow gradually worsened. Mycobacterium intracellulare was detected in two consecutive sputum cultures. Thus, the patient was diagnosed with Mycobacterium avium complex (MAC) lung disease, and treatment for MAC infection was thus initiated, with subsequent improvement of the patient's condition and infiltration shadows. At 7 months after the start of treatment, the sputum cultures became negative for acid-fast bacilli. Since MAC lung disease may develop acutely during immunotherapy with ICIs, clinicians should include it in the differential diagnoses for pneumonia during immunotherapy with ICIs.

Lambert-Eaton Myasthenic Syndrome Caused by Atezolizumab in a Patient with Small-cell Lung Cancer.

We herein report a 74-year-old man who developed Lambert-Eaton myasthenic syndrome (LEMS) during atezolizumab treatment for extensive-stage small-cell lung cancer. He was started on maintenance immunotherapy with atezolizumab every three weeks after four cycles of atezolizumab plus carboplatin plus etoposide combination therapy. After 13 cycles of maintenance atezolizumab therapy, he complained of muscular weakness and fatigue. Findings from a nerve conduction study and positive findings for anti-P/Q-type voltage-gated calcium channel antibody resulted in a diagnosis of LEMS. This was a rare case of LEMS as a neurological immune-related adverse event induced by atezolizumab therapy.

Streptococcal Toxic Shock Syndrome Induced by Group A Streptococcus with the emm28 Genotype That Developed after a Uterine Cancer Test.

A 69-year-old woman without pre-existing disease visited our hospital due to general malaise, diarrhea, and arthralgia 3 days after a uterine cancer test. We diagnosed her with sepsis of unknown focus and started treatment immediately, but she died 20 hours after the first visit due to multi-organ failure and septic shock. Later, group A streptococcus was detected from the blood culture, and streptococcal toxic shock syndrome (STSS) was diagnosed. The strain had the emm28 genotype and a mutation in csrR with increased NADase activity. These virulence factors were considered to be related to STSS development in this patient.

Clinical utility of liquid biopsy for EGFR driver, T790M mutation and EGFR amplification in plasma in patients with acquired resistance to afatinib.

BACKGROUND: Cell-free DNA (cfDNA) genotyping in plasma using the cobas EGFR Mutation Test v2 (cobas) is the first liquid biopsy as a companion diagnosis to identify the EGFR T790M mutation (T790M) after the failure of treatment of EGFR-tyrosine kinase inhibitors (TKIs) (1st generation, gefitinib [G] and erlotinib [E] and 2nd generation, afatinib [A]). This study investigated the clinical utility of a liquid biopsy for patients who acquired resistance to afatinib. METHODS: We prospectively collected plasma from 51 patients who had acquired resistance to afatinib between April 2015 and November 2016 to evaluate the frequency of T790M by cobas and digital droplet PCR (UMIN000025112). Additionally, we retrospectively reviewed 38 patients who tested by cobas in plasma after G/E failure to compare for T790M detection between A and with G/E. RESULTS: The detection rate of EGFR-driver and T790M in plasma in patients treated with A (A group) as a first-line EGFR-TKI was lower than with G/E followed by A (G/E→A group), although the differences were not significant (EGFR-driver: 41% [A] vs. 67% [G/E→A], P=0.1867; and T790M: 8% [A] vs. 17% [G/E→A], P=0.5798). In first-line setting, the detection rate for EGFR-driver and T790M in plasma by cobas was lower in A group than in G/E group, although there was no significant difference (EGFR-driver: 34% [A] vs. 52% [G/E], P=0.2072; and T790M: 10% [A] vs. 27% [G/E], P=0.1161). CONCLUSION: The detection of EGFR-driver and T790M in plasma by cobas in patients treated with afatinib might be lower than with G/E in a real-world setting.

Concurrent Chemo-Proton Therapy Using Adaptive Planning for Unresectable Stage 3 Non-Small Cell Lung Cancer: A Phase 2 Study.

PURPOSE: This study prospectively evaluated the efficacy and safety of concurrent chemo-proton therapy (CCPT) using adaptive planning for unresectable stage III non-small cell lung cancer (NSCLC). METHODS AND MATERIALS: The primary endpoint was overall survival (OS). Secondary endpoints were local control rate (LCR), progression-free survival (PFS), incidence of grade 3 or higher adverse events, and changes in quality of life (QOL). Patients received cisplatin (60 mg/m2) on day 1 and S-1 (∼40 mg/m2 twice daily) on days 1 to 14, q4w, for up to 4 cycles, plus concurrent proton therapy at a total dose of 70 GyRBE for the primary lesion and 66 GyRBE for lymph node metastasis with 2 GyRBE per day. Proton therapy was performed using respiratory-gated and image guided techniques, and adaptive plans were implemented. RESULTS: Forty-seven patients were enrolled between August 2013 and August 2018. Four cycles of cisplatin plus S-1 were completed in 34 patients. The mean number of cycles was 4 (range, 1-4). The median follow-up of all and surviving patients was 37 (range, 4-84) and 52 months (range, 26-84), respectively. The mean number of replanning sessions was 2.5 (range, 1-4). The 2- and 5-year OS, LCR, and PFS were 77% (95% confidence interval 64%-89%) and 59% (43%-76%), 84% (73%-95%) and 61% (44%-78%), and 43% (28%-57%) and 37% (22%-51%), respectively. The median OS was not reached. No grade 3 or higher radiation pneumonitis was observed. There was no significant deterioration in the QOL scores after 24 months except for alopecia. CONCLUSIONS: CCPT with adaptive planning was well tolerated and yielded remarkable OS for unresectable stage III NSCLC.

Nestin Expression Affects Resistance to Chemotherapy and Clinical Outcome in Small Cell Lung Cancer.

Objectives: Small cell lung cancer (SCLC) is an aggressive and highly metastatic lung cancer subtype. Nestin is a member of the intermediate filament family and serves as a potential proliferative and multipotency marker in neural progenitor and stem cells. Aberrant expression of nestin is linked to poor prognosis in different cancers, including non-small cell lung cancer. However, the association between nestin expression and clinicopathological feature or prognosis has remained unclear for SCLC. This study examined whether nestin expression was associated with malignant features and clinical outcomes in SCLC. Materials and Methods: Using previously established Nestin knock-down cells and a newly established Nestin-overexpressing cell line, we examined the relationship between nestin expression and cell proliferation in vitro and in vivo and chemosensitivity. We also analyzed nestin expression in three drug-resistant lung cancer cell lines. Furthermore, we examined samples from 84 SCLC patients (16 patients with surgical resection, and 68 patients with biopsy), and immunohistochemically analyzed nestin expression. Results: Nestin expression correlated positively with cell proliferation, but negatively with chemosensitivity. Nestin expression in drug-resistant cell lines was upregulated compared to their parental cells. Among the 84 SCLC patients, 24 patients (28.6%) showed nestin-positive tumor. Nestin-positive ratio tended to be higher in operated patients than in biopsied patients. Nestin-positive and -negative patients showed no significant differences in response rate (RR) or progression-free survival (PFS) following first-line chemotherapy. However, positive expression of nestin was associated with shorter PFS following second-line chemotherapy (median PFS: nestin-positive, 81 days vs. nestin-negative, 117 days; P = 0.029). Conclusions: Nestin expression may be associated with malignant phenotype and worse outcome in SCLC patients.

Disseminated Mycobacterium avium Infection Complicated with Chylous Ascites in a Patient with Neutralizing Autoantibodies to Interferon-γ.

A 68-year-old man visited our hospital due to anorexia, weight loss and a fever. We diagnosed the patient with disseminated Mycobacterium avium complex (MAC) and confirmed the presence of interferon (IFN)-γ neutralizing autoantibodies (IFN-γAb). His lesions improved following antibiotic therapy, but chylous ascites (CA) developed seven months after treatment. CA was able to be controlled by subcutaneous octreotide and diet therapy. IFN-γAb is recognized as having a critical role in the pathogenesis of disseminated MAC disease, but its clinical features are not fully understood. CA may be a complication that develops during the treatment of disseminated MAC infection.

Propensity score analysis of overall survival between first- and second-generation EGFR-TKIs using real-world data.

We constructed a data set of EGFR-mutant non-small-cell lung carcinoma (NSCLC) patients, and compared the overall survival of first-generation (1G), and second-generation (2G) EGFR-tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR-mutated NSCLC patients who received EGFR-TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR-TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR-TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5-33.5] in the 1G group (gefitinib, 32.0 [28.1-35.8]; erlotinib, 27.5 [23.9-31.7]), and 38.6 [32.2-NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR-TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P < .0001; adjusted by matching, HR 0.725, P = .0418). Exploratory analysis showed that OS using the 2G EGFR-TKI was superior to that of the 1G EGFR-TKIs, suggesting the potential of sequential therapy of 2G EGFR-TKI followed by osimertinib. (HR 0.419, P = .0519) Real-world data analysis using 1354 data records, using propensity scoring, indicated that 2G EGFR-TKI had a trend of longer OS compared with 1G EGFR-TKIs.

ABCC11 gene polymorphism as a potential predictive biomarker for an oral 5-fluorouracil derivative drug S-1 treatment in non-small cell lung cancer.

PURPOSE: ABCC11/MRP8 (ABCC11) is an ATP-binding cassette transporter that is involved in regulating cellular sensitivity and resistance for many anti-cancer drugs. Since 5-fluorouracil (5-FU) is one of the substrates for ABCC11, we examined whether ABCC11 is a predictive marker for an oral 5-FU derivative drug S-1 treatment in non-small cell lung cancer (NSCLC). METHODS: Real-time PCR and MTS assay were carried on 21 human NSCLC cell lines. The drug resistance capabilities of ABCC11 are evaluated by analyzing the resistance profiles of a clone of HeLa cell in which the pump was ectopically expressed. Blood samples of 106 NSCLC patients were collected. RESULTS: There was a significant correlation between dihydropyrimidine dehydrogenase (DPD) gene expression and the IC50 for 5-FU. We then classified NSCLC cell lines into two groups based on the phenotype of the SNP538 (G > A) in ABCC11: a combined G/G and G/A group, and an A/A group. The distribution of the IC50 for 5-FU in combination with a potent inhibitor of DPD 5-chloro-2, 4-dihydropyrimidine (CDHP), which is contained in S-1, showed a significant reduction in the A/A group compared with the combined G/G and G/A group. Next, the clinical usefulness of the ABCC11 SNP in treatment containing S-1 was examined in 106 NSCLC patients, and the disease control rate was found to be significantly better in the A/A group than in the combined G/G and G/A group. CONCLUSIONS: These results indicate that the SNP538(G > A) in the ABCC11 gene is a potential determinant for S-1 treatment.

Pulmonary Mycobacterium abscessus Subspecies abscessus Disease That Showed a Discrepancy Between the Genotype and Phenotype of Clarithromycin Resistance.

Mycobacterium abscessus subspecies abscessus is major subspecies in the M. abscessus complex and is usually refractory to standard antibiotherapy. Genetic tracing of erm (41) T28 is a mechanism for monitoring macrolide resistance. We treated a patient with a pulmonary infection caused by M. abscessus subsp. abscessus with the erm (41) T28 polymorphism, which was susceptible to clarithromycin, and his clinical treatment course was good. The identification of the M. abscessus complex genotype is important, but clinical confirmation of clarithromycin susceptibility is also needed to plan individual treatment strategies.

A folylpoly-γ-glutamate synthase single nucleotide polymorphism associated with response to pemetrexed treatment combined with platinum for non-small cell lung cancer.

OBJECTIVES: In this study, we investigated whether single nucleotide polymorphisms (SNPs) in folylpoly-γ-glutamate synthase (FPGS), which catalyzes the polyglutamation of pemetrexed (PEM), is related to FPGS expression and the response to PEM in non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: We first examined FPGS protein expressions according to FPGS SNPs genotype groups in 15 lung adenocarcinoma cell lines. Next, 101 non-squamous NSCLC patients treated with PEM and platinum drugs were classified into FPGS SNP genotype groups to investigate the relation between FPGS SNP genotypes and treatment outcome. RESULTS: When the 15 adenocarcinoma cell lines were classified into FPGS SNP 2572C>T genotype groups, we found that the FPGS protein expression was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0022). In contrast, there was no significant difference in FPGS expression when another FPGS SNP was analyzed. We also examined the FPGS SNP 2572C>T genotype in 101 non-squamous NSCLC patients treated with PEM and platinum drugs. Among these 101 patients, response rate was significantly higher in the CC genotype group than in the TT+CT genotype group (p=0.0034). When we examined the patients treated with PEM, platinum drugs and Bev, almost all (29/33) were classified into the TT+CT genotype group. The response rate, progression-free survival, and over-all survival were all significantly better in the patients of the TT+CT genotype group who also received Bev than in those who did not receive Bev (p=0.034, 0.021, 0.018, respectively). CONCLUSION: FPGS SNP 2572C>T is a predictive marker of the efficacy of PEM and platinum drugs for NSCLC.

Organic cation transporter 6 directly confers resistance to anticancer platinum drugs.

Organic cation transporters (OCTs) of the solute carrier family 22 have a critical role in the cellular uptake of anticancer platinum drugs. Recently, we found that a decreased OCT6 expression is associated with a reduced intracellular uptake of cisplatin (CDDP), and concomitant resistance to CDDP. In the present study, we examined whether OCTs directly confer resistance to another platinum drug, oxaliplatin (L-OHP). To address this, we used parental lung cancer cell lines, PC-14 and SBC3; L-OHP-resistant sublines, PC-14/L-OHP and SBC3/L-OHP; and one CDDP-resistant subline PC-14/CDDP, to examine the relationships between the expression of OCTs and intracellular platinum drug concentration or platinum drug resistance. The two L-OHP-resistant sublines showed cross resistance to CDDP and L-OHP, and a decreased expression of OCT6. The intracellular accumulation of L-OHP in PC-14/L-OHP cells was reduced compared with the parental cells. The findings suggested that a reduced OCT6 expression confers platinum drug resistance in the sublines by decreasing the uptake of platinum drugs. Using the PC-14/CDDP cell line engineered to overexpress OCT6, we confirmed that the intracellular L-OHP concentration was increased concomitantly with OCT6 overexpression compared with the parental cell line. Additionally, OCT6 was expressed in a screening panel of lung and colon cancer tissues and matched normal control tissues. Taken together with the previous results, the present findings indicate that OCT6 is directly involved in platinum drug resistance by mediating platinum drug uptake in cancer cells.

Reversal of c-MET-mediated Resistance to Cytotoxic Anticancer Drugs by a Novel c-MET Inhibitor TAS-115.

BACKGROUND: The cellular N-methyl-N'-nitroso-guanidine human osteosarcoma transforming gene (c-MET) protein is the receptor tyrosine kinase for hepatocyte growth factor. We recently found that c-MET protein expression and activation were enhanced in the majority of small cell lung cancer cell lines with cytotoxic anticancer drug resistance, and that down-regulation of c-MET reduced resistance to these drugs. MATERIALS AND METHODS: Expression of c-MET was studied in three non-small cell lung cancer (NSCLC) cell lines, including six resistant cell strains to cytotoxic anticancer drugs. To assess the effect of c-MET activation on drug resistance, we studied drug sensitivity in the presence of a novel c-MET inhibitor TAS-115. RESULTS: c-MET expression and activation are also enhanced in some cytotoxic anticancer drug-resistant NSCLC cell lines, and inhibition of c-MET activation by TAS-115 reduced resistance of these cell lines to anticancer drugs. CONCLUSION: The mechanism of cellular resistance to anticancer drugs via hepatocyte growth factor/c-MET signal activation is not restricted to small cell lung cancer cell lines, and TAS-115 might be able to reverse the drug resistance of these cancer cells.

Organic cation transporter OCT6 mediates cisplatin uptake and resistance to cisplatin in lung cancer.

PURPOSE: The purposes of this study were to determine whether organic cation transporters (OCTs) can mediate platinum uptake, and whether OCT down-regulation confers resistance against cisplatin (CDDP) in cancer cells. METHODS: Two lung cancer cell lines, PC-6 and PC-14, and their CDDP-resistant derivatives, PC-6/CDDP and PC-14/CDDP, were analyzed. OCT expression levels were assayed using quantitative RT-PCR and Western blotting. Additionally, the effect of OCT6 overexpression, induced by transfection of the OCT6 gene SLC22A16 using a forced expression vector, on cellular sensitivity to CDDP and on intracellular platinum accumulation was measured using PC-14/CDDP cells. RESULTS: Both gene and protein expression of OCT6 were decreased in both CDDP-resistant cell lines compared with their expression in their respective parental cells. Intracellular accumulation of platinum was decreased in PC-14/CDDP cells compared with the parental cells after CDDP treatment. Furthermore, OCT6 overexpression induced by transfection of the OCT6 gene (SLC22A16) forced expression vector-sensitized PC-14/CDDP cells to CDDP and oxaliplatin (L-OHP) concomitant with increased intracellular concentration of platinum. CONCLUSION: OCT6 is a mediator of platinum uptake in cancer cells, and down-regulation of OCT6 is possibly one of the mechanisms of resistance against cisplatin in lung cancer.

ABCB1 polymorphism as a predictive biomarker for amrubicin-induced neutropenia.

BACKGROUND: Amrubicin is a promising therapy for lung cancer, but is associated with a high incidence of severe neutropenia. The present study assessed the utility of ABCB1 and NAD(P)H quinone oxidoreductase 1 (NQO1) polymorphism as a predictor of amrubicin-induced neutropenia. MATERIALS AND METHODS: Fifty-four Japanese lung cancer patients who received amrubicin chemotherapy were consecutively recruited and toxicities and SNPs (MDR1; C1236T, C3435T and G2677T/A, NQO1; C609T) were evaluated. RESULTS: The incidence of neutropenia was higher in patients treated with 40 mg/m2 of amrubicin (n=32) compared to patients treated with 35 mg/m2 of amrubicin (n=22) (53.1% vs. 22.7%). Patients who were homogenous for the wild-type allele of C3435T were at significantly higher risk of neutropenia compared to patients with other genotypes. By contrast, the C609T genotype of NQO1 was not related to neutropenia. CONCLUSION: C3435T polymorphisms of ABCB1 might be able to predict severe amrubicin-induced neutropenia.

Significance of c-MET overexpression in cytotoxic anticancer drug-resistant small-cell lung cancer cells.

The c-MET receptor tyrosine kinase is the receptor for hepatocyte growth factor. Recently, activation of the c-MET/hepatocyte growth factor signaling pathway was associated with poor prognosis in various solid tumors and was one of the mechanisms of acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib. But the link between c-MET activation and the cytotoxic anticancer drug has not been fully examined. Here, we found that the enhanced expression and activation of c-MET in cytotoxic anticancer agent-resistant small-cell lung cancer cells. Downregulation of c-MET expression by siRNA against the c-MET gene or inhibition of c-MET activation by SU11274, a c-MET inhibitor, in the resistant cells altered resistance to the cytotoxic anticancer agent. These results indicated that c-MET overexpression might play an important role in acquired resistance to cytotoxic anticancer drugs. Furthermore, the number of c-MET gene loci was increased in the resistant cells compared to the parental cells. In conclusion, increased c-Met expression through an increase in the number of c-MET gene loci is one of the mechanisms of acquired resistance to cytotoxic anticancer drugs. Our results add a new strategy, the targeting of c-MET, for overcoming resistance to cytotoxic agents in small-cell lung cancer.

Transformed lymphoplasmacytic lymphoma involving the main carina: A case report.

A 41-year-old male was admitted to Nagoya City University Hospital subsequent to experiencing a cough with bloody sputum for a few days. The patient had a 4-year history of lymphoplasmacytic lymphoma (LPL) and had achieved a good partial response to anticancer chemotherapy. Chest computed tomography (CT) showed an endobronchial tumor of the main carina. A bronchoscopy revealed an exophytic tumor at the main carina, and autofluorescence imaging bronchovideoscopy showed that the tumor and surrounding area were magenta in color. The biopsy specimens demonstrated that the endobronchial tumor was composed of large atypical lymphoid cells. The patient was diagnosed with a high-grade transformation of LPL. In addition to describing a rare case of transformed LPL involving the main carina, the present study also summarizes and discusses endobronchial lymphomas, with a brief review of a number of published studies.

Thymidylate synthase gene copy number as a predictive marker for response to pemetrexed treatment of lung adenocarcinoma.

BACKGROUND: Pemetrexed is a key drug for therapy of non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In a search for biomarkers for study of the efficacy of pemetrexed treatment, we examined the thymidylate synthase (TYMS) copy number in NSCLC cell lines and in clinical NSCLC samples treated with pemetrexed, combined with platinum drugs. RESULTS: TYMS copy numbers in lung adenocarcinoma cell lines were significantly lower than in squamous cell carcinoma (p=0.0105), and a significant correlation was found between the TYMS copy number and the 50% inhibitory concentration value for pemetrexed in all 17 lung cancer cell lines tested (r=0.6814, p=0.0026). Moreover, TYMS copy number was significantly lower in clinical NSCLC samples responsive to treatment with pemetrexed combined with platinum drugs (p=0.0067). Furthermore, the decrease in the baseline CT size measurement of pemetrexed combined with platinum drug treatment correlated significantly with TYMS copy number (r=0.7967, p=0.0011). CONCLUSION: To our knowledge, this is the first report of a significant association between TYMS copy number and response to pemetrexed treatment in tumor biopsy specimens. Our results suggest that TYMS copy number could be a predictive biomarker for pemetrexed based chemotherapy.