Kentaro Nakashima

Diagnostic test accuracy of loop-mediated isothermal amplification assay for Mycobacterium tuberculosis: systematic review and meta-analysis

Diagnostic test accuracy of the loop-mediated isothermal amplification (LAMP) assay for culture proven tuberculosis is unclear. We searched electronic databases for both cohort and case-control studies that provided data to calculate sensitivity and specificity. The index test was any LAMP assay including both commercialized kits and in-house assays. Culture-proven M. tuberculosis was considered a positive reference test. We included 26 studies on 9330 sputum samples and one study on 315 extra-pulmonary specimens. For sputum samples, 26 studies yielded the summary estimates of sensitivity of 89.6% (95% CI 85.6–92.6%), specificity of 94.0% (95% CI 91.0–96.1%), and a diagnostic odds ratio of 145 (95% CI 93–226). Nine studies focusing on Loopamp MTBC yielded the summary estimates of sensitivity of 80.9% (95% CI 76.0–85.1%) and specificity of 96.5% (95% CI 94.7–97.7%). Loopamp MTBC had higher sensitivity and lower specificity for smear-positive sputa compared to smear-negative sputa. In-house assays showed higher sensitivity and lower specificity compared to Loopamp MTBC. LAMP promises to be a useful test for the diagnosis of TB, however there is still need to improve the assay to make it simpler, cheaper and more efficient to make it competitive against other PCR methods already available.

Topotecan for Relapsed Small-cell Lung Cancer: Systematic Review and Meta-Analysis of 1347 Patients

Topotecan is the most reliable chemotherapy regimen for relapsed small-cell lung carcinoma (SCLC). The efficacy and adverse effects of topotecan as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for 6-month over-all survival (OS) rate, 1-year OS rate, objective responses, and/or adverse effects of single agent topotecan as a second line chemotherapy for SCLC, written in English language as a full article. Any topotecan regimen were allowed. Binary data were meta-analyzed with the random-model generic inverse variance method. We included 14 articles consisted of 1347 patients. Pooled values were estimated as follows. Six-month OS rate: 37% (95% CI: 28–46%). One-year OS rate: 9% (95% CI: 5–13%). Response rate: 5% (95% CI: 1–8%). Six-month OS rate: 57% (95% CI: 50–64%). One-year OS rate: 27% (95% CI: 22–32%). Response rate: 17% (95% CI: 11–23%). Grade III/IV neutropenia 69% (95% CI: 58–80%). Grade III/IV thrombopenia 41% (95% CI: 34–48%). Grade III/IV anemia 24% (95% CI: 17–30%). Non-hematorogical events were rare. Chemotherapy-related death 2% (95% CI: 1–3%). In conclusion, Topotecan provided a possibly promising outcome for sensitive-relapse SCLC and poor outcome for refractory relapse SCLC. Adverse events were mainly hematological.

Diagnostic test accuracy of anti-glycopeptidolipid-core IgA antibodies for Mycobacterium avium complex pulmonary disease: systematic review and meta-analysis.

Currently, an anti-glycopeptidolipid (GPL)-core IgA antibody assay kit for diagnosing Mycobacterium avium complex (MAC) is commercially available. We conducted this systematic review and meta-analysis to reveal the precise diagnostic accuracy of anti-GPL-core IgA antibodies for MAC pulmonary disease (MAC-PD). We systematically searched reports that could provide data for both sensitivity and specificity by anti-GPL-core IgA antibody for clinically diagnosed MAC-PD. Diagnostic test accuracy was estimated using the bivariate model. Of the 257 articles that we had found through primary search, we finally included 16 reports consisted of 1098 reference positive subjects and 2270 reference negative subjects. The diagnostic odds ratio was 24.8 (95% CI 11.6–52.8, I2 = 5.5%) and the area under the hierarchical summary receiver operating characteristic curves was 0.873 (95% CI 0.837–0.913). With a cutoff value of 0.7 U/mL, the summary estimates of sensitivity and specificity were 0.696 (95% CI 0.621–0.761) and 0.906 (95% CI 0.836–0.951), respectively. The positive and negative likelihood ratios were 7.4 (95% CI 4.1–13.8) and 0.34 (95% CI 0.26–0.43), respectively. The demanding clinical diagnostic criteria may be a cause of false positive of the index test. The index test had good overall diagnostic accuracy and was useful to ruling in MAC-PD with the cutoff value.

Progression-Free Survival, Response Rate, and Disease Control Rate as Predictors of Overall Survival in Phase III Randomized Controlled Trials Evaluating the First-Line Chemotherapy for Advanced, Locally Advanced, and Recurrent Non–Small Cell Lung Carcinoma

Introduction: Recent improvements in chemotherapy agents have prolonged postprogression survival of non–small cell lung cancer. Thus, primary outcomes other than overall survival (OS) have been frequently used for recent phase III trials to obtain quick results. However, no systematic review had assessed whether progression‐free survival (PFS), response rate (RR), and disease control rate (DCR) can serve as surrogates for OS at the trial level in the phase III first‐line chemotherapy setting. Methods: We included phase III randomized clinical trials (RCTs) comparing two arms that were reported as a full article regardless of their primary end point. We included only RCTs that evaluated chemonaive patients with advanced, locally advanced, or metastatic non–small cell lung cancer and were published after January 1, 2005. We systematically searched four public electronic databases. Two investigators independently screened and scrutinized candidate articles. How surrogate outcomes represented hazard ratios (HRs) for OS was examined. Results: Among 1907 articles, we ultimately found 44 eligible articles covering 22,709 subjects. HR for PFS, median PFS in the experimental arm minus median PFS in the control arm in months, OR for RR (ORrr), and OR for DCR were evaluated in 34, 35, 44, and 35 RCTs, respectively. HR for OS (HRos), median PFS in the experimental arm minus median PFS in the control arm, ORrr, and OR for DCR had weighted Spearmans rank correlation coefficients with an HRos of 0.496, 0.477, 0.570, and 0.470, respectively; the standardized weighted regression coefficients were 0.439, –0.376, –0.605, and –0.381, respectively; and the adjusted weighted coefficients of determination were 0.224, 0.161, 0.350, and 0.176, respectively. Conclusions: ORrr, followed by HRpfs, had the strongest association with HRos at the trial level. However, these measures were not strong enough to replace OS.

Sensitivity and specificity of Cobas TaqMan MTB real-time polymerase chain reaction for culture-proven Mycobacterium tuberculosis: meta-analysis of 26999 specimens from 17 Studies

Since 2010, studies on the diagnostic accuracy of COBAS TaqMan MTB (CTM) have been frequently reported with an unignorable discrepancy. The key inclusion criterion for this systematic review was original studies that could provide sufficient data for calculating the sensitivity and the specificity of CTM for M tuberculosis (TB) or M tuberculosis complex. The reference test was Mycobacterium culture. We used bivariate model for meta-analyses. Of the 201 candidate articles, we finally identified 17 eligible articles.Concerning the respiratory specimens, 1900 culture positive specimens and 20983 culture negative specimens from 15 studies were assessed. This provided the summary estimate sensitivity of 0.808 (95% CI 0.758–0.850) and the summary estimate specificity of 0.990 (95% CI 0.981–0.994). The area under curve was 0.956. The diagnostic odds ratio was 459 (95% CI 261–805, I2 26%). For the smear positive respiratory specimens, the sensitivity was 0.952 (95% CI 0.926–0.969) and the specificity was 0.916 (95% CI 0.797–0.968). For the smear negative respiratory specimens, the sensitivity and the specificity were 0.600 (95% CI 0.459–0.726) and 0.989 (95% CI 0.981–0.993), respectively. The diagnostic accuracy was poorer for the non-respiratory specimens, than for the respiratory specimens, but was acceptable. We believe that the information obtained from this study will aid physicians’ decision making.

Amrubicin for relapsed small-cell lung cancer: a systematic review and meta-analysis of 803 patients

Currently, amrubicin is permitted for relapsed small-cell lung carcinoma (SCLC) only in Japan. The efficacy and adverse effects of amrubicin as reported by previous studies varied greatly. The inclusion criterion was a prospective study that was able to provide data for efficacy and safety by the AMR single agent regimen as second-line chemotherapy for a patient with SCLC. Binary data were meta-analyzed with the random-model generic inverse variance method. We included nine articles consisted of 803 patients. The pooled three-, six-, and nine-month progression-free survival were 63% (95% CI 57–69%, I2 = 53%), 28% (95% CI 21–35%, I2 = 71%), and 10% (95% CI 6–14%, I2 = 41%), respectively. The pooled six-, 12-, and 18-month overall survival were 69% (95% CI 61–78%, I2 = 83%), 36% (95% CI 28–44%, I2 = 80%), and 15% (95% CI 8–21%, I2 = 81%), respectively. Amrubicin seemed much more beneficial for Japanese patients. However, compared to the efficacy of topotecan presented in a previous meta-analysis, amrubicin may be a better treatment option than topotecan for both Japanese and Euro-American. Adverse effects by amrubicin were almost exclusively observed to be hematological. Notably, grade III/IV neutropenia incidence was 70% and febrile neutropenia incidence was 12%.

The Platelet Count can Predict In-hospital Death in HIV-negative Smear-positive Pulmonary Tuberculosis Inpatients

Objective This retrospective cohort study investigated whether the three components of the blood cell count have prognostic implications in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis. Methods We reviewed patients who were treated by the isoniazid, rifampicin, pyrazinamide, and ethambutol regimen or by the isoniazid, rifampicin, and ethambutol regimen. The association between the patient data on admission and the survival outcome was evaluated. Results We reviewed 367 consecutive patients (male, 60.5%) with a median age of 72 [interquartile range (IQR), 54-82] years. While the white blood cell count did not differ between the two groups, (discharged alive: 7,000/μL; IQR, 5,500-9,300; died in hospital: 7,200/μL; IQR, 5,600-9,400; p=0.797), hemoglobin level (discharged alive: 11.5 g/dL; IQR, 10.0-13.1; died in hospital: 9.9 g/dL; IQR, 8.6-11.3; p<0.001) and the platelet count (discharged alive: 275,000/μL; IQR, 206,000-345,000; died in hospital: 149,000/μL; IQR, 93,000-236,000; p<0.001) were lower in patients who died in hospital. After dividing patients into hemoglobin- and platelet-based quantiles, the lower quantile class tended to show poorer survival (log-rank test for trend p<0.001 for both). A multi-variable Cox proportional hazards model revealed that hazard ratio for in-hospital death for every 1,000/μL increase of platelet count was 0.997 (95%CI, 0.995-0.999; p=0.010); the hazard ratio for the hemoglobin level was not significant. Conclusion A low platelet count was clearly related to a poor life prognosis in HIV-negative Japanese adult inpatients with smear-positive pulmonary tuberculosis.

HbA1c level cannot predict the treatment outcome of smear-positive non-multi-drug-resistant HIV-negative pulmonary tuberculosis inpatients

We conducted a single-center retrospective cohort study to evaluate whether the HbA1c level on admission could predict the in-hospital treatment outcome of smear-positive non-multi-drug-resistant HIV-negative culture-proven pulmonary tuberculosis inpatients. Our standard regimens under the direct observation were HRZE or HRE for the first two months followed by combination therapy with isoniazid and rifampicin. Our cohort consisted of consecutive 239 patients consisted of 147 men and 92 women with a median age of 73 years. The HbA1c level of patients whose HbA1c was above 7.0% on admission showed clear declining trends after admission. HbA1c on admission had no Spearman’s rank correlation with time to discharge alive (r = 0.17) and time to becoming non-infective (r = 0.17). By Kaplan-Meier curves and a log-rank trend test, HbA1c quartile subgroups showed no association with times to discharge alive (p = 0.431), becoming non-infective (p = 0.113), and in-hospital death (p = 0.427). Based on multi-variate Cox analysis, HbA1c on admission had no significant impact on time to discharge alive (hazard ratio = 1.03, 95% CI 0.89–1.20, p = 0.659), becoming non-infective (hazard ratio = 0.93, 95% CI 0.80–1.06, p = 0.277), and in-hospital death (hazard ratio = 0.68, 0.43–1.07, p = 0.097). In conclusion, the HbA1c level on admission did not seem to affect in-hospital tuberculosis treatment outcomes in Japanese cohort.

The best platinum regimens for chemo-naive incurable non-small cell lung cancer: network meta-analysis

Platinum regimens still play a key role in chemotherapy for incurable non-small cell lung cancer (NSCLC). Although guidelines list many platina regimens, the best regimens have not yet clarified. Electronic searches were carried out during November 26th-28th, 2016. We included individually randomized trials comparing two or more platinum regimes for incurable chemo-naive NSCLC published in English full papers. The platinum doublets should be either Cisplatin (CDDP), Carboplatin (CBDCA), or Nedaplatin (CDGP) plus one of the third-generation agents. The platinum triplet should be the doublet plus bevacizumab (BEV). The data were independently extracted and cross-checked by two investigators. We did not observed heterogeneity (whole network level Q = 28.9, df = 34, P = 0.717) among 59 pairwise comparisons from 45 studies with 16141 cases for the primary outcome, hazard ratio for overall survival (HRos). Using CBDCA + Paclitaxel (PTX) + BEV as a common comparator, CDGP + Docetaxel (DTX) (HRos = 0.98, 95%CI: 0.75–1.29, P = 0.884), CDDP + Tegafur gimeracil oteracil (S1) (HRos = 1.23, 95%CI: 0.96–1.57, P = 0.099), CBDCA + S1 (HRos = 1.23, 95%CI: 0.99–1.53, P = 0.062), and CDGP + Gemcitabine (GEM) (HRos = 1.24, 95%CI: 0.71–2.17, P = 0.45) did not have significantly poorer HRos. We suggest that these regimens as acceptable first-choice regimens.

Factors for Predicting Outcomes among Non-HIV Patients with Pulmonary Tuberculosis

Objective Onoderas Prognostic Nutritional Index (PNI), determined as “10× albumin (g/dL) + 0.005× lymphocyte count (/μL),” was originally designed to determine the risk of complications following gastrointestinal surgery. This single-center, retrospective observational study was designed to investigate whether or not the PNI can predict the treatment outcome. Methods We consecutively reviewed HIV-negative pulmonary tuberculosis adults in an isolation ward. Most patients were being treated with standard three- or four-drug regimens. Patients were discharged after consecutive negative smears/cultures were confirmed. The risk of all-cause death was assessed using a multivariable Cox proportional hazard model and a log-rank trend test. Results During the observation period, we observed 371 consecutive patients with a median age of 72 (interquartile range [IQR]: 54-82) years. In our cohort, 295 (79.5%) patients were discharged alive, and 76 (20.5%) died in-hospital. Patients who died in-hospital had a lower PNI [median 21.2 (IQR: 18.5-25.9)] than those who were discharged alive [median 35.1 (IQR: 28.0-43.3); p<0.001]. The area under the receiver operating characteristic curve was 0.87. After dividing the patients based on the baseline PNI quartile, those patients with a lower PNI showed a poorer survival than those with a higher PNI (log-rank trend p<0.001). After adjusting for other baseline variables, the baseline PNI was still associated with in-hospital death with a hazard ratio of 0.86 (95% confidence interval: 0.82-0.91, p<0.001). Conclusion Our results showed that a low PNI was clearly related to a poor survival prognosis in smear-positive HIV-negative pulmonary tuberculosis inpatients.