Activities of Daily Living, Hypoxemia, and Lymphocytes Score for Predicting Mortality Risk in Patients With Pulmonary TB.

BACKGROUND: A clinically applicable mortality risk prediction system for pulmonary TB may improve treatment outcomes, but no easy-to-calculate and accurate score has yet been reported. The aim of this study was to construct a simple and objective disease severity score for patients with pulmonary TB. RESEARCH QUESTION: Does a clinical score consisting of simple objective factors predict the mortality risk of patients with pulmonary TB? STUDY DESIGN AND METHODS: The data set from our previous prospective study that recruited patients newly diagnosed with pulmonary TB was used for the development cohort. Patients for the validation cohort were prospectively recruited between March 2021 and September 2022. The primary end point was all-cause in-hospital mortality. Using Cox proportional hazards regression, a mortality risk prediction model was optimized in the development cohort. The disease severity score was developed by assigning integral points to each variate. RESULTS: The data from 252 patients in the development cohort and 165 patients in the validation cohort were analyzed, of whom 39 (15.5%) and 17 (10.3%), respectively, died in the hospital. The disease severity score (named the AHL score) included three clinical parameters: activities of daily living (semi-dependent, 1 point; totally dependent, 2 points); hypoxemia (1 point), and lymphocytes (< 720/µL, 1 point). This score showed good discrimination with a C statistic of 0.902 in the development cohort and 0.842 in the validation cohort. We stratified the score into three groups (scores of 0, 1-2, and 3-4), which clearly corresponded to low (0% and 1.3%), intermediate (13.5% and 8.9%), and high (55.8% and 39.3%) mortality risk in the development and validation cohorts. INTERPRETATION: The easy-to-calculate AHL disease severity score for patients with pulmonary TB was able to categorize patients into three mortality risk groups with great accuracy. CLINICAL TRIAL REGISTRATION: University Hospital Medical Information Network Center; No. UMIN000012727 and No. UMIN000043849; URL: www.umin.ac.jp.

Serum Procalcitonin Levels Predict Mortality Risk in Patients With Pulmonary Tuberculosis: A Single-Center Prospective Observational Study.

Globally, tuberculosis is the leading infectious cause of death; discovering biomarkers that predict a high mortality risk may improve treatment outcomes. We prospectively enrolled 252 pulmonary tuberculosis patients who were not coinfected with human immunodeficiency virus and initiated antituberculosis treatment, measured serum procalcitonin levels (PCT), and assessed mortality risk. PCT serum levels higher than 0.13 (day 0), 0.05 (day 7), 0.12 (day 14), or 0.06 (day 28) ng/mL predicted nonsurvivors with odds ratios of 7.9, 14.3, 20.0, and 7.3, respectively (P ≤ .005 for all), respectively. Therefore, serum PCT levels are a promising mortality risk indicator for patients with pulmonary tuberculosis. Main Point. For patients with pulmonary tuberculosis, a promising mortality risk indicator is the level of serum procalcitonin, which is weakly associated with sputum bacterial load and independent of radiographic findings.

Treatment strategy for brain metastases from esophageal cancer.

BACKGROUND: This study aimed to examine the treatment outcomes of patients with brain metastases from esophageal cancer. Brain metastases from esophageal cancer are rare and have a poorer prognosis than brain metastases from lung and breast cancer. METHODS: This study included patients who were diagnosed with and treated for esophageal cancer in our department and subsequently developed brain metastases between April 2010 and December 2014. We examined the differences in survival in patients based on receiving chemotherapy. RESULTS: In total, 8 patients (7 men and 1 woman) with a mean age of 65 years (range 51-73) were included. Seven presented with neurologic symptoms. Two were diagnosed via computed tomography (CT), 5 via magnetic resonance imaging, and 1 via positron emission tomography/CT. They were treated using whole-brain irradiation or with a gamma knife. In 5 patients, chemotherapy was administered after treatment of the brain metastases. The mean survival from the start of treatment was 358 days (range 31-1196). CONCLUSION: The relatively successful local control of brain metastases in these patients indicates that long-term survival may be attainable via concomitant chemotherapy.

Treatment of multidrug-resistant pulmonary tuberculosis with delamanid based on Japanese guideline recommendations.

BACKGROUND: In Japan, a new anti-tuberculous drug, delamanid, was recognized as the drug of choice to treat multi-drug resistant pulmonary tuberculosis in July 2014. METHODS: We treated 28 cases of multidrug-resistant tuberculosis (MDR-TB) and three cases of extensively drug-resistant tuberculosis (XDR-TB) with delamanid from July 2014 to June 2018 at our hospital. RESULTS: There were 21 men and 10 women, with the mean age of 48 and 37 years, respectively. We used an average of 4.4 sensitive anti-tuberculous drugs for the MDR-TB cases and 4.7 for the XDR-TB cases with delamanid. We used linezolid in 19 of 31 cases, although it has not been recognized as an anti-tuberculous drug in Japan. On electrocardiography, QTc prolongation of more than 450 ms was seen in two cases (6.4%), but they were asymptomatic, thus the treatment with delamanid could be continued. In 10 cases, surgical resection was performed. We completed the treatment in 20 cases and continued the treatment in seven cases; however, the treatment was discontinued in four cases because of side effects. In all cases, the sputum cultures were negative. CONCLUSIONS: Delamanid is a relatively safe drug with few side effects. However, some patients could not continue it because of difficulty of use in combination, therefore delamanid should be prescribed considering the side effects of all therapies in the regimen.

Limited benefit of CT scans in tuberculosis contact tracing.

OBJECTIVE: The detection of abnormal findings on computed tomography (CT) scans of tuberculosis contacts combined with normal plain radiographs contributes to the early detection of tuberculosis. However, the benefit of the early detection of abnormalities for the prevention of active tuberculosis during follow-up requires evaluation. METHOD: We conducted retrospective comparison of the existence of CT scans of tuberculosis contacts without findings of active tuberculosis on plain radiographs at a hospital in Japan. RESULTS: Among 243 contacts without CT scans, five developed tuberculosis during follow-up. Among 229 contacts with CT scans, 24 were judged as targets of multi-drug therapy since their CT findings were suggestive of active tuberculosis at the time of the CT screening. Among 205 contacts judged as having latent tuberculous infection with CT screening, three developed tuberculosis diseases during follow-up. CONCLUSION: CT scans detected abnormal findings among contacts without abnormalities of plain radiographs but there were some contacts that developed tuberculosis diseases among those with contact investigation including CT scan. The value of CT is equivocal considering the balance of true treatment, overtreatment and harm of radiation.

Interrelational changes in the epidemiology and clinical features of nontuberculous mycobacterial pulmonary disease and tuberculosis in a referral hospital in Japan.

BACKGROUND AND OBJECTIVES: The incidence of nontuberculous mycobacterial pulmonary disease (NTM-PD) is increasing, while that of tuberculosis (TB) is decreasing in many industrialized countries, including Japan. However, the long-term evaluation of clinico-epidemiological features of NTM-PD in relation to TB are limited. We aimed to clarify the long-term changes in the epidemiology and clinical features of NTM-PD in relation to those of TB at a nationally-designated TB center in Japan. METHODS: We reviewed all mycobacterial examination records at Fukujuji Hospital between 2006 and 2016. Cases of NTM-PD were defined according to the 2007 American Thoracic Society/Infectious Disease Society of America microbiologic criteria. The current characteristics of Mycobacterium avium complex pulmonary disease (MAC-PD) were compared with those in the 1980s and circa 2000. RESULTS: We identified a total of 3,546 pulmonary TB cases and 2,155 NTM-PD cases. While the annual number of incident pulmonary TB cases remained stable over the study period (P = 0.59), that of NTM-PD cases increased significantly from 165 to 278 (P < 0.01). The mean age of pulmonary TB cases increased from 59.7 ±â€¯16.3 to 66.2 ±â€¯21.7 years, whereas that of NTM-PD cases remained unchanged. Regarding the age distribution, the greatest increases were observed in patients over 75 years for TB and in patients 50-74 years for NTM. The most common causative organism for NTM was Mycobacterium avium complex (87.3%), M. abscessus complex (5.5%) and M. kansasii (3.9%). Among patients with MAC-PD, the proportion of the nodular bronchiectatic (NB) form increased significantly from 60.0% to 84.4% between circa 2000 and 2016 (P < 0.01). Significant increases in the NB form were observed in both males (33.3%-70.7%, P < 0.01) and females (71.3%-89.2%, P < 0.01). CONCLUSIONS: The annual number of incident NTM-PD cases increased markedly. In contrast to patients with TB, the mean age of new NTM-PD patients did not increase in the last 10 years. Among MAC-PD patients, the proportions accounted for by the NB form increased significantly in both sexes.

Longitudinal Evaluation of Humoral Immunity and Bacterial and Clinical Parameters Reveals That Antigen-Specific Antibodies Suppress Inflammatory Responses in Active Tuberculosis Patients.

A novel tuberculosis vaccine to replace BCG has long been desired. However, recent vaccine trials focused on cell-mediated immunity have failed to produce promising results. It is worth noting that most commercially available successful vaccines rely on humoral immunity. To establish a basic understanding of humoral immunity against tuberculosis, we analyzed and evaluated longitudinal levels and avidity of immunoglobulin to various tuberculosis antigens compared with bacterial and clinical parameters during treatment. We found that levels of IgG antibodies against HrpA and HBHA prior to treatment exhibited a positive correlation with bacterial burden. Analysis of changes in CRP during treatment revealed an association with high levels of specific IgG and IgA antibodies against mycobacterial antigens. Levels of CRP prior to treatment were negatively associated with IgG avidity to CFP-10 and MDP1 and IgA avidity to HrpA, while IgA avidity to MDP1 and Acr exhibited a negative correlation with CRP levels after 60 days of treatment. These results may provide insight for the development of a novel tuberculosis (TB) vaccine candidate to induce protective humoral immunity against tuberculosis.

Adverse Prognostic Factors of Advanced Esophageal Cancer in Patients Undergoing Induction Therapy with Docetaxel, Cisplatin and 5-Fluorouracil.

BACKGROUND/AIM: The purpose of this study was to identify adverse prognostic factors for patients with advanced esophageal cancer undergoing chemotherapy with docetaxel, cisplatin and 5-fluorouracil (DCF). PATIENTS AND METHODS: The study cohort comprised of 45 patients with advanced esophageal cancer who underwent induction DCF therapy followed by esophagectomy or chemoradiotherapy. Treatment outcomes and factors affecting early recurrence and death were analyzed. RESULTS: Overall 3-year survival was 61.4%, and 3-year disease-free survival was 44.7%. Clinically evident lymph node metastasis and clinical stage were associated with recurrence within 1 year and death within 2 years. Low maximum standardized uptake value (SUVmax) after induction DCF therapy and small decreases in SUVmax from pre- to post-DCF therapy were also predictors of recurrence and poor prognosis. CONCLUSION: Induction DCF therapy may be ineffective for advanced-stage esophageal cancer and clinical lymph node metastasis (≥N2, ≥stage IIIB). Moreover, small decreases in SUVmax DCF therapy are associated with early disease relapse and death.

Preventive Effect of Rifampicin on Alzheimer Disease Needs at Least 450 mg Daily for 1 Year: An FDG-PET Follow-Up Study.

BACKGROUND: Rifampicin was reported to inhibit amyloid-ß oligomerization and tau hyperphosphorylation in mouse models and could serve as a promising available medicine for the prevention of Alzheimer disease (AD). To examine whether rifampicin has such preventive effects in humans, we retrospectively reviewed 18F-FDG-PET findings of elderly patients with mycobacterium infection treated with rifampicin. METHODS: Forty nondemented elderly patients treated with rifampicin for mycobacterium infections who showed AD-type hypometabolism were enrolled. The hypometabolic patterns were evaluated with stereotaxic statistical analysis and region of interest analysis. RESULTS: Before treatment, AD-type hypometa bolism was observed in 12 patients. The FDG uptake in the posterior cingulate cortex (PCC) was improved or stabilized in 6 patients after 12-month therapy (450 mg/day), whereas another 6 patients with 6-month therapy showed a decreased FDG uptake in the PCC. In patients who underwent FDG-PET only after treatment, the metabolic decline in the PCC was significantly milder in patients with ≥12 months of rifampicin treatment than in those with 6 months of treatment. Multiple regression analysis revealed that the dose of rifampicin and treatment duration significantly influenced FDG uptake in the PCC. CONCLUSION: The preventive effect of rifampicin depended on the dose and the treatment duration, and the effect needs at least 450 mg daily for 1 year.

Linezolid as a Potentially Effective Drug for the Treatment of Multidrug-Resistant Tuberculosis in Japan.

Linezolid (LZD) is classified as a WHO group 5 drug used in the treatment of tuberculosis (TB). Although its efficacy and long-term safety have not yet been established, it is being increasingly used in the treatment of multidrug resistant tuberculosis (MDR-TB) and extensive multidrug-resistant tuberculosis (XDR-TB). The current study is a single-center retrospective clinical analysis of hospitalized M/XDR-TB patients in Fukujuji Hospital involving 26 patients (18 men and 8 women) consecutively treated with combinations of anti-TB drugs including LZD from 2009 to 2015. The sputum culture results were negative after using LZD for an average period of 28.0 ± 12.0 (average ± SD) days. LZD was reduced or withdrawn in 11 cases due to adverse effects. Nineteen cases including 3 XDR-TB patients were operated on, and their TB was treated following surgery. The average time from the initiation of LZD therapy to surgery was 87.6 ± 38.7 (average ± SD) days. Favorable clinical outcome was maintained in 23 surviving patients, while 3 patients died during treatment because of end stage cancer and aspiration pneumonia. Our study showed that LZD might be clinically effective in the treatment of M/XDR-TB patients in Japan.

[THE FREQUENCIES AND MANAGEMENT OF ADVERSE REACTIONS IN MULTI-DRUG RESISTANT TUBERCULOSIS TREATMENT].

[Objectives] To investigate the adverse reactions of antimicrobial drugs in multidrug-resistant tuberculosis (MDR-TB) and extensively drug-resistant tuberculosis (XDR- TB) patients. [Results] Sixty-six patients with MDR-TB who have been treated from 2010 through 2014 were evaluated in the retro- spective analysis. Variety of adverse reactions including psychological reaction, central nervous system toxicity, ophthalmic toxicity, peripheral neurotoxicity, gastrointestinal reactions, hematologic abnormalities, musculoskeletal adverse effects, and endocrine disorder, were observed. However, there was no fatal case due to the adverse reactions of the anti-tubercu- losis drugs in this observation. [Conclusions] Drugs for MDR-TB and XDR-TB treatment are limited and the adverse reactions of drugs for MDR-TB and XDR-TB are not well-known. Therefore, the treatment may fail due to inappropriate management of adverse events. MDR-TB and XDR-TB should be treated by the experts of the adverse reactions of all anti-tuberculosis drugs.

Effective Mediastinal Lymphadenectomy for Esophageal Cancer Using Slender Tracheal Forceps in Prone Position Thoracoscopic Esophagectomy.

BACKGROUND/AIM: Adequate mediastinal lymphadenectomy during thoracoscopic esophagectomy (TE) requires an extensive operating field. In order to rectify this problem, we developed slender tracheal forceps that can pass through a 12-mm trocar. PATIENTS AND METHODS: TE in the prone position was performed in 58 patients with esophageal cancer using slender tracheal forceps. Perioperative and postoperative clinical data were compared against those of 61 patients who underwent transthoracic open esophagectomy (OE). RESULTS: The mean duration of thoracic manipulation was significantly longer in the TE than OE group: 226.2 versus 171.3 minutes (p<0.0001). Mean blood loss was significantly lower in the TE than OE group: 39.9 versus 176.8 g (p<0.0001). A mean of 23.4 mediastinal lymph nodes were dissected in the TE group and 25.1 in the OE group. The timing of extubation tended to be earlier in the TE group. Postoperative morbidity did not differ between groups. CONCLUSION: Slender tracheal forceps are acceptable for fine mediastinal lymphadenectomy in thoracoscopic surgery for esophageal cancer, and the technique could contribute to development of minimally invasive surgery.

Development of a prediction system for anti-tuberculosis drug-induced liver injury in Japanese patients.

Drug-induced liver injury (DILI) is a common adverse drug reaction in patients receiving antituberculosis (anti-TB) treatment. Among the anti-TB agents, isoniazid (INH) is the primary drug that causes hepatotoxicity in TB patients with DILI. Previous reports in several populations have consistently demonstrated an association between polymorphisms in the N-acetyltransferase 2 (NAT2) gene, which is responsible for INH hepatic metabolism, and a risk of DILI in TB patients. In this study, the genetic and baseline clinical data from 366 Japanese patients with TB (73 patients with DILI and 293 without DILI) were used to develop a system to predict DILI risk due to anti-TB agents. The distribution of the NAT2 acetylator status among the TB patients with DILI was 31 (42.5%), 29 (39.7%), and 13 (17.8%) for rapid, intermediate, and slow acetylators, respectively. A significant association was observed between NAT2 slow acetylators and DILI risk (odds ratio 4.32, 95% confidence interval 1.93-9.66, P value=5.56×10(-4)). A logistic regression model based on age and NAT2 genotype revealed that the area under the curve for the receiver-operating characteristic curve was 0.717. The findings demonstrated that slow NAT2 acetylator status is a significant predictor of the risk of DILI by anti-TB agents, and a personalized anti-TB treatment approach may aid in making treatment decisions and reducing the incidence of DILI.

Expression of DNA double-strand break repair proteins predicts the response and prognosis of colorectal cancer patients undergoing oxaliplatin-based chemotherapy.

DNA intrastrand cross-linking agents such as oxaliplatin induce DNA double-strand breaks (DSBs) during DNA repair and replication. In the present study, we hypothesized that DNA intrastrand cross-linking agents may significantly benefit colorectal cancer patients with deficiencies in DSB repair. Seventy-eight patients with metastatic or recurrent colorectal cancer who had measurable target lesions and who underwent resection for primary colorectal cancer in our institution between April 2007 and March 2013 were included in the present study. The median age was 64.5 years, and the cohort consisted of 49 males and 29 females. The median progression-free survival (PFS) was 10.9 months. The expression of DSB repair proteins such as RAD51 and MRE11 was investigated by immunohistochemistry, and associations between RAD51 and MRE11 expression and clinicopathological factors or chemotherapeutic effect were assessed. MRE11-negative cases and RAD51-negative cases achieved significantly better tumor reduction compared with cases with positive expression. Cases with negative expression of both proteins or negative expression of either protein had significantly longer PFS than cases with positive expression for both proteins. In conclusion, DSB repair protein expression-negative colorectal cancer cases may be more highly sensitive to chemotherapy, and thus DSB repair protein expression may be a useful prognostic indicator for colorectal cancer patients.

[CLINICO-MICROBIOLOGICAL CHARACTERISTICS OF MYCOBACTERIUM KANSASII PULMONARY DISEASE AT A SPECIALIZED MYCOBACTERIOSIS HOSPITAL IN TOKYO, JAPAN].

BACKGROUND: Mycobacterium kansasii is the second most common nontuberculous mycobacterial pulmonary disease pathogen in Japan. Fibrocavitary disease is characteristic of M. kansasii pulmonary disease in male patients. OBJECTIVE: To clarify the clinico-microbiological characteristics of M. kansasii pulmonary disease in recent years in a Tokyo hospital specializing in mycobacteriosis. METHODS: A retrospective chart review was performed on 77 M. kansasii culture-positive cases from January 2003 to December 2010. Sequence analysis of the hsp65 gene using PCR-restriction enzyme pattern analysis (hsp65-PRA) was used to identify bacterial genotypes. RESULTS: Seventy-four cases fulfilled the diagnostic criteria for inclusion. Female patients comprised 22% of cases (16 cases, 63.2 ± 24.6 years of age) and were older than male patients (58 cases, 55.5 ± 17.5 years of age). Although the peak distribution among men was patients in their 50s, female patients showed a bimodal distribution with increased occurrence in older women. Radiological examination showed that approximately 90% of male and younger female patients had fibrocavitary disease. However, elderly female patients tended to have nodular bronchiectatic disease. Genotype analysis revealed that all bacterial strains from both genders were subtype I. CONCLUSIONS: Compared to previous reports, the number of female patients with M. kansasii pulmonary disease had increased, with an unusual age distribution. These different age-related radiological findings might be due to host factors.

Poor nutritional status before and during chemotherapy leads to worse prognosis in unresectable advanced or recurrent colorectal cancer.

OBJECTIVE: This study aimed to clarify the relationship between host nutritional status prior to first-line chemotherapy and therapeutic effect, and, whether these nourishment indexes could become factors that predict long-term convalescence in unresectable advanced or recurrent colorectal cancer or not. Summary of Background Date: It has previously been reported that postoperative complications and long-term prognosis of patients with gastrointestinal malignancies may be affected by their nutritional status. But, there is little information regarding the relationship between prognosis, nutritional status and immunocompetence in unresectable progressive or recurrent colorectal cancer. METHODS: Ninety patients who had measurable target lesions underwent resection for primary colorectal cancer in our institution, between April 2007 and March 2013. The indicators of host nutritional status was body weight (BW), body mass index (BMI), serum albumin, Onodera's prognostic nutritional index (OPNI) and Glasgow Prognostic Score (GPS). The indicators of host immunocompetence was total lymphocyte counts, total neutrophil counts, granulocytes/lymphocytes ratio (G/L ratio). RESULTS: The median overall survival (OS) was 32.5 months, and the median progression-free survival was 10.9 months. The relative change of target lesions were associated with BW, BMI and OPNI. Furthermore, there was strong correlation between the change ratio of the serum CEA level before and after chemotherapy administration and BMI. BW, BMI, serum albumin level, OPNI and GPS were significantly associated with overall survival (OS). CONCLUSION: Poor nutritional status and suppressive immunocompetence is associated with ineffective chemotherapy.

[CLINICAL EFFECTS OF TREATMENT FOR MYCOBACTERIUM TUBERCULOSIS INFECTION IN PATIENTS AT A SPECIALIZED HOSPITAL IN 2011].

OBJECTIVE AND METHODS: We analyzed the clinical effects of treatment for Mycobacterium tuberculosis infection for 1 year in our specialized hospital in 2011. Two hundred and ninety-six (296) patients were admitted and received treatment. RESULTS: Two hundred and fifty-six patients (86.5%) were started on the standard treatment with 3 drugs (isoniazid [INH, rifampicin [RFP], and ethambutol [EB] or streptomycin [SM]) or 4 drugs (INH, RFP, EB or SM, and pyrazinamide [PZA]). One hundred and seventy-one patients (66.8%) continued receiving the standard treatment during the admission period. Of 160 cases who could continue 4 drugs, under 80 year-old patients were 127 cases (76.0%), but over 80 year-old patients were 33 cases (49.3%). The mean duration for negative conversion of sputum culture was 40.6 days. Liver dysfunction due to 4 drugs (INH, RFP, EB, and PZA) was noted in 8.5% of patients. Eighteen of the 296 patients had multi-drug resistant tuberculosis (MDR-TB). Each MDR-TB patient received individualized treatment. Moreover, 7 of the MDR-TB cases were treated surgically. DISCUSSION: Treatment of TB had taken long time, and some patients could not continue the treatment owing to the adverse effects of drugs. Hence, it is important to monitor adverse effects of drugs in each patient.