Osimertinib with or without Chemotherapy in EGFR-Mutated Advanced NSCLC.

BACKGROUND: Osimertinib is a third-generation epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) that is selective for EGFR-TKI-sensitizing and EGFR T790M resistance mutations. Evidence suggests that the addition of chemotherapy may extend the benefits of EGFR-TKI therapy. METHODS: In this phase 3, international, open-label trial, we randomly assigned in a 1:1 ratio patients with EGFR-mutated (exon 19 deletion or L858R mutation) advanced non-small-cell lung cancer (NSCLC) who had not previously received treatment for advanced disease to receive osimertinib (80 mg once daily) with chemotherapy (pemetrexed [500 mg per square meter of body-surface area] plus either cisplatin [75 mg per square meter] or carboplatin [pharmacologically guided dose]) or to receive osimertinib monotherapy (80 mg once daily). The primary end point was investigator-assessed progression-free survival. Response and safety were also assessed. RESULTS: A total of 557 patients underwent randomization. Investigator-assessed progression-free survival was significantly longer in the osimertinib-chemotherapy group than in the osimertinib group (hazard ratio for disease progression or death, 0.62; 95% confidence interval [CI], 0.49 to 0.79; P<0.001). At 24 months, 57% (95% CI, 50 to 63) of the patients in the osimertinib-chemotherapy group and 41% (95% CI, 35 to 47) of those in the osimertinib group were alive and progression-free. Progression-free survival as assessed according to blinded independent central review was consistent with the primary analysis (hazard ratio, 0.62; 95% CI, 0.48 to 0.80). An objective (complete or partial) response was observed in 83% of the patients in the osimertinib-chemotherapy group and in 76% of those in the osimertinib group; the median response duration was 24.0 months (95% CI, 20.9 to 27.8) and 15.3 months (95% CI, 12.7 to 19.4), respectively. The incidence of grade 3 or higher adverse events from any cause was higher with the combination than with monotherapy - a finding driven by known chemotherapy-related adverse events. The safety profile of osimertinib plus pemetrexed and a platinum-based agent was consistent with the established profiles of the individual agents. CONCLUSIONS: First-line treatment with osimertinib-chemotherapy led to significantly longer progression-free survival than osimertinib monotherapy among patients with EGFR-mutated advanced NSCLC. (Funded by AstraZeneca; FLAURA2 ClinicalTrials.gov number, NCT04035486.).

Atezolizumab for First-Line Treatment of PD-L1-Selected Patients with NSCLC.

BACKGROUND: The efficacy and safety of the anti-programmed death ligand 1 (PD-L1) monoclonal antibody atezolizumab, as compared with those of platinum-based chemotherapy, as first-line treatment for patients with metastatic non-small-cell lung cancer (NSCLC) with PD-L1 expression are not known. METHODS: We conducted a randomized, open-label, phase 3 trial involving patients with metastatic nonsquamous or squamous NSCLC who had not previously received chemotherapy and who had PD-L1 expression on at least 1% of tumor cells or at least 1% of tumor-infiltrating immune cells as assessed by the SP142 immunohistochemical assay. Patients were assigned in a 1:1 ratio to receive atezolizumab or chemotherapy. Overall survival (primary end point) was tested hierarchically according to PD-L1 expression status among patients in the intention-to-treat population whose tumors were wild-type with respect to EGFR mutations or ALK translocations. Within the population with EGFR and ALK wild-type tumors, overall survival and progression-free survival were also prospectively assessed in subgroups defined according to findings on two PD-L1 assays as well as by blood-based tumor mutational burden. RESULTS: Overall, 572 patients were enrolled. In the subgroup of patients with EGFR and ALK wild-type tumors who had the highest expression of PD-L1 (205 patients), the median overall survival was longer by 7.1 months in the atezolizumab group than in the chemotherapy group (20.2 months vs. 13.1 months; hazard ratio for death, 0.59; P = 0.01). Among all the patients who could be evaluated for safety, adverse events occurred in 90.2% of the patients in the atezolizumab group and in 94.7% of those in the chemotherapy group; grade 3 or 4 adverse events occurred in 30.1% and 52.5% of the patients in the respective groups. Overall and progression-free survival favored atezolizumab in the subgroups with a high blood-based tumor mutational burden. CONCLUSIONS: Atezolizumab treatment resulted in significantly longer overall survival than platinum-based chemotherapy among patients with NSCLC with high PD-L1 expression, regardless of histologic type. (Funded by F. Hoffmann-La Roche/Genentech; IMpower110 ClinicalTrials.gov number, NCT02409342.).

Utility of prophylactic percutaneous endoscopic gastrostomy tube in head and neck cancer patients undergoing concurrent chemoradiation: A prospective observational cohort.

PURPOSE: The necessity of prophylactic percutaneous endoscopic gastrostomy (PPEG) before concurrent chemoradiation (CCRT) in head and neck cancer (HNC) patients remains uncertain. We evaluated the utilization rate of PPEG tube. Weight changes and tube dependence were also assessed. MATERIALS AND METHODS: This prospective cohort study evaluated the utilization rate of PPEG tube in patients with newly diagnosed HNC undergoing CCRT. Baseline characteristics, nutrition status, and weight loss data were collected and compared between use and non-use groups. RESULTS: 110 patients (94.8%) used PPEG tube (70 fully-used and 40 partially-used groups). Non-users had a tendency to lose weight more than partially and fully-used groups; 9.13%, 3.42%, and 1.95%, respectively (p = 0.085). Fully-used group had significantly longer time of tube dependence than partially-used group, 7.0 months versus 4.9 months (p = 0.012). The type of PPEG tube use (full use or partial use) and presence of dysphagia were significantly related to tube dependence. The time ratio of tube dependence for partially-used patients versus fully-used patients was 0.82 (95% CI: 0.68-0.99) (p = 0.039). The time ratio for patients with symptoms of dysphagia was 1.29 (95% CI: 1.02-1.63) (p = 0.032). At the end of CCRT, 96.6% of patients agreed that PPEG tube was necessary. CONCLUSION: We recommend PPEG for patients undergoing CCRT. Partial use of PPEG with continuous oral intake as tolerated is strongly encouraged to maintain weight, and to reduce risk of tube dependence. Future study to evaluate effective swallowing exercise is warranted.

Benefits of prophylactic percutaneous gastrostomy in patients with nasopharyngeal cancer receiving concurrent chemoradiotherapy: A multicenter analysis.

PURPOSE: Prophylactic percutaneous endoscopic gastrostomy (PPEG) is widely used for patients with head and neck cancer undergoing concurrent chemoradiation (CCRT). Nevertheless, the necessity of its use in patients with nasopharyngeal cancer (NPC) is uncertain. This study aimed to evaluate the benefits of PPEG on prevention of weight loss and treatment tolerance in patients with NPC receiving CCRT. MATERIALS AND METHODS: A retrospective multicenter chart review of 904 patients, 378 in the PPEG group and 526 in the non-PPEG group, was conducted. Baseline characteristics, weight loss, and treatment tolerance were analyzed and compared between the two groups. RESULTS: There was no significant difference in the mean baseline body mass index (BMI) between the groups. At the end of CCRT, no difference in weight loss was found between the 2 groups (non-PPEG group, 6.6%; PPEG group, 5.9%). Nonetheless, the subgroup analysis demonstrated that a baseline BMI < 18.5 kg/m2 (underweight) and non-intensity-modulated radiation therapy (IMRT) technique were independent factors associated with prevention of weight loss by PPEG. More patients in the PPEG group were able to complete planned cycles of chemotherapy (73.3% vs. 49.0%, P < .0001). CONCLUSION: Although the benefits of PPEG on prevention of weight loss were not observed for the entire cohort, we found a potentially protective effect of PPEG in some subgroups of patients. Additionally, PPEG significantly enhanced chemotherapy tolerance. Therefore, PPEG tube insertion should be strongly considered for patients with NPC receiving CCRT, particularly for underweight patients and those undergoing a non-IMRT technique.

First-line ceritinib versus platinum-based chemotherapy in advanced ALK-rearranged non-small-cell lung cancer (ASCEND-4): a randomised, open-label, phase 3 study.

BACKGROUND: The efficacy of ceritinib in patients with untreated anaplastic lymphoma kinase (ALK)-rearranged non-small-cell lung cancer (NSCLC) is not known. We assessed the efficacy and safety of ceritinib versus platinum-based chemotherapy in these patients. METHODS: This randomised, open-label, phase 3 study in untreated patients with stage IIIB/IV ALK-rearranged non-squamous NSCLC was done in 134 centres across 28 countries. Eligible patients were assigned via interactive response technology to oral ceritinib 750 mg/day or platinum-based chemotherapy ([cisplatin 75 mg/m2 or carboplatin AUC 5-6 plus pemetrexed 500 mg/m2] every 3 weeks for four cycles followed by maintenance pemetrexed); randomisation was stratified by World Health Organization performance status (0 vs 1-2), previous neoadjuvant or adjuvant chemotherapy, and presence of brain metastases as per investigator's assessment at screening. Investigators and patients were not masked to treatment assignment. The primary endpoint was blinded independent review committee assessed progression-free survival, based on all randomly assigned patients (the full analysis set). Efficacy analyses were done based on the full analysis set. All safety analyses were done based on the safety set, which included all patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov, number NCT01828099. FINDINGS: Between Aug 19, 2013, and May 11, 2015, 376 patients were randomly assigned to ceritinib (n=189) or chemotherapy (n=187). Median progression-free survival (as assessed by blinded independent review committee) was 16·6 months (95% CI 12·6-27·2) in the ceritinib group and 8·1 months (5·8-11·1) in the chemotherapy group (hazard ratio 0·55 [95% CI 0·42-0·73]; p<0·00001). The most common adverse events were diarrhoea (in 160 [85%] of 189 patients), nausea (130 [69%]), vomiting (125 [66%]), and an increase in alanine aminotransferase (114 [60%]) in the ceritinib group and nausea (in 97 [55%] of 175 patients), vomiting (63 [36%]), and anaemia (62 [35%]) in the chemotherapy group. INTERPRETATION: First-line ceritinib showed a statistically significant and clinically meaningful improvement in progression-free survival versus chemotherapy in patients with advanced ALK-rearranged NSCLC. FUNDING: Novartis Pharmaceuticals Corporation.

Clinical activity of afatinib in patients with advanced non-small-cell lung cancer harbouring uncommon EGFR mutations: a combined post-hoc analysis of LUX-Lung 2, LUX-Lung 3, and LUX-Lung 6.

BACKGROUND: Most patients with non-small-cell lung cancer tumours that have EGFR mutations have deletion mutations in exon 19 or the Leu858Arg point mutation in exon 21, or both (ie, common mutations). However, a subset of patients (10%) with mutations in EGFR have tumours that harbour uncommon mutations. There is a paucity of data regarding the sensitivity of these tumours to EGFR inhibitors. Here we present data for the activity of afatinib in patients with advanced non-small-cell lung cancer that have tumours harbouring uncommon EGFR mutations. METHODS: In this post-hoc analysis, we used prospectively collected data from tyrosine kinase inhibitor-naive patients with EGFR mutation-positive advanced (stage IIIb-IV) lung adenocarcinomas who were given afatinib in a single group phase 2 trial (LUX-Lung 2), and randomised phase 3 trials (LUX-Lung 3 and LUX-Lung 6). Analyses were done in the intention-to-treat population, including all randomly assigned patients with uncommon EGFR mutations. The type of EGFR mutation (exon 19 deletion [del19], Leu858Arg point mutation in exon 21, or other) and ethnic origin (LUX-Lung 3 only; Asian vs non-Asian) were pre-specified stratification factors in the randomised trials. We categorised all uncommon mutations as: point mutations or duplications in exons 18-21 (group 1); de-novo Thr790Met mutations in exon 20 alone or in combination with other mutations (group 2); or exon 20 insertions (group 3). We also assessed outcomes in patients with the most frequent uncommon mutations, Gly719Xaa, Leu861Gln, and Ser768Ile, alone or in combination with other mutations. Response was established by independent radiological review. These trials are registered with ClinicalTrials.gov, numbers NCT00525148, NCT00949650, and NCT01121393. FINDINGS: Of 600 patients given afatinib across the three trials, 75 (12%) patients had uncommon EGFR mutations (38 in group 1, 14 in group 2, 23 in group 3). 27 (71·1%, 95% CI 54·1-84·6) patients in group 1 had objective responses, as did two (14·3%, 1·8-42·8) in group 2 and two (8·7%, 1·1-28·0) in group 3. Median progression-free survival was 10·7 months (95% CI 5·6-14·7) in group 1, 2·9 months (1·2-8·3) in group 2; and 2·7 months (1·8-4·2) in group 3. Median overall survival was 19·4 months (95% CI 16·4-26·9) in group 1, 14·9 months (8·1-24·9) in group 2, and 9·2 months (4·1-14·2) in group 3. For the most frequent uncommon mutations, 14 (77·8%, 95% CI 52·4-93·6) patients with Gly719Xaa had an objective response, as did nine (56·3%, 29·9-80·2) with Leu861Gln, and eight (100·0%, 63·1-100·0) with Ser768Ile. INTERPRETATION: Afatinib was active in non-small-cell lung cancer tumours that harboured certain types of uncommon EGFR mutations, especially Gly719Xaa, Leu861Gln, and Ser768Ile, but less active in other mutations types. Clinical benefit was lower in patients with de-novo Thr790Met and exon 20 insertion mutations. These data could help inform clinical decisions for patients with non-small-cell lung cancer harbouring uncommon EGFR mutations. FUNDING: Boehringer Ingelheim.

Afatinib versus cisplatin-based chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials.

BACKGROUND: We aimed to assess the effect of afatinib on overall survival of patients with EGFR mutation-positive lung adenocarcinoma through an analysis of data from two open-label, randomised, phase 3 trials. METHODS: Previously untreated patients with EGFR mutation-positive stage IIIB or IV lung adenocarcinoma were enrolled in LUX-Lung 3 (n=345) and LUX-Lung 6 (n=364). These patients were randomly assigned in a 2:1 ratio to receive afatinib or chemotherapy (pemetrexed-cisplatin [LUX-Lung 3] or gemcitabine-cisplatin [LUX-Lung 6]), stratified by EGFR mutation (exon 19 deletion [del19], Leu858Arg, or other) and ethnic origin (LUX-Lung 3 only). We planned analyses of mature overall survival data in the intention-to-treat population after 209 (LUX-Lung 3) and 237 (LUX-Lung 6) deaths. These ongoing studies are registered with ClinicalTrials.gov, numbers NCT00949650 and NCT01121393. FINDINGS: Median follow-up in LUX-Lung 3 was 41 months (IQR 35-44); 213 (62%) of 345 patients had died. Median follow-up in LUX-Lung 6 was 33 months (IQR 31-37); 246 (68%) of 364 patients had died. In LUX-Lung 3, median overall survival was 28.2 months (95% CI 24.6-33.6) in the afatinib group and 28.2 months (20.7-33.2) in the pemetrexed-cisplatin group (HR 0.88, 95% CI 0.66-1.17, p=0.39). In LUX-Lung 6, median overall survival was 23.1 months (95% CI 20.4-27.3) in the afatinib group and 23.5 months (18.0-25.6) in the gemcitabine-cisplatin group (HR 0.93, 95% CI 0.72-1.22, p=0.61). However, in preplanned analyses, overall survival was significantly longer for patients with del19-positive tumours in the afatinib group than in the chemotherapy group in both trials: in LUX-Lung 3, median overall survival was 33.3 months (95% CI 26.8-41.5) in the afatinib group versus 21.1 months (16.3-30.7) in the chemotherapy group (HR 0.54, 95% CI 0.36-0.79, p=0.0015); in LUX-Lung 6, it was 31.4 months (95% CI 24.2-35.3) versus 18.4 months (14.6-25.6), respectively (HR 0.64, 95% CI 0.44-0.94, p=0.023). By contrast, there were no significant differences by treatment group for patients with EGFR Leu858Arg-positive tumours in either trial: in LUX-Lung 3, median overall survival was 27.6 months (19.8-41.7) in the afatinib group versus 40.3 months (24.3-not estimable) in the chemotherapy group (HR 1.30, 95% CI 0.80-2.11, p=0.29); in LUX-Lung 6, it was 19.6 months (95% CI 17.0-22.1) versus 24.3 months (19.0-27.0), respectively (HR 1.22, 95% CI 0.81-1.83, p=0.34). In both trials, the most common afatinib-related grade 3-4 adverse events were rash or acne (37 [16%] of 229 patients in LUX-Lung 3 and 35 [15%] of 239 patients in LUX-Lung 6), diarrhoea (33 [14%] and 13 [5%]), paronychia (26 [11%] in LUX-Lung 3 only), and stomatitis or mucositis (13 [5%] in LUX-Lung 6 only). In LUX-Lung 3, neutropenia (20 [18%] of 111 patients), fatigue (14 [13%]) and leucopenia (nine [8%]) were the most common chemotherapy-related grade 3-4 adverse events, while in LUX-Lung 6, the most common chemotherapy-related grade 3-4 adverse events were neutropenia (30 [27%] of 113 patients), vomiting (22 [19%]), and leucopenia (17 [15%]). INTERPRETATION: Although afatinib did not improve overall survival in the whole population of either trial, overall survival was improved with the drug for patients with del19 EGFR mutations. The absence of an effect in patients with Leu858Arg EGFR mutations suggests that EGFR del19-positive disease might be distinct from Leu858Arg-positive disease and that these subgroups should be analysed separately in future trials. FUNDING: Boehringer Ingelheim.

Cerebral venous thrombosis: comparing characteristics of infective and non-infective aetiologies: a 12-year retrospective study.

BACKGROUND: Most cases of cerebral venous thrombosis (CVT) have non-infective causes. Infective CVT, though less common, often results in a catastrophic outcome. The distinctive clinical characteristics of infection-associated CVT (IACVT) and non-infection-associated CVT (NIACVT) would facilitate early detection and proper management. OBJECTIVE: To compare the characteristics of IACVT and NIACVT. METHODS: All patients with CVT admitted to Songklanagarind Hospital between January 2002 and December 2013 with the ICD10 codes I636, I676, O225 and G08 were identified and recruited. We compared the clinical presentations, neuroimaging results and hospital outcomes for patients with IACVT and those with NIACVT. We analysed the differences using descriptive statistics. Additionally, for patients with IACVT, we described the primary sites of infection, associated CVT, host immune status and microbiological results. RESULTS: Twenty of the 83 patients with CVT (24.1%) had IACVT. Male gender (70.0% vs 34.9%) and pre-existing diabetes mellitus (35.0% vs 4.8%) were significantly more prevalent in the IACVT than the NIACVT group. Additionally, cavernous sinus thrombosis predominated in IACVT (80.0% vs 11.1%), whereas focal neurological syndrome was more common among patients with NIACVT (50.8% vs 15.0%). Paracranial infections, mostly sinusitis and orbital cellulitis, were common primary infections (80.0%) among patients with IACVT. Lastly, fungus was a devastating causative pathogen in IACVT-five of six patients with fungal infection had intracranial complications. CONCLUSIONS: Cavernous sinus thrombosis is a distinctive clinical presentation of IACVT, whereas focal neurological syndrome is a hallmark feature of NIACVT. Paracranial fungal infections are highly virulent and frequently associated with intracranial complications.

Transthoracic imaging-guided biopsy of lung lesions: evaluation of benign non-specific pathologic diagnoses.

OBJECTIVE: Explore the definitive diagnoses of imaging-guided transthoracic needle biopsies (TNB) with a pathological result of benign non-specific diagnosis in a tuberculosis-endemic area. The secondary goal was to characterize the initial CT imaging findings between malignancy and benign lesions. MATERIAL AND METHOD: All TNB diagnoses considered to have benign non-specific features at the Radiology Department between January 2007 andDecember 2011 were retrospectively reviewedfor definitive diagnosis based on clinical impressions andfor CT imaging characteristics. RESULTS: Sixty-seven cases with TNB were given a benign non-specific diagnosis and had complete pathologic or radiologic follow-ups. Of these 67 cases, 16 (23.9%) were malignant and 51 were benign. Two main definitive diagnoses of benign cases were pulmonary tuberculosis (32.8%) and pneumonia/lung abscess (23.9%). On the CT images, most of lesions in the group of pulmonary tuberculosis (14/22, 63.6%) were not enhanced after contrast administration (p < 0.005), and necrotic mediastinal lymph nodes were significantly found more in final malignancy diagnoses (p < 0.005). CONCLUSION: The definitive diagnoses of benign non-specific diagnoses based on TNB in this tuberculosis-endemic area had a high rate of both malignancy and pulmonary tuberculosis. Hence, repeated biopsies or radiological follow-ups are advised.

Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial.

BACKGROUND: Afatinib-an oral irreversible ErbB family blocker-improves progression-free survival compared with pemetrexed and cisplatin for first-line treatment of patients with EGFR mutation-positive advanced non-small-cell lung cancer (NSCLC). We compared afatinib with gemcitabine and cisplatin-a chemotherapy regimen widely used in Asia-for first-line treatment of Asian patients with EGFR mutation-positive advanced NSCLC. METHODS: This open-label, randomised phase 3 trial was done at 36 centres in China, Thailand, and South Korea. After central testing for EGFR mutations, treatment-naive patients (stage IIIB or IV cancer [American Joint Committee on Cancer version 6], performance status 0-1) were randomly assigned (2:1) to receive either oral afatinib (40 mg per day) or intravenous gemcitabine 1000 mg/m(2) on day 1 and day 8 plus cisplatin 75 mg/m(2) on day 1 of a 3-week schedule for up to six cycles. Randomisation was done centrally with a random number-generating system and an interactive internet and voice-response system. Randomisation was stratified by EGFR mutation (Leu858Arg, exon 19 deletions, or other; block size three). Clinicians and patients were not masked to treatment assignment, but the independent central imaging review group were. Treatment continued until disease progression, intolerable toxic effects, or withdrawal of consent. The primary endpoint was progression-free survival assessed by independent central review (intention-to-treat population). This study is registered with ClinicalTrials.gov, NCT01121393. FINDINGS: 910 patients were screened and 364 were randomly assigned (242 to afatinib, 122 to gemcitabine and cisplatin). Median progression-free survival was significantly longer in the afatinib group (11·0 months, 95% CI 9·7-13·7) than in the gemcitabine and cisplatin group (5·6 months, 5·1-6·7; hazard ratio 0·28, 95% CI 0·20-0·39; p<0·0001). The most common treatment-related grade 3 or 4 adverse events in the afatinib group were rash or acne (35 [14·6%] of 239 patients), diarrhoea (13 [5·4%]), and stomatitis or mucositis (13 [5·4%]), compared with neutropenia (30 [26·5%] of 113 patients), vomiting (22 [19·5%]), and leucopenia (17 [15·0%]) in the gemcitabine and cisplatin group. Treatment-related serious adverse events occurred in 15 (6·3%) patients in the afatinib group and nine (8·0%) patients in the gemcitabine and cisplatin group. INTERPRETATION: First-line afatinib significantly improves progression-free survival with a tolerable and manageable safety profile in Asian patients with EGFR mutation-positive advanced lung NSCLC. Afatinib should be considered as a first-line treatment option for this patient population. FUNDING: Boehringer Ingelheim.

Predictors of hospital outcome in patients with cerebral venous thrombosis.

BACKGROUND: The studies regarding clinical presentations, risk factors, and outcomes of cerebral venous thrombosis (CVT) in Thai people are scarce. This study aims to identify predictors of hospital outcomes among the Thai patients with CVT. METHODS: Patients diagnosed with CVT in Songklanagarind Hospital from January 2002 to December 2013 were identified from computerized medical record system. Demographic data, clinical presentations, associated factors, method of neuroimaging studies and results, treatment, and hospital outcomes were presented by descriptive statistics. Predictors of hospital outcomes were analyzed by both univariate and multivariate logistic regression analysis. RESULTS: There were 90 patients with a diagnosis of CVT. The mean age (± standard deviation) was 41.22 (± 17.13) years (range, 15-80). The common clinical presentations were focal neurologic deficits (36.7%), seizure (33.3%), and cavernous sinus syndrome (32.2%). The common associated conditions were intracranial or paracranial infections (30.0%) and cancer (11.1%). Intracranial hemorrhage was found in 33 patients (36.7%). Forty-seven patients (52.2%) were dependent or death (Modified Rankin Scale [mRS], 3-6) on hospital discharge. Eleven patients (12.2%) were dead, of which 7 cases (7.78%) were CVT-related deaths. The independent predictors of dependency or death (mRS, 3-6) identified by multivariate logistic regression analysis were focal neurologic (odds ratio [OR], 14.26; 95% confidence interval [CI], 2.28-89.04; P = .001), mRS score of 3-5 on admission (OR, 35.26; 95% CI, 7.30-170.42; P = .000), and seizure (OR, .19; 95% CI, .03-1.02; P = .037). CONCLUSIONS: Focal neurologic deficit and severely disabled patients (mRS, 3-5) on admission were independent predictors of dependency or death in CVT patients. However, seizure predicted the lower incidence of dependency or death. The characteristic findings of CVT among Thai patients were the higher incidence of cavernous sinus syndrome and rhinosinal or intracranial infection.

Outcome of ultrasound-guided small-bore catheter drainage in exudative pleural effusions.

OBJECTIVE: To evaluate the outcome and safety of ultrasound-guided percutaneous catheter drainage of exudative pleural effusion. MATERIAL AND METHOD: The present study was a retrospective analysis of 412 pleural effusions from 373 patients that underwent ultrasound-guided small-bore catheter drainage in exudative pleural effusions between 2004 and 2009. RESULTS: The two most common causes for drainage were parapneumonic effusion or empyema (52.2%) and malignant effusion (30.3%), while the remains were trauma, iatrogenic, and others. Overall clinical success rate was 76.5%. The success rate was lower among malignant pleural effusion (p = 0.003). Causes of effusion were the only independent predictors related to success. Only five (1.2%) patients developed complication during the procedure. Seventy-five of 412 effusions (15.8%) developed complication during the period of drainage; the majority were drain blockage (9%) and accidental dislodgment (4.1%). CONCLUSION: Ultrasound-guided small-bore catheter drainage was a safe and efficient procedure for exudative pleural effusions.

Blood Eosinophil Count Stability and Clinical Outcomes in Patients With Chronic Obstructive Pulmonary Disease in a High Endemic Area of Parasitic Infection: A Prospective Study.

Background: The blood eosinophil count (BEC) is an effective biomarker for predicting inhaled corticosteroid responsiveness in patients with chronic obstructive pulmonary disease (COPD). Methods: A 12-month prospective observational study was conducted in patients with COPD. BEC was measured at enrolment, and after 6 and 12 months. Patients were classified into three groups according to their baseline BEC: <100, 100 - 299, and ≥300 cells/µL. We aimed to describe the patterns of blood eosinophil stability in patients with stable COPD and compare the exacerbation rates and other clinical outcomes at 6 and 12 months. Results: A total of 252 patients with COPD were included. The <100, 100 - 299, and ≥ 300 cells/µL groups consisted of 14.7, 38.9, and 46.4% of patients, respectively. BEC stability was highest (85%) in the ≥300 cells/µL group for both durations. The lowest stability was observed in the <100 cells/µL group at 57 and 46% after 6 and 12 months, respectively. The persistent ≥ 300 cells/µL group had a higher incidence of moderate-to-severe exacerbation (IRR 2.44, 95% confidence interval (CI): 1.13-5.27, p value 0.023, as well as severe exacerbation (IRR 2.19, 95%CI: 1.39-3.45, p value 0.001). Other patient-reported outcomes did not differ significantly between groups. Conclusion: Blood eosinophil levels had good stability in patients with COPD with BEC ≥300 cells/µL and was associated with a high risk of exacerbation in the persistent ≥300 cells/µL group. The variability of BEC was higher in patients with COPD with BEC <300 cells/µL.

Correlation of fractional exhaled nitric oxide (FeNO) and clinical outcomes in patients with chronic obstructive pulmonary disease: A prospective cohort study.

BACKGROUND: Fractional exhaled nitric oxide (FeNO) is an acceptable and noninvasive marker for defining eosinophilic airway inflammation. Further study is necessary to clarify the role of FeNO in patients with chronic obstructive pulmonary disease (COPD). This study aimed to determine the association between FeNO levels and clinical outcomes. METHODS: A prospective observational study was conducted at Songklanagarind Hospital from October 2020 to November 2022. FeNO testing and spirometry were performed at the initial visit and 12-month follow-up. Exacerbation, hospitalization, lung function decline, and all-cause mortality were analyzed to determine the association between FeNO levels and clinical outcomes. RESULTS: A total of 60 patients with COPD were enrolled, 88.3 % of whom were male, with a mean age of 71.3 ± 9.5 years. There were 18 patients (30 %) in the high FeNO group (≥25 ppb) and 42 patients (70 %) in the low (<25 ppb) FeNO group. The mean blood eosinophil count (BEC) was significantly higher in the high FeNO group (p < 0.001). After a 12-month follow-up period, high FeNO group had higher exacerbation events (HR of 1.26, 95 % confidence interval (CI), 1.10-1.97, p= 0.025). Hospitalization and mortality rates were significantly higher in the high FeNO group. Regardless of the inhaled corticosteroids used, patients with high BEC and FeNO levels tended to have a greater risk of exacerbation. CONCLUSION: In patients with COPD, FeNO levels are strongly correlated with BEC. Poor clinical outcomes were reported in patients with high FeNO levels. FeNO may be a useful biomarker for predicting clinical outcomes in patients with COPD.

Exploring previously used thresholds for computed tomography-defined low skeletal muscle mass in predicting functional limitations among lung cancer patients.

BACKGROUND: Various cutoffs have been used to diagnose computed tomography (CT)-defined low skeletal muscle mass; however, the impact of this variability on predicting physical functional limitations (PFL) remains unclear. In the present study we aimed to evaluate the diagnostic test metrics for predicting PFLs using a fixed cutoff value from previous reports and sought to create a prediction score that incorporated the skeletal muscle index (SMI) and other clinical factors. METHODS: In this cross-sectional study including 237 patients with lung cancer, the SMI was assessed using CT-determined skeletal muscle area at the third lumbar vertebra. Physical function was assessed using the short physical performance battery (SPPB) test, with PFL defined as an SPPB score ≤9. We analyzed the diagnostic metrics of the five previous cutoffs for CT-defined low skeletal muscle mass in predicting PFL. RESULTS: The mean age of participants was 66.0 ± 10.4 years. Out of 237 patients, 158 (66.7%) had PFLs. A significant difference was observed in SMI between individuals with and without PFLs (35.7 cm2/m2 ± 7.8 vs. 39.5 cm2/m2 ± 8.4, p < 0.001). Diagnostic metrics of previous cutoffs in predicting PFL showed suboptimal sensitivity (63.29%-91.77%), specificity (11.39%-50.63%), and area under the receiver operating characteristic curve (AUC) values (0.516-0.592). Age and the SMI were significant predictors of PFL; therefore, a score for predicting PFL (age - SMI + 21) was constructed, which achieved an AUC value of 0.748. CONCLUSION: Fixed cutoffs for CT-defined low skeletal muscle mass may inadequately predict PFLs, potentially overlooking declining physical functions in patients with lung cancer.

Positive Airway Pressure Treatment of Obstructive Sleep Apnea-Hypopnea in Hypertensive Disorders of Pregnancy: A Pilot Randomized Proof-of-Concept Clinical Trial.

Rationale: Maternal obstructive sleep apnea-hypopnea (OSAH) is associated with hypertensive disorders of pregnancy (HDP). OSAH treatment with positive airway pressure (PAP) in the general population lowers blood pressure (BP). However, there are limited data on the effects of PAP therapy in maternal OSAH. Objectives: Our primary objective was to assess the feasibility of recruitment to a pilot randomized trial and adherence to PAP therapy for OSAH in women with HDP. Secondary objectives included assessment of PAP effects on 24-h BP, arterial stiffness, and maternal and fetal outcomes. Methods: Women with singleton pregnancies at ⩾12 weeks' gestation and hypertension underwent home level 2 polysomnography; those with mild to moderate OSAH (apnea-hypopnea index ⩾ 5 events/h; women with severe OSAH with apnea-hypopnea index > 30 events/h and oxygen desaturation index > 30 were excluded) were randomized to either PAP or nasal dilator strip (NDS; control) therapy. After PAP education, adherence was monitored online with episodic phone or in-person support by research personnel. Twenty-four-hour BP and arterial stiffness were assessed at baseline and before delivery. Maternal and fetal outcomes were also recorded. Results: Of 105 potentially eligible participants, 67 agreed to undergo screening for OSAH over 38 months; 48 women meeting OSAH inclusion criteria were randomized to PAP (n = 27) or NDS (n = 21) therapy. Of these, 14 PAP (52%) and 13 NDS (62%) participants completed all predelivery measurements, with lack of completion due to urgent delivery (19% in the PAP group, 14% in the NDS group), PAP intolerance at initiation (19%), or other factors. Mean PAP use was 3.1 ± 2.5 h/night, with use ⩾4 h/night on 38.4 ± 33.7% of nights during 9.6 ± 4.0 weeks of treatment. BP was controlled within the target range in most participants. There were no differences in mean change in 24-hour BP or arterial stiffness measurements or in adverse maternal and fetal outcomes between the PAP and NDS groups in either intention-to-treat or per-protocol analyses. Conclusions: PAP adherence was suboptimal in this HDP cohort despite education and troubleshooting. Further work is required to identify optimal OSAH treatment strategies during pregnancy. Clinical trial registered with www.clinicaltrials.gov (NCT03309826).

CNS Efficacy of Osimertinib With or Without Chemotherapy in Epidermal Growth Factor Receptor-Mutated Advanced Non-Small-Cell Lung Cancer.

PURPOSE: We report CNS efficacy of first-line osimertinib plus chemotherapy versus osimertinib monotherapy in patients with epidermal growth factor receptor (EGFR)-mutated advanced non-small-cell lung cancer (NSCLC) from the phase III FLAURA2 study according to baseline CNS metastasis status. METHODS: Patients were randomly assigned to osimertinib plus platinum-pemetrexed (combination) or osimertinib monotherapy until disease progression or discontinuation. Brain scans were performed in all patients at baseline and progression and at scheduled assessments until progression for patients with baseline CNS metastases; scans were assessed by neuroradiologist CNS blinded independent central review (BICR). RESULTS: On the basis of baseline CNS BICR, 118 of 279 (combination) and 104 of 278 (monotherapy) randomly assigned patients had ≥one measurable and/or nonmeasurable CNS lesion and were included in the CNS full analysis set (cFAS); 40 of 118 and 38 of 104 had ≥one measurable target CNS lesion and were included in the post hoc CNS evaluable-for-response set (cEFR). In the cFAS, the hazard ratio (HR) for CNS progression or death was 0.58 (95% CI, 0.33 to 1.01). In patients without baseline CNS metastases, the HR for CNS progression or death was 0.67 (95% CI, 0.43 to 1.04). In the cFAS, CNS objective response rates (ORRs; 95% CI) were 73% (combination; 64 to 81) versus 69% (monotherapy; 59 to 78); 59% versus 43% had CNS complete response (CR). In the cEFR, CNS ORRs (95% CI) were 88% (73 to 96) versus 87% (72 to 96); 48% versus 16% had CNS CR. CONCLUSION: Osimertinib plus platinum-pemetrexed demonstrated improved CNS efficacy compared with osimertinib monotherapy, including delaying CNS progression, irrespective of baseline CNS metastasis status. These data support this combination as a new first-line treatment for patients with EGFR-mutated advanced NSCLC, including those with CNS metastases.

Prevalence, associated factors, and clinical consequences of metabolic syndrome in chronic obstructive pulmonary disease patients: a 5-year prospective observational study.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) is characterized by multiple systemic comorbidities, not only airflow limitation. Metabolic syndrome (MetS) is a common comorbidity. Patients with COPD have a higher risk of MetS than do healthy individuals. OBJECTIVES: We aimed to investigate the prevalence of and explore the factors associated with MetS in Thai COPD patients and to assess the clinical consequences of MetS after a 5-year follow-up period. METHODS: A prospective observational study was conducted in patients with stable COPD at Songklanagarind Hospital between June 2015 and November 2019. MetS was defined according to the International Diabetes Federation 2005 criteria. The patients were followed-up for 5 years. The prevalence, associated factors, and consequences of MetS were analyzed. RESULTS: A total of 115 patients with COPD were enrolled, of whom 95.3% were male. The overall prevalence of MetS was 37.4% (43 patients). Chronic bronchitis and high C-reactive protein (CRP) levels were independently and significantly associated with MetS in patients with COPD (p = 0.036 and 0.044, respectively). After following patients for 5 years, the incidence of cardiovascular disease and stroke, exacerbation rate, and mortality rate were significantly higher in the COPD with MetS group [relative risk (RR) = 15.36, 95% confidence interval (CI) = (2.13-110.67), RR = 45.43, 95% CI = (4.61-447.07), RR = 1.94, 95% CI = (1.40-2.70), and RR = 48.01, 95% CI = (1.12-2049.43), respectively]. CONCLUSION: The prevalence of MetS is high in patients with COPD. Chronic bronchitis and high CRP levels are associated with MetS in COPD. The incidence of clinical consequences was significantly higher in patients with COPD and MetS after a 5-year follow-up. Screening for MetS is strongly recommended for all patients with COPD.

Prevalence, predictors, dynamic bone change, and treatment efficacy of osteoporosis among chronic obstructive pulmonary disease patients: a prospective cohort study.

Background: Osteoporosis is a silent chronic obstructive pulmonary disease (COPD) comorbidity that is often under-detected. We aimed to study the prevalence and potential predictors of osteoporosis in COPD. Dynamic changes in bone mass density (BMD) and treatment efficacy of bisphosphonate were also assessed. Methods: This prospective cohort study included COPD patients between January 2017 and January 2019. Demographics data, spirometric parameters, and C-reactive protein (CRP) were collected. Bone mineral density (BMD) at the lumbar spine (L2-4) and both femoral necks were measured after enrollment and the 12-month follow-up. Participants were categorized into three groups per the baseline BMD T-score: normal (≥ - 1.0), osteopenia (between -1.0 and - 2.5), and osteoporosis (≤ - 2.5). In the osteoporosis group, alendronate 70 mg/week with vitamin D and calcium was prescribed. Results: In total, 108 COPD patients were enrolled. The prevalence of osteoporosis and osteopenia were 31.5 and 32.4%, respectively. Advanced age, lower body mass index (BMI), history of exacerbation in the previous year, and high CRP levels were significant predictors of osteoporosis. After 12 months, 35.3% in the osteoporosis group reported new vertebral and femoral fractures, compared to none in the non-osteoporosis group (p < 0.001). In the normal BMD and osteopenia groups showed a further decline in BMD after 12-month. Conversely, the osteoporosis group showed a statistically significant improvement in BMD after anti-resorptive treatment (p < 0.001). Conclusion: The prevalence of osteoporosis was high in Thai COPD patients. Advanced age, lower BMI, history of exacerbation, and high CRP levels were potential predictors. A rapid decline in BMD was observed in COPD patients without treatment.

Predictive and Prognostic Value of TUBB3, RRM1, APE1, and Survivin Expression in Chemotherapy-Receiving Patients with Advanced Non­Small Cell Lung Cancer.

BACKGROUND: This study aimed to evaluate the expression of class III ß-tubulin (TUBB3), ribonucleoside-diphosphate reductase 1 (RRM1), apurinic/apyrimidinic endonuclease 1 (APE1), and survivin in patients with advanced non-small cell lung cancer (NSCLC) to predict response to chemotherapy. METHODS: TUBB3, RRM1, APE1, and survivin expression levels were determined using immunohistochemistry. Protein expression was validated in Car/Pac-resistant human H1792 and A549 cells. This study included 86 patients, among whom 34 received cisplatin (Cis)/gemcitabine (Gem) and 52 received carboplatin (Car)/paclitaxel (Pac). RESULTS: Patients with low TUBB3 expression and high RRM1 and survivin expression had higher response rates than those with low RRM1 and survivin expression and high TUBB3 expression in the Car/Pac regimen. The multivariate analysis indicated that TUBB3 and RRM1 were significant independent predictive biomarkers for the Car/Pac regimen; however, there was no association between any protein and overall response in patients treated with this regimen. In the Cis/Gem regimen, only high TUBB3 expression was associated with poor overall survival; however, it did not exhibit a prognostic ability. CONCLUSION: The expression levels of TUBB3 and RRM1 in NSCLC cells are potential predictive biomarkers, but not prognostic factors, of response to chemotherapy in patients with NSCLC receiving the Car/Pac regimen.