Serum lactate level and mortality in metformin-associated lactic acidosis requiring renal replacement therapy: a systematic review of case reports and case series.

BACKGROUND: The current practice concerning timing, mode, and dose of renal replacement therapy (RRT) in patients with metformin-associated lactic acidosis (MALA) with renal failure remains unknown. To investigate whether serum lactate level and prescription pattern of RRT are associated with mortality in patients with MALA requiring RRT. METHODS: We searched PubMed/Medline and EMBASE from inception to Sep 2014 and applied predetermined exclusion criteria. Case-level data including case's demographics and clinical information related to MALA were abstracted. Multiple logistic regression modeling was used to examine the predictors of mortality. RESULTS: A total of 253 unique cases were identified with cumulative mortality of 17.2%. Eighty-seven percent of patients had acute kidney injury. Serum lactate level was significantly higher in non-survivors (median 22.5 mmol/L) than in survivors (17.0 mmol/L, p-value <0.01) and so did the median blood metformin concentrations (58.5 vs. 43.9 mg/L, p-value = 0.05). The survival advantage was not significantly different between the modalities of RRT. The adjusted odds ratio of mortality for every one mmol/L increase in serum lactate level was 1.09 (95% CI 1.02-1.17, p-value = 0.01). The dose-response curve indicated a lactate threshold greater than 20 mmol/L was significantly associated with mortality. CONCLUSIONS: Our study suggests that predialysis level of serum lactate level is an important marker of mortality in MALA patients requiring RRT with a linear dose-response relationship. To better evaluate the optimal prescription of RRT in MALA, we recommend fostering an international consortium to support prospective research and large-scale standardized case collection.

Frequent EGFR mutations in nonsmall cell lung cancer presenting with miliary intrapulmonary carcinomatosis.

Nonsmall cell lung cancer (NSCLC) presenting with miliary intrapulmonary carcinomatosis (MIPC) is rare. We investigated the clinical characteristics and epidermal growth factor receptor (EGFR) mutation rate of NSCLC patients with MIPC at initial diagnosis. From June 2004 to December 2008, we screened newly diagnosed NSCLC patients for MIPC using image-based criteria. We recorded clinical data and analysed EGFR mutation status. For comparison, we collected specimens from stage IV NSCLC patients without MIPC tested for EGFR mutations from April 2001 to November 2008. From 3,612 NSCLC patients, 85 patients with MIPC at initial diagnosis were identified; 81 had adenocarcinoma. Of the 85 patients, 60 had specimen sequencing to detect EGFR mutation; 42 (70%) were positive. Compared with 673 stage IV patients without MIPC, patients with MIPC had higher EGFR mutation rate (p=0.036); even male smokers had a high EGFR mutation rate (91%). Multivariate analysis of prognostic factors for overall survival of the 85 patients with MIPC revealed that adenocarcinoma, absence of extrapulmonary metastasis and having EGFR mutation were associated with longer overall survival. NSCLC patients with MIPC at initial diagnosis had higher rates of adenocarcinoma and EGFR mutation. EGFR tyrosine kinase inhibition may be the treatment of choice for NSCLC patients with MIPC at initial diagnosis among Asians.

Second-line treatments after first-line gefitinib therapy in advanced nonsmall cell lung cancer.

Gefitinib is effective as first-line therapy for advanced nonsmall cell lung cancer (NSCLC). However, after failure of gefitinib, it is unknown whether any second-line regimens could lead to better outcomes. To study the influence of different second-line antitumor regimens on the outcomes of patients with NSCLC after failure of first-line gefitinib, we carried out a retrospective study in a tertiary referral medical center to investigate the prognosis of patients with NSCLC receiving second-line antitumor treatment after gefitinib therapy. Clinical data and epidermal growth factor receptor (EGFR) mutational status of tumors were collected. A total of 195 patients with Stage IIIb or IV NSCLC receiving first-line gefitinib and at least 1 subsequent line therapy were identified. A second-line therapy with a platinum-based combination or taxane-containing regimen were associated with a higher therapy response, whereas a platinum-based combination was linked to better overall survival. Ninety-five patients had tumors with known EGFR mutation status; 61 had EGFR mutations and 34 had wild-type EGFR. A second-line therapy with a gemcitabine/platinum combination regimen resulted in better overall survival than erlotinib in patients with EGFR mutations (p = 0.035) but not in patients with wild-type EGFR (p = 0.785). The study suggested that, after failure of first-line gefitinib therapy, second-line platinum-based combination regimens were associated with a better overall survival than other regimens, including erlotinib. The survival benefit of platinum-based combination regimens existed in patients with mutant EGFR but not wild-type EGFR.

Lung cancer with epidermal growth factor receptor exon 20 mutations is associated with poor gefitinib treatment response.

PURPOSE: Clinical reports about responsiveness to gefitinib treatment in patients of non-small cell lung cancer (NSCLC) with mutations in exon 20 of epidermal growth factor receptor (EGFR) are limited. To increase understanding of the influence of exon 20 mutations on NSCLC treatment with gefitinib, we investigated the clinical features of lung cancer in patients with exon 20 mutations and analyzed the gefitinib treatment response. EXPERIMENTAL DESIGN: We surveyed the clinical data and mutational studies of NSCLC patients with EGFR exon 20 mutations in the National Taiwan University Hospital and reviewed the literature reports about EGFR exon 20 mutations and the gefitinib treatment response. RESULTS: Twenty-three patients with mutations in exon 20 were identified. Nine (39%) had coexisting mutations in EGFR exons other than exon 20. Sixteen patients received gefitinib treatment, and a response was noted in 4 patients. The gefitinib response rate of NSCLC with exon 20 mutations was 25%, far lower than those with deletions in exon 19 and L858R mutations. Interestingly, different exon 20 mutations and coexisting mutations seemed to have a different influence on gefitinib response. CONCLUSIONS: EGFR exon 20 mutations of NSCLC patients result in poorer responsiveness to gefitinib treatment, but variability exists between different individuals.

First- or second-line therapy with gefitinib produces equal survival in non-small cell lung cancer.

RATIONALE: Gefitinib is effective in treating patients with non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations. Deletions in exon 19 and L858R in exon 21 are the best-documented EGFR mutations that are associated with effective gefitinib responsiveness. OBJECTIVES: To clarify the influence of gefitinib timing, we conducted a study to compare the outcomes of different lines of gefitinib treatment in patients with exon 19 deletions or L858R. METHODS: We surveyed the clinical data and mutational studies of patients with NSCLC with EGFR mutations in the National Taiwan University Hospital (Taipei, Taiwan). MEASUREMENTS AND MAIN RESULTS: Three hundred and twenty-eight patients, who received gefitinib for stage IIIb or IV NSCLC, were adequately sequenced for EGFR mutations; 192 patients had mutant EGFR, including 77 patients with exon 19 deletions and 75 patients with L858R. The 152 patients with exon 19 deletions or L858R and who were receiving gefitinib were classified into a chemonaive group (91 patients) or a chemotherapy-treated group (61 patients). Chemonaive status before gefitinib and female sex were associated with clinical response to gefitinib (P = 0.006 and 0.053, respectively). Neither overall survival after the start of antitumor therapy nor progression-free survival after gefitinib therapy was significantly different between these two groups (P = 0.207 and 0.804, respectively). Clinical response to gefitinib was the only factor associated with better overall survival (P = 0.001). CONCLUSIONS: This study suggests that gefitinib is effective in patients with EGFR mutations. The gefitinib response rate in chemonaive patients is higher than in chemotherapy-treated patients; however, there is no difference in overall survival.

Effectiveness of Treatments for Advanced Non-Small-Cell Lung Cancer With Exon 20 Insertion Epidermal Growth Factor Receptor Mutations.

BACKGROUND: Two main categories of epidermal growth factor receptor (EGFR) mutations in non-small-cell lung cancer (NSCLC) patients are deletions in exon 19 and L858R in exon 21. Treatments of advanced NSCLC patients with these mutations are well documented, and clinical responses to tyrosine kinase inhibitors (TKIs) are favorable. However, effective treatments for patients with exon 20 insertion mutations are not well verified. We investigated the clinical response to various treatments (chemotherapy and TKIs) of advanced NSCLC patients with EGFR exon 20 insertions. PATIENTS AND METHODS: In this study, specimens from 3805 NSCLC patients were examined for EGFR mutations. Different first-line treatments and their effectiveness in NSCLC patients with exon 20 insertion EGFR mutations were investigated. RESULTS: In the cohort of the 3805 patients, 2112 (55.5%) had EGFR mutations, including 84 patients (4.0%) with exon 20 insertion mutations. Efficacy of different first-line chemotherapy or TKIs were evaluated. Pemetrexed-containing therapies were related to better progression-free survival (6.2 vs. 2.7 months; P < .001) and overall survival (28.0 vs. 15.4 months; P = .009) than regimens without pemetrexed. Patients with exon 20 insertions had a poor response to TKIs. However, the mutation Ala763_Tyr764insPheGlnGluAla (A763_Y764 insFQEA) was related to a favorable response to TKIs. CONCLUSION: Exon 20 insertion EGFR mutations comprised a considerable group of the entire population of patients with EGFR mutations. Different first-line treatments and variants of the exon 20 insertions might be related to different outcomes in advanced NSCLC patients.

Good response to gefitinib in lung adenocarcinoma of complex epidermal growth factor receptor (EGFR) mutations with the classical mutation pattern.

BACKGROUND: Epidermal growth factor receptor (EGFR) mutations are usually detected in lung adenocarcinoma and are associated with a response to EGFR tyrosine kinase inhibitors (TKIs). However, not all EGFR mutations have similarly high clinical response rates. This study aimed to investigate the clinical characteristics and response to gefitinib in lung adenocarcinoma patients with complex EGFR mutations. MATERIALS AND METHODS: Three hundred thirty-nine specimens of lung adenocarcinoma from patients treated with gefitinib were collected for EGFR sequencing. Nineteen patients with complex EGFR mutations were enrolled for the study after excluding three patients with the EGFR T790M mutation, which confers resistance to gefitinib. RESULTS: Among the 19 patients, 12 had complex mutations with the classical mutation pattern (L858R or deletion in exon 19). When compared with those without the classical mutation pattern, patients with this mutation pattern had a higher response rate (83% versus 29%), longer progression-free survival duration (median, 12.7 months versus 4.9 months), and longer overall survival time (median, 24.7 months versus 12.3 months) after gefitinib treatment. Comparing patients harboring complex EGFR mutations with a classical mutation pattern with those harboring single classical mutations, there were no statistical differences in the response rate (83% versus 73%), progression-free survival time (median, 12.7 months versus 8.1 months,) or overall survival time (median, 24.7 months versus 16.4 months). CONCLUSION: Patients with complex EGFR mutations with the classical mutation pattern had the same response rate, progression-free survival duration, and overall survival time as those with single classical mutations. EGFR TKIs may be the choice of treatment for this type of lung adenocarcinoma.

Adrenal insufficiency in prolonged critical illness.

INTRODUCTION: Adrenal insufficiency is common in critically ill patients and affects their prognosis, but little is known about how adrenal function changes during prolonged critical illness. This study was conducted to investigate dynamic changes in cortisol levels in patients with critical illness who do not improve after treatment. METHODS: This observational cohort study was performed in the intensive care units of a university hospital. We studied acutely ill patients with initial cortisol level above 34 microg/dl, but who did not improve after treatment and in whom follow-up cortisol levels were determined during critical illness. All clinical information and outcomes were recorded. RESULTS: Fifty-seven patients were included. Ten patients had follow-up cortisol levels above 34 microg/dl, 32 patients had levels between 34 and 15 microg/dl, and 15 patients had levels under 15 microg/dl. Outcomes did not differ significantly among the three groups with different follow-up cortisol levels. In Cox regression analysis, those patients who survived to hospital discharge with second cortisol levels under 15 microg/dl had a longer hospital length of stay (odds ratio = 14.8, 95% confidence interval = 2.4 to 90.0; P = 0.004). CONCLUSION: The majority of acutely ill patients who remained in a critical condition had decreased serum cortisol levels. Depressed cortisol levels at follow up may lead to worse clinical outcomes. We propose that repeated adrenal function testing be conducted in patients with prolonged critical illness.

Effectiveness of tyrosine kinase inhibitors on uncommon E709X epidermal growth factor receptor mutations in non-small-cell lung cancer.

BACKGROUND: Clinical features of epidermal growth factor receptor (EGFR) mutations: L858R, deletions in exon 19, T790M, insertions in exon 20, G719X, and L861X in non-small-cell lung cancer (NSCLC) are well-known. The clinical significance of other uncommon EGFR mutations, such as E709X, is not well understood. This study aimed to improve the understanding of E709X, and the clinical response to tyrosine kinase inhibitors (TKIs) of NSCLC patients with such an uncommon mutation. METHODS: Specimens from 3,146 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of TKI treatment in NSCLC patients with EGFR mutations E709X. RESULTS: Of the 3,146 patients, 1,689 (53.7%) had EGFR mutations. This included 726 patients with deletions in exon 19, 733 patients with L858R, and 230 (13.6%) patients with other EGFR mutations. In the 230 patients who had mutations other than single deletion in exon 19 or single L858R in exon 21, 25 (1.5%) patients had the uncommon E709X mutations. Twenty patients had complex E709X mutations and five had single E709X mutation: delE709-T710insD. Of these 25 patients, 18 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 50.0%, and the median progression-free survival was 6.2 months. All 5 patients who had delE709-T710insD were non-responders to TKI treatments. CONCLUSION: E709X EGFR mutations constituted a small part of the whole group of EGFR mutations. Most patients had complex mutations. The mutation delE709-T710insD was a single mutation and was not associated with good response to TKI treatment.

Clinical outcomes in non-small cell lung cancers harboring different exon 19 deletions in EGFR.

PURPOSE: Several deletions in exon 19 of epidermal growth factor receptor (EGFR) gene have been reported in non-small cell lung cancer (NSCLC). It is unknown if deletions occurring at different amino acid positions or of different sizes are associated with different clinical outcome to EGFR tyrosine kinase inhibitors (TKI). EXPERIMENTAL DESIGN: This study enrolled NSCLC patients with deletions in EGFR exon 19. Patients who had received EGFR TKIs for advanced NSCLC were further evaluated for response rate (RR), progression-free survival (PFS), and overall survival (OS). RESULTS: In 308 patients with deletions in EGFR exon 19, 298 had deletions encompassing the entire amino acid string from L747 through E749 (LRE deletions). EGFR TKIs were used in 204 patients with advanced NSCLC. Patients with non-LRE deletions had the least RR, compared with those with deletions from E746 or L747 (42.9%, 68.2%, and 79.6%, respectively; P = 0.022). Patients with non-LRE deletions had relatively short median PFS, though not significantly different from those with deletions from E746 or L747 (5.9, 9.8, and 10.5 months, respectively; P = 0.665). The OS was not different among patients with deletions occurring at different amino acid positions (P = 0.776). Deletions in exon 19 of different sizes were not associated with different RR, PFS, or OS. CONCLUSIONS: Non-LRE deletions in exon 19 were associated with worse response to EGFR TKIs, compared with LRE deletions. Therefore, the expected clinical outcome under EGFR TKIs depends on not only the existence but also the types of deletions in exon 19.

Effectiveness of tyrosine kinase inhibitors on "uncommon" epidermal growth factor receptor mutations of unknown clinical significance in non-small cell lung cancer.

PURPOSE: Clinical features of epidermal growth factor receptor (EGFR) mutations, L858R, deletions in exon 19, T790M, and insertions in exon 20, in non-small cell lung cancer (NSCLC) are well known. The clinical significance of other uncommon EGFR mutations, such as their association with the effectiveness of EGFR tyrosine kinase inhibitors (TKI), is not well understood. This study aimed to improve the understanding of these uncommon EGFR mutations of unknown clinical significance. PATIENTS AND METHODS: Specimens from 1,261 patients were tested for EGFR mutations. We surveyed the clinical data and the effectiveness of gefitinib and erlotinib in NSCLC patients with uncommon EGFR mutations. RESULTS: Of the 1,261 patients, 627 (49.8%) had EGFR mutations. This included 258 patients with deletions in exon 19, 260 patients with L858R, 25 patients with insertions or duplications in exon 20, 6 patients with de novo T790M, and 78 (12.4%) patients with uncommon mutations. Of the 78 patients, 62 received either gefitinib or erlotinib treatment. The response rate of TKIs treatment was 48.4%, and the median progression-free survival (PFS) was 5.0 months. Mutations on G719 and L861 composed a major part (28 of 62) of uncommon mutations, and were associated with a favorable effectiveness of EGFR TKIs (response rate, 57.1%; median PFS, 6.0 months). Mutations other than G719 and L861 led to a worse response to EGFR TKIs (response rate, 20.0%; median PFS, 1.6 months). CONCLUSIONS: Uncommon EGFR mutations constituted a distinct part of the whole group of EGFR mutations. Their composition was heterogeneous, and their associations with EGFR TKIs differed.

Gefitinib therapy in patients with advanced non-small cell lung cancer with or without testing for epidermal growth factor receptor (EGFR) mutations.

Gefitinib is effective in treating advanced non-small cell lung cancer (NSCLC), especially in Asian patients in whom the prevalence of epidermal growth factor receptor (EGFR) mutation was high. We analyzed our gefitinib treatment use in patients for advanced NSCLC to study the influence of clinical factors on the treatment outcomes in a tertiary referral medical center in Taiwan. Clinical data and EGFR mutational status of the tumors were collected. A total of 907 patients received gefitinib for advanced NSCLC: 466 patients (51.4%) underwent testing for EGFR mutations, and the other 441 patients did not. In the 466 patients who were tested for EGFR mutations, 272 (58.4%) had EGFR mutations, and an EGFR mutation was a prominent factor for objective response to gefitinib (67.3% vs. 18.3% in wildtype EGFR, p < 0.001). In the 441 patients who did not receive EGFR mutation sequencing, nonsmoker status, female sex, and adenocarcinoma cell type were predictors for better gefitinib response (p < 0.005). We found that testing for EGFR mutations was helpful in NSCLC patients in Taiwan to guide the use of gefitinib. In patients with positive activating EGFR mutations, gefitinib efficacy was prominent and significant. Therefore, analysis for EGFR mutation should be advocated. In those patients who have unknown EGFR mutation status, demographic and histopathology characteristics can be relied on to judge the potential efficacy of gefitinib use.

Comparison of gefitinib and erlotinib in advanced NSCLC and the effect of EGFR mutations.

INTRODUCTION: Erlotinib and gefitinib are tyrosine kinase (TK) inhibitors of epidermal growth factor receptor (EGFR) that are effective in treating non-small cell lung cancer (NSCLC). This study aimed to compare their clinical uses and the influence of EGFR mutation. METHODS: The usages of erlotinib and gefitinib in advanced NSCLC were analyzed. Clinical data and EGFR mutational status of tumors were collected. RESULTS: Seven hundred and sixteen (716) patients received gefitinib (n=440) or erlotinib (n=276) for stage IIIb or IV NSCLC. Erlotinib was prescribed more frequently than gefitinib in males (58.2% vs. 41.8%, p<0.001), smokers (60.5% vs. 39.5%, p<0.001), and non-adenocarcinoma (70.6% vs. 29.4%, p<0.001). Of the 716 study patients, 327 underwent testing for EGFR mutations (170 with mutant EGFR and 157 with wild-type EGFR). Adenocarcinoma in patients with mutant EGFR and non-smoker status in patients with wild-type EGFR were associated with better overall survival after TK inhibitor treatment. In both patient groups with mutant EGFR or wild-type EGFR, the effectiveness of gefitinib and erlotinib, including drug response or overall survival, were not different. CONCLUSIONS: Our study revealed the obvious disparity in drug selection between erlotinib and gefitinib in clinical practice. Type of TK inhibitors did not influence treatment outcomes in patients with EGFR mutation or wild-type EGFR.

Influence of first-line chemotherapy and EGFR mutations on second-line gefitinib in advanced non-small cell lung cancer.

PURPOSE: Gefitinib is a valid second-line therapy for previously treated non-small cell lung cancer (NSCLC) patients. The influences of various chemotherapy regimens and EGFR mutations on effectiveness of second-line gefitinib are not clear, and laboratory studies revealed that previous chemotherapy changed the effectiveness of treatment with gefitinib. In order to clarify the factors changing the effectiveness of second-line gefitinib, we performed a retrospective analysis of the prognosis of NSCLC patients who received gefitinib after first-line chemotherapy. DESIGN: We analyzed the clinical data and mutational studies of NSCLC patients with EGFR mutations from the National Taiwan University Hospital. RESULTS: One hundred and two previously treated patients received second-line gefitinib for stage IIIB or IV NSCLC. Fifty of all the 102 patients were sequenced for EGFR status. Twenty-eight had EGFR mutation and 22 had wild type EGFR. The response rate and progression-free survival of second-line gefitinib was not changed by different previous chemotherapy regimens. The potent factor with regards to the effectiveness of second-line gefitinib was EGFR mutation which led to a better response rate and longer progression-free survival of gefitinib than wild type EGFR. CONCLUSIONS: Gefitinib is effective as a second-line therapy for previously treated NSCLC patients. The effectiveness was influenced by EGFR status rather than previous chemotherapy regimens.

Use of cetuximab after failure of gefitinib in patients with advanced non-small-cell lung cancer.

BACKGROUND: Gefitinib and cetuximab are both epidermal growth factor receptor (EGFR) target therapies used to treat patients with non-small-cell lung cancer (NSCLC) with different mechanisms. To clarify the effectiveness of cetuximab after failure of gefitinib treatment, we investigated the clinical features of patients with NSCLC who received cetuximab-containing chemotherapy after failure of gefitinib. PATIENTS AND METHODS: We analyzed the clinical data and mutational studies of patients with NSCLC in the National Taiwan University Hospital who had received gefitinib and, after failure of gefitinib, cetuximab-containing chemotherapy. RESULTS: Fifteen patients who received cetuximab-containing chemotherapy after failure of gefitinib were identified. Four were responders to gefitinib therapy, and 3 were responders to cetuximab-containing chemotherapy. Ten were sequenced for EGFR and KRAS mutations. Six of the 10 patients had EGFR mutations, and all 10 patients had wild-type (WT) KRAS. In the 4 patients who had the gefitinib-resistant EGFR T790M mutation, 2 were responders to cetuximab-containing chemotherapy. The other cetuximab responder had WT EGFR. CONCLUSION: Cetuximab might add benefit in treatment after failure of gefitinib, regardless of EGFR mutational status. Treatment with cetuximab should be further explored, even in patients who have previously received gefitinib treatment.

The role of non-invasive ventilation and factors predicting extubation outcome in myasthenic crisis.

INTRODUCTION: Myasthenic crisis is a great threat to patients with myasthenia gravis. Usage of non-invasive ventilation (NIV) to prevent intubation and timing of extubating of patients in myasthenic crisis are important issues though not well documented. METHODS: To explore the factors predicting NIV success and extubation outcome in myasthenic crisis, we reviewed the records of 41 episodes of myasthenia crisis. RESULTS: NIV was applied to 14 episodes of myasthenic crisis and eight (57.1%) of them were successfully prevented from intubation. An Acute Physiology and Chronic Health Evaluation (APACHE) II score of <6 and a serum bicarbonate level of <30 mmol/l were independent predictors of NIV success. For patients undergoing invasive mechanical ventilation, extubation failure was observed in 13 (39.4%) of 33 episodes, and the most common cause was sputum impaction due to a poor cough strength (61.5%). A maximal expiratory pressure (Pemax) of > or = 40 cmH(2)O was a good predictor of extubation success. Extubation failure led to poorer outcomes. CONCLUSIONS: NIV may be applied to those patients with a low APACHE II score and a lesser degree of metabolic compensation for respiratory acidosis. For patients undergoing invasive mechanical ventilation, extubation failure is associated with significant in-hospital morbidity in myasthenic crisis. Adequate levels of Pemax and cough strength correlate significantly with extubation success.

Critical illness polyneuromyopathy in a patient with disseminated cryptococcal infection.

Critical illness polyneuromyopathy is frequent in patients in intensive care units. We report a case of critical illness polyneuromyopathy in a patient with disseminated cryptococcal infection in an intensive care unit.