Review, role of lactoferrin in preventing preterm delivery.

Prevention of preterm birth (PTB) is a global challenge and is one of the most important issues to be addressed in perinatal care. The hypothesis that ascending lower genital infection leads to PTB has been tested in numerous in vitro and in vivo studies. For patients with intractable vaginitis or high-risk patients with successive PTBs, mainly due to intra-uterine infection, the vaginal flora is enhanced to increase systemic immunity and locally propagate Lactobacillus species. It has been shown that the administration of lactoferrin (LF), a prebiotic with minimum side effects, may be effective in suppressing PTB. This hypothesis has been evaluated in this review using various relevant test examples. The findings suggest that LF may play a role in inflammatory protection in pregnant human cervical tissue. The antibacterial and anti-cytokine effects of LF in human-derived mucus-producing cervical cell lines were also demonstrated. It was also clarified that LF suppresses PTB and improves the prognosis of pups in inflammation-induced PTB animal models. Thus, we have identified that LF, a prebiotic contained in breast milk, can be clinically applied to suppress PTB in humans and to prevent PTBs in high-risk pregnancies.

Association between soluble immune mediators and tumor responses in patients with nonsmall cell lung cancer treated with anti-PD-1 inhibitor.

Although programmed death (PD)-1 immune checkpoint therapies target the immune system, the relationship between inflammatory factors and the clinical outcome of anti-PD-1 therapy for nonsmall cell lung cancer (NSCLC) is not fully understood. Here we examined the association between soluble immune mediators and the outcome of treatment with PD-1 inhibitors in patients with advanced/recurrent NSCLC. In two independent cohorts, we assessed the levels of 88 different soluble immune mediators in peripheral blood before and after anti-PD-1 treatment, and evaluated their associations with clinical outcomes. In the training cohort, the plasma levels of chitinase 3-like-1 and GM-CSF before treatment (p = 0.006 and p = 0.005, respectively) and changes in the plasma levels of CXCL2, VEGF, IFNα2, and MMP2 after treatment (p < 0.001, p = 0.019, p = 0.019, and p = 0.012, respectively) were significantly correlated with PFS. The change in the plasma CXCL2 level was also significantly associated with treatment-related AEs (p = 0.017). In the validation cohort, however, only the changes in the plasma levels of CXCL2 and MMP2 after treatment were associated with PFS (p = 0.003 and p = 0.006, respectively), and these changes were maintained during the course of anti-PD-1 therapy in patients who showed better clinical outcomes, even in those with tumor pseudoprogression. Since CXCL2 and MMP2 can be easily measured by minimally invasive blood sampling, they could be useful for monitoring of clinical outcomes in NSCLC patients receiving PD-1 inhibitor therapy.

Phase II study of bevacizumab, cisplatin, and pemetrexed in advanced non-squamous non-small cell lung cancer (NS-NSCLC) with EGFR wild-type.

BACKGROUND: Continuation maintenance therapy with pemetrexed (PEM) and bevacizumab (BEV) following induction therapy with cisplatin (CDDP), PEM, and BEV is beneficial in advanced non-squamous non-small-cell lung cancer (NS-NSCLC), but the survival benefit of addition of BEV to CDDP/PEM as induction therapy is still unclear. The aim of this phase II study was to evaluate the feasibility and safety of a CDDP/PEM/BEV regimen in Japanese patients with EGFR wild-type NS-NSCLC. PATIENTS AND METHODS: This study included 25 patients who receive intravenous CDDP, PEM, and BEV (15 mg/kg) from August 2010 to February 2013. The primary endpoint of this study was the response rate (RR) and the secondary endpoint was progression free survival (PFS), overall survival (OS), and safety. RESULTS: The median cycles of induction chemotherapy were four (range 1-6). RR was 64%. Most patients (64%) transitioned to maintenance therapy. The median PFS was 9.7 months. Median OS was 21.6 months. Haematological adverse events reaching grade 3 to 4 were neutropenia (8%) without febrile neutropenia, thrombocytopenia (4%), and anemia (4%). BEV-related non-haematological toxicities of grade 3/4 were hypertension (16%), thrombosis (4%), and gastrointestinal perforation (4%). Each adverse events was controllable, and there were no treatment-related deaths. CONCLUSIONS: CDDP/PEM/BEV regimen is effective and tolerable in patients with EGFR wild-type advanced NS-NSCLC, but should be paid attention to some BEV-related toxicities.

Phase II study of bevacizumab, cisplatin, and docetaxel plus maintenance bevacizumab as first-line treatment for patients with advanced non-squamous non-small-cell lung cancer combined with exploratory analysis of circulating endothelial cells: Thoracic Oncology Research Group (TORG)1016.

BACKGROUND: Preclinical studies have demonstrated that docetaxel and bevacizumab may act synergistically by decreasing endothelial cell proliferation and preventing circulating endothelial progenitor mobilization. The objective of this study was to assess the efficacy and safety of a combination therapy of bevacizumab, cisplatin, and docetaxel in chemotherapy-naive Japanese patients with advanced non-squamous non-small-cell lung cancer (NSCLC). METHODS: Eligible patients were chemotherapy-naive and had advanced/recurrent non-squamous NSCLC. The patients received 4 cycles of docetaxel (60 mg/m2), cisplatin (80 mg/m2), and bevacizumab (15 mg/kg) once every 3 weeks, followed by bevacizumab as maintenance therapy, every 3 weeks until disease progression or attainment of unacceptable toxicity level. The primary endpoint was objective response rate (ORR). The numbers of circulating endothelial cells (CEC) were also estimated on days 1 and 8 of the first cycle for the exploratory analysis of efficacy prediction. RESULTS: A total of 47 patients were enrolled from October 2010 to April 2012. Bevacizumab as maintenance therapy was administered to 41 patients (87.2%), and the median number of total treatment cycles was 9 (range: 1-36). ORR, median progression-free survival (PFS), and median overall survival of the patients were 74.5%, 9.0 months, and 27.5 months, respectively. The most common grade 3/4 adverse event was neutropenia (95.7%), followed by leukopenia (59.6%) and hypertension (46.8%). PFS was longer in patients with ≥10 count increase in CECs than that in patients with < 10 count increase in CECs (respective median PFS of 11.0 months versus 6.90 months) although the difference was not statistically significant (p = 0.074). CONCLUSIONS: A combination therapy of bevacizumab, cisplatin, and docetaxel, followed by bevacizumab as maintenance was highly effective in patients with non-squamous NSCLC despite the high incidence of grade 3/4 neutropenia. The increase in CEC count between days 1 and 8 may predict the efficacy of our bevacizumab-contained treatment regimen. TRIAL REGISTRATION: UMIN Clinical Trial Registry; UMIN000004368 . Registered date; October 11, 2010 (Retrospectively registered).

Nedaplatin and irinotecan with concurrent thoracic radiotherapy followed by docetaxel consolidation in patients with locally advanced non-small cell lung cancer.

OBJECTIVE: We conducted a phase II study of nedaplatin (NP) and irinotecan (CPT) with concurrent thoracic radiotherapy (TRT) followed by docetaxel for locally advanced non-small cell lung cancer (NSCLC) to determine the safety and efficacy of the treatment. Patients with stage IIIA or IIIB NSCLC were treated with 3 cycles of chemotherapy comprising NP at 50 mg/m2 and CPT at 50 mg/m2 on days 1 and 8 every 4 weeks with concurrent TRT (2 Gy/day, total 66 Gy) followed by 3 cycles of docetaxel at 60 mg/m2 on day 1 every 3 weeks. CONCLUSION: Fifteen patients were registered, and 8 were able to receive the entire treatment regimen. Grade 4 neutropenia and thrombocytopenia occurred in 6 and 1 patient, respectively, receiving NP and CPT with concurrent TRT. Major non-hematological toxicities were nausea, vomiting and fatigue. Grade 3 pneumonitis and esophagitis occurred in one patient each, and 4 patients developed febrile neutropenia. Docetaxel consolidation was associated with mild toxicities. Two patients died of late pulmonary failure 3 to 4 months after treatment completion, and the study was terminated. Twelve patients responded, and the median survival time, and the 1-year and 3-year survival rates were 39.3 months, 86.7% and 60.0%, respectively. In conclusion, NP and CPT with concurrent TRT is effective for patients with locally advanced NSCLC, but frequently induces pulmonary damage.

Clinicopathological features and EGFR gene mutation status in elderly patients with resected non-small-cell lung cancer.

BACKGROUND: The rapid aging of the population in Japan has been accompanied by an increased rate of surgery for lung cancer among elderly patients. It is thus an urgent priority to map out a treatment strategy for elderly patients with primary lung cancer. Although surgical resection remains standard treatment for early stage non-small-cell lung cancer (NSCLC), it is now essential to confirm the status of epidermal growth factor receptor (EGFR) gene mutations when planning treatment strategies. Furthermore, several studies have reported that EGFR mutations are an independent prognostic marker in NSCLC. However, the relations between age group and the molecular and pathological characteristics of NSCLC remain unclear. We studied the status of EGFR mutations in elderly patients with NSCLC and examined the relations of EGFR mutations to clinicopathological factors and outcomes according to age group. METHODS: A total of 388 consecutive patients with NSCLC who underwent complete tumor resection in our hospital from 2006 through 2008 were studied retrospectively. Formalin-fixed, paraffin-embedded tissue sections were used to isolate DNA from carcinoma lesions. Mutational analyses of EGFR gene exons 19, 20, and 21 and KRAS gene exons 12 and 13 were performed by loop-hybrid mobility shift assay, a highly sensitive polymerase chain reaction-based method. RESULTS: EGFR mutations were detected in 185 (47.7%) and KRAS mutations were detected in 33 (8.5%) of the 388 patients. EGFR mutations were found in a significantly higher proportion of patients younger than 80 years (younger group; 178/359, 49.6%) than in patients 80 years or older (older group; 7/29, 24.1%) (P = 0.008). In contrast, KRAS mutations were more common in the older group (6/29, 20.7%) than in the younger group (27/359, 7.5%) (P = 0.014). The older group showed a trend toward a higher rate of 5-year overall survival among elderly patients with EGFR mutations (100%) than among those with wild-type EGFR (66.2%), but the difference was not significant. CONCLUSIONS: Our results suggest that the EGFR status of patients with NSCLC differs between patients 80 years or older and those younger than 80 years. EGFR mutation status might be a prognostic marker in elderly patients with completely resected NSCLC.

Comparison between next-generation sequencing and multiplex polymerase chain reaction assays for nonsmall-cell lung cancer molecular diagnosis.

PURPOSE: Genetic mutation detection has become an important step in nonsmall-cell lung cancer (NSCLC) treatment because of the increasing number of drugs that target genomic rearrangements. A multiplex test that can detect multiple gene mutations prior to treatment is thus necessary. Currently, either next-generation sequencing (NGS)-based or polymerase chain reaction (PCR)-based tests are used. We evaluated the performance of the Oncomine Dx Target Test (ODxTT), an NGS-based multiplex biomarker panel test, and the AmoyDx Pan Lung Cancer PCR Panel (AmoyDx PLC panel), a real-time PCR-based multiplex biomarker panel test. MATERIALS AND METHODS: Patients with histologically diagnosed NSCLC and a sufficient sample volume to simultaneously perform the AmoyDx PLC panel and ODxTT-M were included in the study. The success and detection rates of both tests were evaluated. RESULTS: Biopsies revealed 116 cases of malignancies, 100 of which were NSCLC. Of these, 59 met the inclusion criteria and were eligible for analysis. The success rates were 100% and 98% for AmoyDx PLC panel and ODxTT-M, respectively. Nine driver mutations were detected in 35.9% and 37.3% of AmoyDx PLC and ODxTT-M panels, respectively. EGFR mutations were detected in 14% and 12% of samples using the AmoyDx PLC panel and ODxTT-M, respectively. Of the 58 cases in which both NGS and AmoyDx PLC panels were successful, discordant results were observed in seven cases. These differences were mainly due to different sensitivities of the detection methods used and the gene variants targeted in each test. DISCUSSION: The AmoyDx PLC panel, a PCR-based multiplex diagnostic test, exhibits a high success rate. The frequency of the nine genes targeted for treatment detected by the AmoyDx PLC panel was comparable to the frequency of mutations detected by ODxTT-M. Clinicians should understand and use the AmoyDx PLC panel and ODxTT-M with respect to their respective performances and limitations.

Mutation profile and programmed death ligand 1 status of patients with non-small cell lung cancer diagnosed with "adenocarcinoma" and "non-small cell carcinoma favor adenocarcinoma".

BACKGROUND: The terminology for lung cancer diagnosis in small biopsies was adopted in the 2015 World Health Organization classification. If non-small cell lung cancer (NSCLC) has no clear adenocarcinoma (AD) or squamous cell carcinoma morphology, the tumor is further classified based on mucin or immunohistochemical staining as NSCLC favor AD (NFAD), NSCLC favor squamous cell carcinoma, or NSCLC not otherwise specified. Since this new term was defined, the difference between AD and NFAD has not yet been fully explored. This study aimed to examine the differences in clinical background, gene alteration frequency, and programmed death ligand 1 (PD-L1) expression. METHODS: We included patients diagnosed with AD or NFAD with small samples, and who underwent testing with the Oncomine Dx target test between August 2019 and April 2023 in Kanagawa Cancer Center. RESULTS: This study comprised 268 patients. A total of 96 patients underwent surgery after AD or NFAD diagnosis. The clinical stage was more advanced and pathological N0 was lower in NFAD than in AD. The pathology of the surgical specimens revealed that solid predominant AD was significantly more common in NFAD than in AD (p < 0.001). In both AD and NFAD, EGFR mutation was the most frequent gene alteration, followed by KRAS mutation. The frequency of EGFR mutations was significantly higher in AD than in NFAD. PD-L1 expression was significantly higher in NFAD than in AD (p < 0.001). CONCLUSION: This study shows a clear difference between AD and NFAD in terms of cancer progression, pathological features of the main tumor, genetic characteristics, and PD-L1 expression.

Phase II Study of Durvalumab Immediately after Completion of Chemoradiotherapy in Unresectable Stage III Non-small Cell Lung Cancer: TORG1937 (DATE Study).

PURPOSE: Concurrent chemoradiotherapy (CCRT) followed by durvalumab consolidation for up to 12 months is the standard of care for patients with unresectable stage III non-small cell lung cancer (NSCLC). However, exactly when to initiate durvalumab therapy after chemoradiation completion remains unknown. We evaluated the efficacy and safety of durvalumab, administered immediately after CCRT completion, for patients with unresectable stage III NSCLC. PATIENTS AND METHODS: This study was a prospective, single-arm, open-label phase II clinical trial. Patients without disease progression after definitive CCRT (two cycles of platinum-based doublet chemotherapy with 60 Gy/30 Fr radiotherapy) received durvalumab (every 2 weeks for up to 12 months) from the next day (up to 5 days) after the final radiation dose. The primary endpoint was the 1-year progression-free survival (PFS) from registration before the start of CCRT. RESULTS: From January 2020 to August 2020, 47 of 50 enrolled patients were evaluable for treatment efficacy and safety. The 1-year PFS from registration was 75.0% [60% confidence interval (CI), 69.0-80.0 and 95% CI, 59.4-85.3]. The objective response rate throughout the study treatment and median PFS from registration were 78.7% and 14.2 months (95% CI, 13.4 to not reached), respectively. Grade 3/4 pneumonitis and febrile neutropenia were each 4.3%. CONCLUSIONS: Our study met the primary endpoint. The incidence of pneumonitis was similar to that of a Japanese subset in the PACIFIC study. Our data support the efficacy and safety of durvalumab administered immediately after the completion of CCRT for patients with unresectable stage III NSCLC.

Prospective study of paclitaxel and irinotecan for elderly patients with unresectable non-small cell lung cancer.

We conducted a phase II study of combination chemotherapy with paclitaxel (Pac) and irinotecan (CPT) to determine the effects and toxicities in patients 70 years or older with unresectable non-small cell lung cancer (NSCLC). Eligible patients were entered to receive three courses of Pac at 160 mg/m2 and CPT at 60 mg/m2 every 2-3 weeks. Twenty-one patients were registered. Thirteen patients were male and 8 were female, with a median age of 72 years (range: 70-82 years). Eight patients had a performance status (PS) of 0 and the other 13 patients had a PS of 1. Six and 15 patients were stage IIIB and stage IV, respectively. Ten patients received 3 to 6 cycles of the chemotherapy. Of the hematological toxicities, grade 4 neutropenia was observed in 23.8% of the patients. Of the non-hematological toxicities, grade 3 or 4 fatigue, anorexia and nausea were observed in 5, 3 and 4 patients, respectively. Three of 6 patients with infection developed grade 3 pneumonia. Grade 3 allergy with rash occurred in a patient. Cerebral infarction occurred in two patients and grade 3 peripheral neuropathy in one. The outcome of the Pac and CPT regimen in 21 patients was 8 PR, 10 SD and three PD, and the response rate was 38.1% The median survival time was 9.1 months. The one- and 2-year survival rates were 38.1% and 19.0%, respectively. The Pac plus CPT regimen is feasible and active with moderate toxicity for elderly patients with NSCLC.

Randomized, Phase II study of pemetrexed plus bevacizumab versus pemetrexed alone after treatment with cisplatin, pemetrexed, and bevacizumab in advanced non-squamous, non-small cell lung cancer: TORG (thoracic oncology research group) 1321.

INTRODUCTION: Cisplatin plus pemetrexed followed by pemetrexed is an efficacious platinum combination regimen for advanced non-squamous, non-small cell lung cancer (NSCLC). Data regarding the addition of bevacizumab, especially in maintenance treatment, are insufficient. METHODS: Eligibility criteria included: no prior chemotherapy; advanced, non-squamous, NSCLC; performance status ≤1; and epidermal growth factor receptor mutation-negative. Patients (N = 108) received induction chemotherapy with cisplatin, pemetrexed, and bevacizumab every 3 weeks for four cycles, and tumor response was needed to confirm four-week response duration. Patients with at least stable disease were randomized to pemetrexed/bevacizumab or pemetrexed alone. The primary endpoint was progression-free survival (PFS) after induction chemotherapy. Myeloid-derived suppressor cell (MDSC) counts of peripheral blood samples were also analyzed. RESULTS: Thirty-five patients each were randomized to the pemetrexed/bevacizumab group and the pemetrexed alone group. PFS was significantly better in the pemetrexed/bevacizumab group than in the pemetrexed alone group (7.0 vs. 5.4 months, hazard ratio: 0.56 [0.34-0.93], log-rank p = 0.023). In patients with partial response to induction therapy, median overall survival was 23.3 months in the pemetrexed alone group and 29.6 months in the pemetrexed/bevacizumab group (log-rank p = 0.077). Pretreatment monocytic (M)-MDSC counts tended to be greater in the pemetrexed/bevacizumab group with poor PFS than in those with good PFS (p = 0.0724). CONCLUSIONS: Addition of bevacizumab to pemetrexed as maintenance therapy prolonged PFS in patients with untreated, advanced, non-squamous NSCLC. Furthermore, an early response to induction therapy and pretreatment M-MDSC counts may be related to the survival benefit of the addition of bevacizumab to the combination of cisplatin and pemetrexed.

Machine learning for prediction of immunotherapeutic outcome in non-small-cell lung cancer based on circulating cytokine signatures.

BACKGROUND: Immune checkpoint inhibitor (ICI) therapy has substantially improved the overall survival (OS) in patients with non-small-cell lung cancer (NSCLC); however, its response rate is still modest. In this study, we developed a machine learning-based platform, namely the Cytokine-based ICI Response Index (CIRI), to predict the ICI response of patients with NSCLC based on the peripheral blood cytokine profiles. METHODS: We enrolled 123 and 99 patients with NSCLC who received anti-PD-1/PD-L1 monotherapy or combined chemotherapy in the training and validation cohorts, respectively. The plasma concentrations of 93 cytokines were examined in the peripheral blood obtained from patients at baseline (pre) and 6 weeks after treatment (early during treatment: edt). Ensemble learning random survival forest classifiers were developed to select feature cytokines and predict the OS of patients undergoing ICI therapy. RESULTS: Fourteen and 19 cytokines at baseline and on treatment, respectively, were selected to generate CIRI models (namely preCIRI14 and edtCIRI19), both of which successfully identified patients with worse OS in two completely independent cohorts. At the population level, the prediction accuracies of preCIRI14 and edtCIRI19, as indicated by the concordance indices (C-indices), were 0.700 and 0.751 in the validation cohort, respectively. At the individual level, patients with higher CIRI scores demonstrated worse OS [hazard ratio (HR): 0.274 and 0.163, and p<0.0001 and p=0.0044 in preCIRI14 and edtCIRI19, respectively]. By including other circulating and clinical features, improved prediction efficacy was observed in advanced models (preCIRI21 and edtCIRI27). The C-indices in the validation cohort were 0.764 and 0.757, respectively, whereas the HRs of preCIRI21 and edtCIRI27 were 0.141 (p<0.0001) and 0.158 (p=0.038), respectively. CONCLUSIONS: The CIRI model is highly accurate and reproducible in determining the patients with NSCLC who would benefit from anti-PD-1/PD-L1 therapy with prolonged OS and may aid in clinical decision-making before and/or at the early stage of treatment.

Nedaplatin and irinotecan for patients with recurrent small cell lung cancer.

BACKGROUND: No standard second-line combination chemotherapy has yet been established for patients with recurrent small cell lung cancer (RSCLC). METHODS: Patients with RSCLC were treated with nedaplatin (NP) at 50 mg/m2 and irinotecan (CPT) at 50 mg/m2 on days 1 and 8 every 4 weeks for four cycles. RESULTS: The clinical outcomes of 12 patients (9 male and 3 female; age range 48-76 years, median 62 years) were retrospectively analyzed. Seven of the patients showed sensitive relapse. Two patients had a performance status of 2. Nine of the patients were able to receive 4 to 6 courses of NP and CPT chemotherapy. Grade 3 or 4 anemia, neutropenia and thrombocytopenia occurred in 25.0%, 50.0% and 41.7% of patients, respectively. There were no grade 3 or 4 non-hematologic toxicities except for febrile neutropenia in 1 patient. There was no treatment-related death. Nine patients achieved PR, and the objective response rate was 75.0%. The median survival time was 11.1 months (range 4.8 to 31.3+ months) and the 1-year survival rate was 50.0%. CONCLUSION: NP and CPT in combination are effective and safe for patients with RSCLC.

Effectiveness of erlotinib in advanced non-small cell lung cancer in cases of gefitinib resistance after treatment of more than 6 months.

BACKGROUND: There have been reports on the use of erlotinib in non-small cell lung cancer (NSCLC) patients after gefitinib resistance occurs, and it has been stated that erlotinib may be beneficial in patients with long stable disease (SD) previously treated with gefitinib. PATIENTS AND METHODS: We retrospectively studied gefitinib-resistant NSCLC patients with favorable clinical features, who received erlotinib following disease progression after gefitinib treatment of more than 6 months. RESULTS: A total of 21 patients with NSCLC were included. Partial response was seen in 2 cases (9%), SD in 6 cases (19%), and progressive disease (PD) in 13 cases (62%). Disease control (DC) was achieved with erlotinib in 8 cases (36%). The median survival time (MST) was 369 days in DC cases and 133 days in PD cases. There were no statistical differences between DC cases and PD cases in terms of MST relative to sex, smoking and skin rash. CONCLUSION: Subsequent erlotinib therapy is one of the therapeutic options in the treatment of gefitinib-resistant NSCLC in which prior gefitinib has shown long-term SD of more than 6 months.

Comparison of next-generation sequencing and cobas EGFR mutation test v2 in detecting EGFR mutations.

BACKGROUND: As the number of genetic mutations that must be tested increases, the Oncomine Dx Target test (ODxTT), which can simultaneously detect multiple cancer-related genes is becoming the main test used in preference to single-molecule testing. In this study, we evaluated the performance of ODxTT and cobas EGFR mutation test v2 (cobas EGFR), one of the single-molecule tests, in detecting EGFR mutations. METHODS: Samples from 211 patients diagnosed with NS-NSCLC were tested simultaneously or sequentially with the cobas EGFR mutation test and ODxTT. We compared the success and detection rates of both tests and evaluated their equivalence by determining the concordance rate and k-coefficient of both tests. RESULTS: The success rate in detecting EGFR mutations was 95.7% for ODxTT and 100% for cobas EGFR. EGFR mutations were detected in 26.5% of samples with ODxTT and in 28.0% with cobas EGFR. For the 200 samples successfully analyzed with both tests, the concordance rate and k-coefficient were 97.5% and 0.938, respectively. ODxTT failed to detect two exon 19 deletion mutations (p.E746_P753delinsVS and p.E746_P753delinsLS), and cobas EGFR failed to detect three instances of an exon 19 deletion (p.L747_P753delinsS), L861R, and an exon 20 insertion. DISCUSSION: The success rate of ODxTT is slightly inferior to that of cobas EGFR. ODxTT shared a high concordance rate and k-coefficient with cobas EGFR in detecting EGFR mutations, but discordant results between the two tests were observed in a few cases, mainly due to the difference of detectable EGFR variants.

Readministration of Pembrolizumab after Treatment of Tuberculosis Activated by Initial Pembrolizumab Therapy.

Increasing the T-cell immune response to Mycobacterium tuberculosis with an anti-programmed cell death 1 (anti-PD-1) antibody may ultimately have detrimental effects. We present the case of a patient with advanced non-small cell lung cancer who developed active tuberculosis (TB) after initial treatment with pembrolizumab, an anti-PD-1 antibody. Pembrolizumab was resumed after completing anti-TB treatment, and no relapse of TB was observed clinically or radiologically. Checkpoint inhibitor-related pneumonitis (CIP) is first suspected when a pulmonary shadow presents during treatment with an anti-PD-1 antibody. It is sometimes difficult to diagnose CIP using computed tomographic images alone. Careful testing, including bacterial examinations and bronchoscopic biopsy, should be performed.

Suitability of Bronchoscopic Biopsy Tissue Samples for Next-Generation Sequencing.

A sufficiently large tissue sample is required to perform next-generation sequencing (NGS) with a high success rate, but the majority of patients with advanced non-small-cell lung cancer (NSCLC) are diagnosed with small biopsy specimens. Biopsy samples were collected from 184 patients with bronchoscopically diagnosed NSCLC. The tissue surface area, tumor cell count, and tumor content rate of each biopsy sample were evaluated. The impact of the cut-off criteria for the tissue surface area (≥1 mm2) and tumor content rate (≥30%) on the success rate of the Oncomine Dx Target Test (ODxTT) was evaluated. The mean tissue surface area of the transbronchial biopsies was 1.23 ± 0.85 mm2 when small endobronchial ultrasonography with a guide sheath (EBUS-GS) was used, 2.16 ± 1.49 mm2 with large EBUS-GS, and 1.81 ± 0.75 mm2 with endobronchial biopsy (EBB). The proportion of samples with a tissue surface area of ≥1 mm2 was 48.8% for small EBUS-GS, 79.2% for large EBUS-GS, and 78.6% for EBB. Sixty-nine patients underwent ODxTT. The success rate of DNA sequencing was 84.1% and that of RNA sequencing was 92.7% over all patients. The success rate of DNA (RNA) sequencing was 57.1% (71.4%) for small EBUS-GS (n = 14), 93.4% (96.9%) for large EBUS-GS (n = 32), 62.5% (100%) for EBB (n = 8), and 100% (100%) for endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) (n = 15). Regardless of the device used, a tissue surface area of ≥ 1 mm2 is adequate for samples to be tested with NGS.

Prospective study of second-line chemotherapy for non-small cell lung cancer selected according to EGFR gene status.

We prospectively investigated the outcome of personalized second-line treatment based on epidermal growth factor receptor (EGFR) gene status in previously treated patients with advanced non-small cell lung cancer (NSCLC). EGFR gene status was evaluable by LH-mobility shift assay in registered patients. Gefitinib (Gef) treatment was recommended if the patients had EGFR mutation (mEGFR). EGFR gene status was evaluable in 146 patients. Seventy-four of the patients were female, 82 were smokers, and 122 had adenocarcinoma. Overall, 67 patients had mEGFR and received Gef. Forty-nine of 79 patients with wild-type EGFR (wEGFR) received other chemotherapies or radiation but 30 selected best supportive care only as a second-line treatment. Patients with mEGFR survived significantly longer than patients with wEGFR (p < 0.0001). However, the survival of patients who received other forms of chemotherapy was not different from that of patients who received best supportive care only as a second-line treatment in patients with wEGFR. Examination of the association between overall survival after first-line chemotherapy and prognostic factors using multivariate regression analysis showed that mEGFR and response to first-line chemotherapy were independent factors (p = 0.003 and p = 0.003, respectively). Selection of second-line treatment according to EGFR gene status may be useful for patients with NSCLC.

Correlations of thin-section computed tomographic, histopathological, and clinical findings of adenocarcinoma with a bubblelike appearance.

OBJECTIVE: We reported that adenocarcinomas with a bubblelike appearance (BLA) appear similar to old inflammation (J Comput Assist Tomogr 2009;33:42-48). The histopathological, clinical, and biological characteristics of adenocarcinomas with BLA need more investigation. METHODS: We retrospectively reviewed the records of 26 patients who had undergone surgical resection between 1993 and 2008. We analyzed correlations between thin-section computed tomographic (TS-CT), histopathological, and clinical findings. We analyzed epidermal growth factor receptor and K-ras gene mutations. RESULTS: The TS-CT findings are unique with one pattern that was the same in all the 26 cases: (1) polygonal with straight and concave margins, (2) slight peripheral ground-glass opacity areas, (3) 3 or more dilated air bronchograms, and (4) clear pleural indentations. The histopathological findings were identical with our TS-CT findings. The mean tumor doubling time was 1165 days. Epidermal growth factor receptor mutations were observed in 17 cases. There were no K-ras mutations. After resection, the 5-year survival rate is 100%. CONCLUSION: The adenocarcinomas with BLA have unique TS-CT, histopathological, and clinical findings.

Tumor invasion in the central airway is a risk factor for early-onset checkpoint inhibitor pneumonitis in patients with non-small cell lung cancer.

BACKGROUND: Anti-programmed death-1 (PD-1) immunotherapy can cause immune-related pneumonitis, also known as checkpoint inhibitor pneumonitis (CIP). CIP that develops early after the initiation of anti-PD-1 immunotherapy is important because it is more severe than CIP that develops later. However, only a few studies have examined the risk factors for early-onset CIP. Previous studies have reported several risk factors for CIP, including imaging findings of airway obstruction adjacent to lung tumors. However, the utility of this factor is debatable. Therefore, we investigated potential risk factors for early-onset CIP, including tumor invasion in the central airway (TICA), in patients with non-small cell lung cancer (NSCLC) receiving anti-PD-1 therapy. METHODS: We retrospectively analyzed the medical records and chest computed tomography scans of patients with NSCLC treated with anti-PD-1 antibodies at the Kanagawa Cancer Center in Japan between 1 January 2016, and 30 June 2018. The clinical characteristics and imaging findings, including TICA, were compared between patients with and without early-onset CIP. RESULTS: Data from 181 eligible patients (114 receiving nivolumab and 67 receiving pembrolizumab) were analyzed. Early-onset CIP occurred in 13 of 79 patients (16.5%) with TICA and 2 of 102 patients (2.0%) without TICA. In multivariate analysis, the odds ratio of early-onset CIP for patients with TICA was 8.2 (95% confidence interval [CI]: 1.98-34.0, P = 0.0037). CONCLUSIONS: TICA was strongly associated with early-onset CIP in patients with NSCLC. Clinicians should carefully observe patients with TICA, especially within three months of anti-PD-1 antibody administration because of high CIP risk. KEY POINTS: Significant study findings Tumor invasion in the central airway (TICA) was a predictor of early-onset checkpoint inhibitor pneumonitis (CIP) TICA had good interobserver variability, indicating its utility in clinical practice Patients with TICA might have a higher immune status than patients without What this study adds This is the first study focusing on risk factors for CIP limited to early-onset CIP.