Whole-genome sequencing predicting phenotypic antitubercular drug resistance: meta-analysis.

BACKGROUND: For simultaneous prediction of phenotypic drug susceptibility test (pDST) for multiple anti-tuberculosis drugs, the whole genome sequencing (WGS) data can be analyzed using either catalogue-based approach, wherein one causative mutation suggests resistance, (e.g., WHO catalog) or non-catalogue-based approach using complicated algorithm (e.g., TB-profiler, machine learning). The aim was to estimate the predictive ability of WGS-based tests with pDST as the reference, and to compare the two approaches. METHODS: Following the systematic literature search, the diagnostic test accuracies for 14 drugs were pooled using a random-effect bivariate model. RESULTS: Out of 779 articles, 44 articles with 16,821 specimens for meta-analysis and 13 articles not for meta-analysis were adopted. The areas under summary receiver operating characteristic curve suggested "excellent" (0.97-1.00) for 2 drugs (isoniazid 0.975, rifampicin 0.975), "very good" (0.93-0.97) for 8 drugs (pyrazinamide 0.946, streptomycin 0.952, amikacin 0.968, kanamycin 0.963, capreomycin 0.965, para-aminosalicylic acid 0.959, levofloxacin 0.960, ofloxacin 0.958), and "good" (0.75-0.93) for 4 drugs (ethambutol 0.926, moxifloxacin 0.896, ethionamide 0.878, prothionamide 0.908). The non-catalogue-based and catalogue-based approaches had similar ability for all drugs. CONCLUSION: WGS accurately identifies isoniazid and rifampicin resistance. For most drugs, positive WGS results reliably predict pDST positive. The two approaches had similar ability.

Regional differences in epidermal growth factor receptor-tyrosine kinase inhibitor therapy in lung cancer treatment using a national database in Japan.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are extensively used in the treatment of non-small cell lung cancer (NSCLC); hence, equal access to them is important. Therefore, this study aimed to identify regional differences in the prescription of EGFR-TKIs and the factors contributing to these differences. In this ecological study, we collected data using the National Database Open Data and the National Cancer Registry. The standardized claim ratio (SCR) was used as an indicator of the number of EGFR-TKI prescriptions. Additionally, we examined the association between SCR and various factors to identify the factors associated with this difference. The average SCR for the top three provinces was 153.4, while the average for the bottom three provinces was 61.6. Multivariate analysis used for evaluating the association of SCR with variables revealed that the number of designated cancer hospitals and radiation therapies were independent factors associated with the SCR of EGFR-TKIs. There were significant regional differences in the prescriptions of EGFR-TKIs in Japan based on the number of coordinated designated cancer hospitals and the number of patients receiving radiotherapy alone. These findings emphasize the need to implement policies to increase the number of hospitals to reduce regional differences.

Adverse events induced by durvalumab and tremelimumab combination regimens: a systematic review and meta-analysis.

Background: Immune checkpoint inhibitors (ICIs) have shown remarkable therapeutic outcomes among cancer patients. Durvalumab plus tremelimumab (DT) is under investigation as a new ICI combination therapy, and its efficacy has been reported in various types of cancer. However, the safety profile of DT remains unclear, especially considering rare adverse events (AEs). Objective: We aimed to assess the frequency of AEs associated with DT. Design: This study type is a systematic review and meta-analysis. Data Sources and Methods: Four databases were searched for articles. Randomized trials, single-arm trials, and prospective and retrospective observational studies were included. The type of cancer, previous treatment, and performance status were not questioned. Major AE indicators such as any AE and the pooled frequency of each specific AE were used as outcomes. As a subgroup analysis, we also compared cases in which DT was performed as first-line treatment with those in which it was performed as second-line or later treatment. The protocol for this systematic review was registered on the University Hospital Medical Information Network (UMIN) Center website (ID: UMIN000046751). Results: Forty-one populations including 3099 patients were selected from 30 articles. Pooled frequencies of key AE indicators are shown below: any AEs, 77.8% [95% confidence interval (CI): 67.9-87.6]; grade ⩾ 3 AEs, 29.3% (95% CI: 24.2-34.4); serious AEs, 34.9% (95% CI: 28.1-41.7); AE leading to discontinuation, 13.3% (95% CI: 9.3-17.4); treatment-related deaths, 0.98% (95% CI: 0.5-1.5). AEs with a frequency exceeding 15% are shown below: fatigue, 30.1% (95% CI: 23.8-36.3); diarrhea, 21.7% (95% CI: 17.8-25.6); pruritus 17.9% (95% CI: 14.4-21.3); decreased appetite, 17.7% (95% CI: 13.7-22.0); nausea, 15.6% (95% CI: 12.1-19.6). There were no significant differences in these pooled frequencies between subgroups. Conclusions: The incidence of any AE in DT therapy was approximately 78%, and the incidence of grade 3 or higher AEs was approximately 30%, which was independent of prior therapy.

Pembrolizumab monotherapy versus pembrolizumab plus chemotherapy in patients with non-small-cell lung cancer: A multicenter retrospective trial.

BACKGROUND: Pembrolizumab alone or in combination with chemotherapy is a standard treatment for patients with non-small-cell lung cancer (NSCLC) with high programmed death-ligand 1 (PD-L1) expression. However, no study has compared the efficacies of these two regimens. Therefore, we aimed to compare the efficacy of pembrolizumab alone and in combination with chemotherapy in NSCLC patients with high PD-L1 expression. METHODS: We conducted a multicenter retrospective trial involving patients with diagnosed unresectable or recurrent NSCLCs who had received pembrolizumab with or without chemotherapy in the first-line setting. Patients were divided into monotherapy and combination therapy groups. The progression-free survival (PFS), overall survival (OS), and response rate (RR) were analyzed and compared between the groups. Clinical characteristics of patients were analyzed to assess their possible relationship with treatment outcomes. RESULTS: We enrolled 96 patients from five hospitals. Of these, 47 and 49 patients received monotherapy and combination therapy, respectively. The median PFS was 343 and 328 days in the monotherapy and combination therapy groups, respectively (hazard ratio 1.003, p = 0.99). No statistically significant differences were observed in the OS and RR between the two groups. However, in patients with metastases to the liver, lung, adrenal glands, bone, or lymph nodes, the PFS was longer in the monotherapy group than in the combination therapy group. CONCLUSION: Although the PFS, OS, and RR were not significantly different between patients treated with pembrolizumab alone and or with pembrolizumab in combination with chemotherapy, patients with NSCLC having metastases to specific sites may benefit more from monotherapy.

A functionally improved case of obstructive impairment caused by systemic lupus erythematosus.

Pulmonary lymphoproliferative diseases are often associated with collagen diseases. In addition to treatment of the primary disease, additional treatments may be considered depending on the pathology presented in the case. https://bit.ly/3vKqsls.

Resistance mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors in non-small cell lung cancer patients: A meta-analysis.

BACKGROUND: Differences in the resistance mechanisms of epidermal growth factor receptor tyrosine kinase inhibitors in patients with non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor mutations are unknown. This meta-analysis aimed to clarify the differences in resistance mechanisms after treatment with various epidermal growth factor receptor tyrosine kinase inhibitors. METHODS: We systematically searched PubMed, Cochrane, and Web of Science on July 29, 2020, for relevant studies on acquired resistance mechanisms against epidermal growth factor receptor tyrosine kinase inhibitors. The primary outcome measure was differences in the resistance mechanism between individual or generations of epidermal growth factor receptor tyrosine kinase inhibitors. RESULTS: In total, 33 trials involving 2418 individuals were included and analyzed. T790M was significantly less frequent after afatinib treatment (40.2%, 95% confidence interval [CI]: 31.7%-48.7%) than after gefitinib and erlotinib treatments (52.5%, 95% CI: 48.7%-56.3%, p = 0.005). There were no significant differences between Asian and non-Asian patients in the incidence of T790M after gefitinib, erlotinib, and afatinib treatments. Regarding epidermal growth factor receptor pathway-independent resistant mechanisms, the incidences of small cell lung cancer transformation (osimertinib: 7.9%, 95% CI: 3.6%-12.2%, others: 2.3%, 95% CI: 0.8%-3.8%) and Kirsten rat sarcoma (KRAS) viral oncogene homolog mutation (osimertinib: 4.6%, 95% CI: 1.5%-7.7%, others: 0.2%, 95% CI: 0.0%-1.7%) were significantly higher following osimertinib treatment than with others. CONCLUSIONS: Significant differences in the incidence of resistance mechanisms among epidermal growth factor receptor tyrosine kinase inhibitors exist, which should be taken into consideration when choosing the treatment strategy.

T-cell response to phytohemagglutinin in the interferon-γ release assay as a potential biomarker for the response to immune checkpoint inhibitors in patients with non-small cell lung cancer.

BACKGROUND: Immune checkpoint inhibitors are a standard treatment for advanced lung cancer, although it remains important to identify biomarkers that can accurately predict treatment response. Immune checkpoint inhibitors enhance the antitumor T-cell response, and interferon-γ plays an important role in this process. Therefore, this study evaluated whether the number of interferon-γ-releasing peripheral T cells after phytohemagglutinin stimulation in the interferon-γ release assay might act as a biomarker for the response of non-small cell lung cancer to immune checkpoint inhibitor treatment. METHODS: Data were retrospectively collected regarding 74 patients with non-small cell lung cancer who had received immune checkpoint inhibitors. Pretreatment screening tests had been performed using the T-SPOT.TB assay, which quantifies the number of interferon-γ-releasing T cells (as immunospots) in response to phytohemagglutinin and tuberculosis-specific antigen stimulation. Clinical factors and the number of spots in the T-SPOT fields were evaluated for associations with patient outcomes. The median number of spots was used to categorize patients as having high or low values, and the two groups were compared. RESULTS: Relative to patients with a low ratio, patients with a high ratio of phytohemagglutinin/tuberculosis-specific antigen spots (i.e. more responsive T cells) had significantly better progression-free survival after immune checkpoint inhibitor treatment. When we only considered patients with negative T-SPOT results, a high number of phytohemagglutinin-stimulated spots corresponded to significantly longer progression-free survival. CONCLUSION: The T-SPOT.TB assay can be used to quantify the number of immunospots in response to antigen stimulation, which may predict the response to immune checkpoint inhibitors in patients with non-small cell lung cancer.

Class A CpG oligodeoxynucleotide inhibits IFN-γ-induced signaling and apoptosis in lung cancer.

BACKGROUND: Currently, anticancer immunotherapy based on PD-1/PD-L1 blockade with immune checkpoint inhibitors (ICIs) is being used as a standard therapy for non-small cell lung cancer (NSCLC). However, more effective treatments are required as these tumors are often resistant and refractory. Here, we aimed to determine the effects of immunomodulatory oligodeoxynucleotides (ODNs) in terms of the presence or absence of CpG motifs and the number of consecutive guanosines. METHODS: Western blots were used to measure the molecules which regulate the expression of PD-L1 in human lung cancer cell lines after incubation with several cytokines and ODNs. The expression of PD-L1 and ß2-microglobulin (ß2-MG) on A549 cells, and IFN-γ-induced apoptosis with ODNs were examined by flow cytometry. The relationship between IFN-γ receptor and ODN was analyzed by ELISA and immunofluorescence chemistry. RESULTS: Our results verified that A-CpG ODNs suppress the upregulation of IFN-γ-induced PD-L1 and ß2-MG expression. In addition, we found that ODNs with six or more consecutive guanosines (ODNs with poly-G sequences) may competitively inhibit the IFN-γ receptor and abolish the effect of IFN-γ, thereby suppressing apoptosis and indoleamine 2,3-dioxygenase 1 expression in human lung cancer cells. The tumor microenvironment regulates whether this action will promote or suppress tumor immunity. Thus, in immunotherapy with CpG ODNs, it is essential to consider the effect of ODNs with poly-G sequences. CONCLUSIONS: This study suggests that ODNs containing six or more consecutive guanosines may inhibit the binding of IFN-γ to IFN-γ receptor. However, it does not directly show that ODNs containing six or more consecutive guanosines competitively inhibit the IFN-γ receptor, and further studies are warranted to confirm this finding. KEY POINTS: Significant findings of the study: Oligodeoxynucleotides with a contiguous sequence of six or more guanosines may competitively inhibit the IFN-γ receptor and abolish the action of IFN-γ. This may suppress IFN-γ-induced apoptosis and indoleamine-2,3-dioxygenase-1 expression in human lung cancer cells. WHAT THIS STUDY ADDS: A-CpG and poly-G ODN may overcome tolerance if the cause of ICI tolerance is high IDO expression. However, IFN-γ also has the effect of suppressing apoptosis of cancer cells, and it is necessary to identify the cause of resistance.

Identification of a novel biomarker based on lymphocyte count, albumin level, and TBAg/PHA ratio for differentiation between active and latent tuberculosis infection in Japan.

Data from China have shown that the ratio of Mycobacterium tuberculosis-specific antigen (TBAg) spots obtained from the T-SPOT.TB test to the number of positive control phytohemagglutinin (PHA) spots (TBAg/PHA ratio) could help distinguish between active tuberculosis infection (ATBI) and latent tuberculosis infection (LTBI). As the applicability of the T-SPOT.TB test may differ according to region and race, we retrospectively verified the utility of the TBAg/PHA ratio in distinguishing between ATBI and LTBI in Japan. The TBAg/PHA ratio was significantly lower in the LTBI group than in the ATBI group. Area under the receiver operating characteristic curve (AUC) analysis between ATBI and LTBI according to the TBAg/PHA ratio was 0.76, with a sensitivity of 65.8% and a specificity of 75.6%. The best AUC was obtained when the TBAg/PHA ratio was divided by both lymphocyte count and albumin levels. Our results demonstrate that, in Japan, the TBAg/PHA ratio is superior to TBAg alone for distinguishing between ATBI and LTBI. In addition, the sensitivity and specificity were improved by combining the TBAg/PHA ratio with lymphocyte count and albumin levels.

Identification of Biomarkers for Non-small-cell Lung Cancer Patients Treated With an Immune Checkpoint Inhibitor.

BACKGROUND/AIM: Immune checkpoint inhibitors (ICIs) have an important role in lung cancer therapy. Although the programmed cell death protein-1 (PD-L1) tumor proportion score (TPS) and tumor mutational burden are known prognostic factors, they are insufficient to predict clinical outcomes. This study was conducted to identify novel biomarkers for ICI treatment. PATIENTS AND METHODS: We performed univariable and multivariable analyses of 110 patients with advanced non-small-cell lung cancer (NSCLC) who were treated with an ICI to identify novel biomarkers related to prognosis. We assessed their backgrounds, such as performance status (PS), PD-L1 TPS, smoking status, and peripheral white blood cell counts at baseline and on the day the second course of ICI administration. RESULTS: In the multivariable analysis, PS, driver gene, immune-related adverse events, and post-treatment absolute neutrophil counts (post-ANCs) were significantly associated with progression-free survival. CONCLUSION: A high level of post-ANCs was associated with poor outcome in ICI-treated NSCLC patients.

MicroRNA-200b is a potential biomarker of the expression of PD-L1 in patients with lung cancer.

BACKGROUND: Advanced non-small cell lung cancer (NSCLC) has a high mortality rate and poor prognosis. However, outcomes have gradually improved after the introduction of novel immunotherapies, including immune checkpoint inhibitors (ICIs). Although programmed death-ligand 1 (PD-L1) expression in tumor tissues is a known biomarker for guiding ICI treatment of NSCLC, challenges such as difficulty of liquid biopsy and heterogeneous results during treatment persist. This study evaluated the potential of miR200b as a surrogate biomarker for PD-L1 expression. METHODS: We used the human lung cancer cell lines H226, H460, H520, A549, and H1975. miR200b expression in blood and bronchoscopy specimens of NSCLC patients was evaluated using reverse-transcription-quantitative PCR. Using flow cytometry, PD-L1 expression in vitro, as well as in tumor tissues, was evaluated after transfection with a mimic miR200b or siRNA. RESULTS: miR200b expression negatively correlated with PD-L1 expression in all cell lines. The induction or knockdown of miR200b also altered PD-L1 expression in vitro. The patient group with a PD-L1 tumor proportion score ≥ 50% had significantly lower miR200b expression in the bronchoscopy specimens (P = 0.025) and serum-derived exosomes (P = 0.022) than that with PD-L1 tumor proportion score < 50%. CONCLUSIONS: miR200b can regulate PD-L1 expression in lung cancer cells, and miR200b expression in clinical specimens negatively correlated with PD-L1 expression. Thus, miR200b may be a useful surrogate biomarker for PD-L1 expression in lung cancer patients. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: High PD-L1 expression was linked to low miR200b expression, whereas low PD-L1 expression was linked to high miR200b expression in human lung cancer patients. Thus, miR200b overexpression or silencing can control PD-L1 expression in cancer cells. What this study adds We demonstrated the potential of miR200b as a surrogate biomarker for PD-L1 expression in lung cancer patients.

Afatinib + bevacizumab combination therapy in EGFR-mutant NSCLC patients with osimertinib resistance: Protocol of an open-label, phase II, multicenter, single-arm trial.

INTRODUCTION: As most patients with epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC) develop progressive disease after treatment with osimertinib, it is important to develop more effective treatment options. Afatinib has been shown to be more effective in in vitro studies than osimertinib when used in cancer cell lines containing some specific EGFR mutations. Therefore, afatinib may be an effective solution, especially when used in combination with an anti-VEGF agent such as bevacizumab. METHODS: A phase II multicenter, open-label, single-arm trial has been initiated to evaluate the efficacy and safety of afatinib and bevacizumab combination as salvage therapy for EGFR-mutated lung cancer in patients previously treated with osimertinib. The primary endpoint will be the objective response rate (ORR) and secondary endpoints are progression-free survival (PFS), overall survival (OS), disease control rate (DCR), and adverse events (AEs). DISCUSSION: A previous study indicated that afatinib inhibits lung cancer cells with specific EGFR mutations more effectively than other EGFR-TKIs such as osimertinib. Therefore, we expect that combination therapy using afatinib and bevacizumab will be effective in patients previously treated with osimertinib (registration no. jRCTs031190077).