Recent Management of Patients with Advanced Epidermal Growth Factor Receptor Mutation Non-small Cell Lung Cancer: Role of Afatinib and Lesson Learned for Developing Countries.

Lung cancer is a devastating disease with a high incidence, mortality and morbidity rate, especially in developing countries. Conventional treatment with cytotoxic chemotherapy has some limitations attributed to chemoresistance and toxicity. Recent advances have shown that first generation Tyrosine Kinase Inhibitor (TKI), Gefitinib and Erlotinib, and the newest available second generation Tyrosine Kinase Inhibitor (TKI), Afatinib, have the potential to be an option in the management of patients with epidermal growth factor receptor/ EGFR mutation positive advanced/ metastatic non-small cell lung cancer. Afatinib works by binding to EGFR irreversibly, thus inactivating the tyrosine kinase receptor. Some studies demostrated that Afatinib first-line may result in longer progression free survival (PFS) and better disease control, and as an alternative for patients who intolerance to Gefitinib or Erlotinib. In Indonesia, the era of National Health Insurance has been implemented and National Health Insurance has covered treatment for cancer, including first generation TKIs, Gefitinib dan erlotinib, for patients with EGFR mutation positive advanced/ metastatic non-small cell lung cancer at Cipto Mangunkusumo National Hospital. Afatinib, as one of the newest available second generation TKI, may be given free of charge too as an alternative if the National Health Insurance will be covered in the future. Further research is needed to know the efficacy and adverse effects that may occur in patients from developing countries.

Prognostic Factors of 30-day Survival of Patients with Malignant Pleural Effusion.

BACKGROUND: Treatment of malignant pleural effusion (MPE) depends on the 1 month prognosis of patients. Until now, there is no study evaluate factors affecting 1 month survival. AIMS: This study aims to determine the predictors of survival within 1 month. METHODS: Prospective study of 102 patients with MPE. Biochemistry data of pleural fluid, characteristics of tumor, and massiveness of the effusion were analyzed to determine their effect on 30-day survival of the patients. Univariate analysis was performed using Chi-square. All prognostic factors that had P < 0.25 were included in multivariate analysis using Cox regression. RESULTS: Median age of patients was 51 years, most of them were female (56%). Common primary sites of tumor were lung (31%), breast (19%), and lymphatic tissue (11%). In univariate analysis, factors that have P < 0.25 were low glucose concentration in pleural fluid (P = 0.01), high lactate dehydrogenase concentration in pleural fluid (P = 0.25), and high risk tumor (P = 0.24). In multivariate analysis, only low glucose concentration was significantly related to poor survival within 1 month (hazard ratio 2.85 [1.10-7.61], P = 0.03). CONCLUSIONS: Low level of glucose in pleural fluid is an important factor related to 30-day survival in patients with MPE. It can be used to determine prognosis-based treatment objectively.

Obstructive Sleep Apnea and Atherosclerosis.

Obstructive sleep apnea (OSA) is a sleep respiratory disorder characterized by recurrent episodes of complete or partial airway obstruction, resulting in apneas or hypopneas. OSA could contribute to atherosclerosis through direct and indirect mechanisms. Endothelial dysfunction, sympathetic stimulation, and proinflammatory cytokine modulation caused by OSA play significant role to an atherosclesrotic event. Other risk factors of atherosclerosis like hypertension and diabetes mellitus also associated with OSA. Animal and clinical studies recently showed promising data to prove association between OSA, atherosclerosis, and its risk factors. However, provided data has not showed consistent result. In the future, demand of further research both basic and clinical sciences need to be fulfilled.

Short-term Survival of Acute Respiratory Distress Syndrome Patients at a Single Tertiary Referral Centre in Indonesia.

AIM: to identify the 28-day short-term survival rate in patients with acute respiratory distress syndrome (ARDS). METHODS: this is a retrospective cohort study conducted at a tertiary referral hospital in Jakarta, Indonesia. We conducted the study for 10 months and data was extracted from medical records between October 2015 and August 2016. The primary end point of the study was 28-day short-term survival rate using the initial date of ARDS diagnosis as the index time. Overall survival rate was analyzed using Kaplan-Meier test and multivariate Cox regression analysis. RESULTS: there were 101 ARDS subjects during 10 months of study. The overall rate of  28-day survival was 47.5% and the median time of survival was 10 days (95% CI 2.47-17.52). The survival rate in ARDS patients was reduced significantly at the first week after the diagnosis of ARDS was made, which indicated that the highest mortality occured in the first week. Subjects with APACHE II score of >20 had a hazard ratio (HR) of 2.45 (95% CI 1.40-4.28) and those with moderate-severe of ARDS had HR of 2.27 (95% CI 1.25-4.12). CONCLUSION: the short-term survival rate of ARDS in developing countries  including Indonesia is still low and early management with optimal treatment provided within the first week may improve the survival rate.

Profile and factors associated with mortality in mediastinal mass during hospitalization at Cipto Mangunkusumo Hospital, Jakarta.

AIM: to obtain characteristics, variations of the type of mass, diagnostic modalities, and mortality factors during hospitalization in patients with mediastinal mass at our institute during a 10-year period. METHODS: a case-control study was conducted, by browsing through the medical records of 113 mediastinal mass patients who were treated at Cipto Mangunkusumo Hospital, Jakarta, during a 10-year period (January 2000-December 2009). Factors associated with mortality, i.e; sepsis, septic shock, pneumonia, lung tuberculosis, superior vena cava syndrome, massive pleural effusion, pericard effusion, and respiratory failure were analyzed by logistic regresion multivariate analysis. RESULTS: two hundred and one mediastinal mass patients were diagnosed and treated at our institute, 113 medical records were available to be included in this study. There were 69 males and 44 females with the age range of 18-60 years. One-hundred and seven patients were symptomatic at presentation. Mediastinal tumor was the most common mediastinal mass found among the subjects. The most frequent mass location was in the anteriosuperior compartement. Chest X-ray imaging were able to detect 61 cases of mediastinal mass, while 42 patients underwent thoracotomy (open biopsy) to acquire histopathology diagnosis. The proportion of mortality during hospitalization reached 39.8%. Logistic regression multivariate analysis found sepsis (p=0.000), superior vena cava syndrome (p = 0.000), and massive pleural effusion (p=0.047), were significant factors associated with mortality during hospitalization. CONCLUSION: the clinical and radiologic features of mediastinal mass patients in our institute showed that mediastinal mass may resemble the symptoms of other diseases. Types and diagnostic modalities performed in our study differs from other studies previously reported in other countries with a high proportion of mortality during hospitalization.

Update on the role of intrapleural fibrinolytic therapy in the management of complicated parapneumonic effusions and empyema.

A parapneumonic effusion is the collection of exudative fluid in the pleural space associated with a concurrent pulmonary infection. Parapneumonic effusions account for approximately one-third of all effusions, and about 40% of patients with pneumonia develop a concomitant effusion. Patients with pneumonia who develop an effusion have an increased risk of morbidity and mortality. Some of the excess mortality is due to mismanagement of the parapneumonic effusion. Bacterial and white cell metabolism can rapidly turn a simple exudative parapneumonic effusion into a multiloculated purulent empyema with low pH and high lactate dehydrogenase levels. The optimal approach to treating parapneumonic effusions and pleural empyemas remains controversial. Accepted management consists of systemic antibiotics and drainage of the pleural cavity, which is achieved by either medical chest tube drainage or surgery. Several investigators have studied the efficacy and safety of intrapleural fibrinolytics in the treatment of pleural effusion and empyema. Intrapleural instillation of fibrinolytic agents is undertaken to dissolve fibrinous clots and membranes, to prevent fluid sequestration, and hence to improve drainage. Recombinant deoxyribonuclease has been reported to improve drainage in a single patient who did not respond to fibrinolytic therapy.

Low BALF CD4 T cells count is associated with extubation failure and mortality in critically ill covid-19 pneumonia.

BACKGROUND: Critically ill COVID-19 pneumonia is one of the main causes of extubation failure and mortality. Understanding clinical characteristics, laboratory profiles and bronchoalveolar lavage fluid (BALF) immunopathology may help improve outcomes in critically ill COVID-19 pneumonia. We aimed to describe clinical characteristics, laboratory profiles and BALF immunopathology based on lung severity in critically ill COVID-19 pneumonia patients. MATERIALS AND METHODS: Forty critically ill severe pneumonia patients requiring invasive mechanical ventilation in Cipto Mangunkusumo General (National Tertiary Referral Hospital), Indonesia within November 2020-January 2021 were enrolled in this study. Early BALF collection was performed after patients' intubation. Clinical characteristics, laboratory profiles and BALF biomarkers (sTREM-1, alveolar macrophage amount and function, IL-6, IL-17, CD4 T-cells, Tregs, SP-A and Caspase-3) were observed and analysed. Outcomes were measured based on extubation failure (within 19 days) and 28-days mortality. Univariate and bivariate analyses were performed. RESULTS: Early bronchoscopy was performed in an average of 4 h (SD = 0.82) after patients' intubation. Twenty-three and twenty-two patients had extubation failure (within 19 days) and 28-days mortality, respectively. In the baseline clinical characteristics of critically ill COVID-19 patients, we found no significant differences in the extubation and mortality status groups. In the laboratory profiles of critically ill COVID-19 patients, we found no significant differences in the extubation status groups. In critically ill COVID-19 pneumonia patients, there was a significant high D-dimer levels in survived group (p = .027), a significant low BALF CD4 T-cells count in the right lung (p = .001) and a significant low BALF CD4 T-cells count (p = .010 and p = .018) in severely affected lung with extubation failure and mortality. CONCLUSIONS: BALF CD4 T-cells count evaluation of severely affected lung is associated with early extubation failure and mortality in critically ill COVID-19 pneumonia patients. KEY MESSAGEFew studies have been conducted during the peak COVID-19 period analysing combined bronchoalveolar lavage fluid (BALF) immunopathology biomarkers within four hours of intubation to assess extubation failure and mortality. In this study, we reported eight BALF immunopathology biomarkers (sTREM-1, alveolar macrophage, IL-6, IL-17, CD4 T-cells, Tregs, SP-A and Caspase-3).We found significantly low BALF CD4 T-cells count in the right lung, and low BALF CD4 T-cells count in severely affected lung of critically ill COVID-19 pneumonia patients in extubation failure and mortality.

Thymoma: Diagnosis and treatment.

Mediastinal tumors are tumors inside the mediastinum, i.e. the cavity between the left and right lungs. Overseas literatures suggest that the most common anterior mediastinal tumors found are lymphoma, thymoma and germ cell tumor. Thymoma accounts for 20% of mediastinal tumor and is the most common anterior mediastinal tumor reaching approximately 50% of all tumors in adults. Ninety percent of all thymomas are located in the anterior mediastinum and some of them occur at the neck region or other mediastinal areas. Surgery still becomes the main treatment followed by adjuvant radiation for invasive thymoma. For inoperable patients, induction chemotherapy followed by a surgical reassessment post-therapy, and adjuvant radiation therapy is generally recommended, in spite of the lacking prospective studies for such treatment. Durable responses can be obtained both in the metastatic and recurrent condition, and various novel therapies are currently being studied.

Recent insight into potential acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is an acute inflammatory lung injury, characterized by increased pulmonary capillary endothelial cells and alveolar epithelial cells permeability leading to respiratory failure in the absence of cardiac failure. Despite recent advances in treatments, the overall mortality because of ARDS remains high. Biomarkers may help to diagnose, predict the severity, development, and outcome of ARDS in order to improve patient care and decrease morbidity and mortality. This review will focus on soluble receptor for advanced glycation end-products, soluble tumor necrosis factor-receptor 1, Interluken-6 (IL-6), IL-8, and plasminogen activator inhibitor-1, which have a greater potential based on recent studies.

Clinical tuberculosis problems and management.

Tuberculosis (TB) is a chronic disease caused by M. tuberculosis. WHO (World Health Organization) 1993 has estimated that one third of world population has been infected by M. tuberculosis bacillus. It is also estimated that 8 million people contract the disease annually and two to three million deaths occur every year due to TB. Major factors that have aggravated the spread of TB are: 1) ineffective TB control programs, leading to the development of multi drug resistant bacilli, 2) co infection with HIV (human immunodeficiency virus) where TB progress rapidly and deadly,3) existence of other co-morbid that need higher expert (Internist etc). Vaccination with BCG does not seem to protect the adult population consistently and effectively from developing pulmonary TB, and has had no significant impact on the global TB epidemiology. Tuberculosis in Indonesia results in high death rate because it is the second highest infection with national prevalence rate of 0.24%. Effective medicine standard of anti-tuberculosis is available, but many obstacles in the program from lack of knowledge among health officers, low consciousness and compliances of person with tuberculosis to carry out the treatment schedule and so on make the success of TB eradication unsatisfied. Clinical appearances of TB are multiple with non-specific symptoms, the cases that are exposed to similar source of infection but will show different clinical consequence from mild to severe. Nevertheless, with the rise of multi drug resistance strains of M. tuberculosis, the spread of HIV infection and the variation of BCG efficacy, the search for more powerful drugs, more effective vaccines, better diagnostics and other intervention strategies have become an urgent goal worldwide. Also written here how to diagnose, choose of category of treatment, cocktail anti TB according the category and some clue in handling problems during treatment.

The effect of vitamin D as supplementary treatment in patients with moderately advanced pulmonary tuberculous lesion.

AIM: to compare the vitamin D group of pulmonary tuberculosis patients with a placebo group in terms of clinical improvement, nutritional status, sputum conversion, and radiological improvement. METHODS: sixty seven tuberculosis patient visiting the Pulmonary Clinic, of Cipto Mangunkusumo Hospital, Jakarta, from January 1st to August 31st, 2001 were included in this study. The subjects were randomised to receive vitamin D (0.25 mg/day) or placebo in a double blind method, during the 6th initial week of Tb treatment. The rate of sputum conversion, complete blood counts, blood chemistry as well as radiologic examination were evaluated. RESULTS: there were more male patients than females (39:28), 78.7% were in the productive age group, 71.6% had low nutritional status, 62.4% with low education level, and 67.2% with low income. One hundred percent of the vitamin D group and only 76.7% of the placebo group had sputum conversion. This difference is statistically significant (p=0.002). CONCLUSION: the sputum conversion had no correlation with the hemoglobin level, blood clotting time, calcium level, lymphocyte count, age, sex, and nutritional status. There were more subjects with radiological improvement in the vitamin D group.

Hepatopulmonary Syndrome: A Brief Review.

Hepatopulmonary syndrome (HPS) is a pulmonary complication of liver disease characterized by arterial hypoxemia. Mechanisms related to this event are diffusion-perfusion flaw, ventilation-perfusion (V/Q) mismatch, and direct arteriovenous shunts. Diagnosis of HPS is based on the presence of liver disease or portal hypertension, increased alveolar-arterial (A-a) PO2, and intrapulmonary vascular dilatations (IPVD). Lung transplantation (LT) remains the most effective therapy for HPS. In spite of its poor prognosis, we could improve the quality of life and survival rate of patients.

A double-blind, placebo-controlled study of vitamin A and zinc supplementation in persons with tuberculosis in Indonesia: effects on clinical response and nutritional status.

BACKGROUND: The results of cross-sectional studies indicate that micronutrient deficiencies are common in patients with tuberculosis. No published data exist on the effect of vitamin A and zinc supplementation on antituberculosis treatment. OBJECTIVE: Our goal was to investigate whether vitamin A and zinc supplementation increases the efficacy of antituberculosis treatment with respect to clinical response and nutritional status. DESIGN: In this double-blind, placebo-controlled trial, patients with newly diagnosed tuberculosis were divided into 2 groups. One group (n = 40) received 1500 retinol equivalents (5000 IU) vitamin A (as retinyl acetate) and 15 mg Zn (as zinc sulfate) daily for 6 mo (micronutrient group). The second group (n = 40) received a placebo. Both groups received the same antituberculosis treatment recommended by the World Health Organization. Clinical examinations, assessments of micronutrient status, and anthropometric measurements were carried out before and after 2 and 6 mo of antituberculosis treatment. RESULTS: At baseline, 64% of patients had a body mass index (in kg/m(2)) < 18.5, 32% had plasma retinol concentrations < 0.70 micromol/L, and 30% had plasma zinc concentrations < 10.7 micromol/L. After antituberculosis treatment, plasma zinc concentrations were not significantly different between groups. Plasma retinol concentrations were significantly higher in the micronutrient group than in the placebo group after 6 mo (P < 0.05). Sputum conversion (P < 0.05) and resolution of X-ray lesion area (P < 0.01) occurred earlier in the micronutrient group. CONCLUSION: Vitamin A and zinc supplementation improves the effect of tuberculosis medication after 2 mo of antituberculosis treatment and results in earlier sputum smear conversion.

Cytokines related to nutritional status in patients with untreated pulmonary tuberculosis in Indonesia.

Although several studies have dealt with the patterns of cytokine production in tuberculosis, little is known about the association between nutrient deficiencies and cytokines in tuberculosis. The objective of this study was to assess the concentration of cytokines related to nutritional status during tuberculosis. In 41 untreated tuberculosis patients and matched healthy controls in an urban hospital in Indonesia, we measured: height and weight, parameters of iron, vitamin A and zinc; and cytokines concentrations in the circulation and production in whole blood cultures. Plasma interleukin-6 (IL-6) and interleukin-1 receptor antagonist (IL-1ra) were significantly higher in patients than in controls. Patients with cavities (n=26) had higher concentrations of IL-6 than patients without cavities (n=15). Body mass index <18.5 kg/m2 was associated with high concentrations of tumor necrosis factor-alpha (TNF-alpha) and IL-6. Anaemia was associated with high concentrations of IL-6 and IL-1ra. Zinc deficiency was associated with high LPS-stimulated production of TNF-alpha and IL-1ra. Marginal plasma retinol concentrations were associated with high concentrations of IL-6 after LPS stimulation. In conclusion, low concentrations of micronutrients in tuberculosis were associated with increased cytokine production. An intervention study would allow causality to be examined.