Dasatinib-induced chylothorax in a patient with chronic myeloid leukaemia: a case report and literature review.

Dasatinib is a potent and effective second-generation oral tyrosine kinase inhibitor that is clinically indicated for the treatment of imatinib-resistant or imatinib-intolerant breakpoint cluster region-Abelson (BCR-ABL)-positive chronic myeloid leukaemia (CML) or for Philadelphia chromosome-positive acute lymphocytic leukaemia. The most common adverse events associated with dasatinib therapy are skin rash, gastrointestinal upset, pancytopenia, pulmonary hypertension, and fluid retention, including pleural effusion. However, chylothorax secondary to dasatinib administration has rarely been reported. Although the underlying mechanism leading to dasatinib-induced chylothorax is uncertain, the preferred treatment options are usually supported with diuretics or systemic steroids. Moreover, the discontinuation of the drug is mandatory in refractory cases. Here, we present the case of a patient with dasatinib-induced chylothorax, and review the previously reported cases in the literature.

Lung Cancer Cell-Derived Secretome Mediates Paraneoplastic Inflammation and Fibrosis in Kidney in Mice.

Kidney failure is a possible but rare complication in lung cancer patients that may be caused by massive tumor lysis or a paraneoplastic effect. Clinical case reports have documented pathological characteristics of paraneoplastic syndrome in glomeruli, but are short of molecular details. When Lewis lung carcinoma 1 (LLC1) cells were implanted in mice lungs to establish lung cancer, renal failure was frequently observed two weeks post orthotopic xenograft. The high urinary albumin-to-creatinine ratio (ACR) was diagnosed as paraneoplastic nephrotic syndrome in those lung cancer mice. Profiling the secretome of the lung cancer cells revealed that the secretory proteins were potentially nephrotoxic. The nephrotoxicity of lung cancer-derived secretory proteins was tested by examining the pathogenic effects of 1 × 106, 2 × 106, and 5 × 106 LLC1 cell xenografts on the pathogenic progression in kidneys. Severe albuminuria was present in the mice that received 5 × 106 LLC1 cells implantation, whereas 106 cell and 2 × 106 cell-implanted mice have slightly increased albuminuria. Pathological examinations revealed that the glomeruli had capillary loop collapse, tumor antigen deposition in glomeruli, and renal intratubular casts. Since IL-6 and MCP-1 are pathologic markers of glomerulopathy, their distributions were examined in the kidneys of the lung cancer mice. Moderate to severe inflammation in the kidneys was correlated with increases in the number of cells implanted in the mice, which was reflected by renal IL-6 and MCP-1 levels, and urine ACR. TGF-ß signaling-engaged renal fibrosis was validated in the lung cancer mice. These results indicated that lung cancer cells could provoke inflammation and activate renal fibrosis.

Pin1 coordinates HDAC6 upregulation with cell migration in lung cancer cells.

Histone deacetylase 6 (HDAC6) controls many cellular processes via its catalyzing deacetylation of downstream substrates or interacting with its partner proteins. Dysregulation of HDAC6 signaling links to many diseases. Our previous study has been reported peptidyl-prolyl cis/trans isomerase, and NIMA-interacting 1 (Pin1) involving in HDAC6-mediated cell motility. To gain insight into precisely coordination of HDAC6 and Pin1 in cell migration, shRNA-mediated gene silencing and ectopic expression were applied to manipulate protein expression level to evaluate relationship between HDAC6 and Pin1 expression. Quantitative RT-PCR and the cycloheximide (CHX) chase assay resulted in HDAC6 expression is correlated with Pin1 level in H1299 cells. It hints that the Pin1 increases HDAC6 expression through increased transcripts and posttranslational stabilization. Furthermore, wound healing assay and transwell invasion assay evidenced the contribution of Pin1 on cell motility in H1299 cells. Our data suggest that Pin1 acts as an important regulator to manage HDAC6 expression for cell motility in lung cancer cells.

Clinical efficacy of concurrent bevacizumab for malignant ascites in nonsquamous cell carcinoma of the lung.

PURPOSE: Lung cancer with malignant peritoneal carcinomatosis and malignant ascites is rare, often indicates the terminal stage, and is refractory to treatment. The median survival time of lung cancer patients with malignant ascites has been reported to be as short as 15 days to 2 months in retrospective studies. METHODS: We reviewed all lung cancer patients who had cytologically or pathologically proven malignant ascites and received aggressive therapy including chemotherapy, anti-angiogenesis agents and target therapy at a Taiwan hospital from January 2015 to December 2017. In addition, we searched PubMed using the terms "lung cancer," "peritoneal carcinomatosis" and "malignant ascites" to find other studies reporting experience of such treatment. RESULTS: Three consecutive lung cancer patients with malignant ascites (3/265, 1.13%) were included in this case series study, all of whom received bevacizumab with three other drugs (erlotinib, afatinib and gemcitabine). All of the patients showed a good response to treatment with a marked decrease in ascites. Two of the patients had a long progression-free survival time of more than 5 months. In the literature review, several cases reports and case series documented the treatment efficacy, however no prospective or retrospective studies reported treatment strategies. CONCLUSIONS: Aggressive treatment for lung cancer with malignant ascites is encouraged when possible. Bevacizumab-based treatment may serve as one effective treatment strategy for non-squamous cell lung carcinoma with malignant ascites. Further prospective trials are urgently needed.

Regression of a metastatic lung mass after receiving whole brain irradiation: Can the abscopal effect cross the blood-brain barrier?

An abscopal effect refers to distant tumor regression after localized irradiation. The mechanism is thought to be via local radiotherapy triggering the immune system which then attacks distant tumor sites. Only several cases of solid tumors with an abscopal effect have been reported in the past few decades, and whether an abscopal effect can cross the blood-brain barrier is still unknown. Herein, we present a female patient who was admitted due to unsteady gait and dyspnea. Chest X-ray (CXR) and chest CT showed a huge lung mass with left lung collapse and multiple liver masses. Brain MRI also showed multiple brain metastases. A bronchoscopic biopsy proved metastatic adenocarcinoma from colorectal cancer based on immunohistochemical staining. She therefore received 30 Gy (10 fractions) for the brain metastases; however, she refused to receive any systemic therapy for her lung mass and asked for hospice care. She was therefore transferred to a nursing home and was lost to follow-up. She returned 2 months later due to right pneumonia with fever and productive cough. Surprisingly, her left lung mass had markedly regressed even though she had not received any additional systemic anticancer therapy. This may be the first case of an abscopal effect after receiving whole brain irradiation for brain metastases.

The clinical efficacy of Afatinib 30 mg daily as starting dose may not be inferior to Afatinib 40 mg daily in patients with stage IV lung Adenocarcinoma harboring exon 19 or exon 21 mutations.

BACKGROUND: Afatinib is a second-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI). Compared to cytotoxic chemotherapy, afatinib has been shown to have better efficacy in the treatment of non-small cell lung cancer harboring EGFR mutations. However, 40 mg daily as the initial dose is often accompanied by serious adverse drug reactions (ADRs) and 28 to 53.3% of patients required a dose reduction. No previous study has compared the clinical efficacy and ADRs of different initial doses (40 mg vs. 30 mg daily) of afatinib in lung cancer treatment. METHODS: Patients with stage IV lung adenocarcinoma diagnosed and treated in two Kaohsiung Medical University-affiliated hospitals in Taiwan between May 2014 and August 2016 were identified and followed until December 2016. Demographic characteristics, responses, progression-free survival (PFS), overall survival (OS), and ADRs were recorded. RESULT: A total of 48 patients with stage IV lung adenocarcinoma harboring susceptible EGFR mutations who received afatinib as their first-line therapy were enrolled. Patients using 30 mg daily as the initial dose tended to be older and female and have a smaller body size. The patients using 30 mg of afatinib daily as their initial dose had a similar response rate to those receiving 40 mg daily (76% vs. 95%, p = 0.0862) and the same disease control rate (100% vs. 100%, p = 0.1486). The PFS was similar between the patients receiving 30 mg or 40 mg of afatinib daily (median PFS: 469 vs. 443 days, log-rank p = 0.8418). Patients receiving 30 mg daily had a significantly lower incidence of diarrhea than those using 40 mg daily (41% vs. 100%, p < 0.0001). CONCLUSION: An initial afatinib dose of 30 mg daily had similar response and progression-free survival rates as an initial dose of 40 mg daily, but resulted in fewer serious ADRs in this study.

Acute respiratory distress syndrome and acute myocarditis developed in a previously healthy adult with influenza B.

BACKGROUND: Influenza B virus infection is generally considered to be mild and is rarely associated pulmonary cardiovascular involvement in adults. However fatal complications may occur. CASE PRESENTATION: A 43-year-old previously healthy Taiwanese male came to our emergency department due to high fever, chills, general malaise and myalgia for about 4 days. An influenza rapid test from a throat swab was negative. Chest radiography showed mild left lung infiltration and levofloxacin was prescribed. However, progressive shortness of breath and respiratory failure developed 48 h later after hospitalization. Emergent intubation was performed and he was transferred to the intensive care unit where oseltamivir (Tamiflu, Roche) 75 mg orally twice daily was given immediately. In the intensive care unit, cardiac catheterization revealed normal coronary arteries. However, a markedly elevated cardiac enzyme level (Troponin I level was up to 71.01 ng/ml), a positive cardiac magnetic resonance imaging findings and no coronary artery stenosis led to the diagnosis of acute myocarditis. Subsequent real-time polymerase chain reaction of endotracheal aspirates was positive for influenza B. His condition gradually improved and he was successfully weaned from the ventilator on day 22. He was discharged without prominent complications on day 35. CONCLUSION: Influenza B infection is not always a mild disease. Early detection, early administration of antiviral agents, appropriate antibiotics and best supportive care, is still the gold standard for patients such as the one reported.

Up-regulation of PER3 Expression Is Correlated with Better Clinical Outcome in Acute Leukemia.

BACKGROUND: Altered expression of circadian clock genes has been linked to various types of cancer. This study aimed to investigate whether these genes are also altered in acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL). MATERIALS AND METHODS: The expression profiles of nine circadian clock genes of peripheral blood (PB) leukocytes from patients with newly-diagnosed AML (n=41), ALL (n=23) and healthy individuals (n=51) were investigated. RESULTS: In AML, the expression of period 1 (PER1), period 2 (PER2), period 3 (PER3), cryptochrome 1 (CRY1), cryptochrome 2 (CRY2), brain and muscle aryl hydrocarbon receptor nuclear translocator (ARNT)-like 1 (BMAL1), and timeless (TIM) was significantly down-regulated, while that of CK1ε was significantly up-regulated. In ALL, the expression of PER3 and CRY1 was significantly down-regulated, whereas those of CK1ε and TIM were significantly up-regulated. Recovery of PER3 expression was observed in both patients with AML and those with ALL who achieved remission but not in patients who relapsed after treatment. CONCLUSION: Circadian clock genes are altered in patients with acute leukemia and up-regulation of PER3 is correlated with a better clinical outcome.

Port type is a possible risk factor for implantable venous access port-related bloodstream infections and no sign of local infection predicts the growth of gram-negative bacilli.

BACKGROUND: Implantable venous access port (IVAP)-related blood stream infections (BSIs) are one of the most common complications of implantable venous ports. The risk factors and pathogens for IVAP-related BSIs are still controversial. METHODS: We retrospectively reviewed all patients who received IVAPs at a Hospital in Taiwan from January 1, 2011 to June 31, 2014. Two types of venous port, BardPort® 6.6 fr (Bard port) and Autosuture Chemosite® 7.5 fr (TYCO port) were used. All patients with clinically proven venous port-related BSIs were enrolled. RESULTS: A total of 552 patients were enrolled. There were 34 episodes of IVAP-related BSIs during the study period for a total incidence of 0.177 events/1000 catheter days. Port type (TYCO vs. Bard, HR = 7.105 (95% confidence interval (CI), 1.688-29.904), p = 0.0075), age > 65 years (HR = 2.320 (95 % CI, 1.179-4.564), p = 0.0148), and lung cancer (HR = 5.807 (95% CI, 2.946-11.447), p < 0.001) were risk factors for port infections. We also found that no local sign of infection was significantly associated with the growth of gram-negative bacilli (p = 0.031). CONCLUSIONS: TYCO venous ports, age > 65 years, and lung cancer were all significant risk factors for IVAP-related BSIs, and no sign of infection was significantly associated with the growth of gram-negative bacilli.

Legionnaires' disease caused by Legionella longbeachae in Taiwan, 2006-2010.

The aim of the present study was to investigate the epidemiology of Legionnaires' disease (LD) caused by Legionella longbeachae in Taiwan during 2006-2010. A total of six cases were identified prospectively, accounting for 1.6% of all laboratory-confirmed LD cases and 4.4% of culture-positive LD cases. All six cases occurred between April and August. The male to female ratio was 0.5. These six LD patients had a higher median age than those with LD due to Legionella pneumophila. Four of the six patients presented with pleural effusion and five survived the infection episode. Only two patients had a potential soil contact history prior to LD onset. The patients resided in divergent geographical areas without a common exposure history. The individual genomic DNA banding patterns of the six L. longbeachae isolates analyzed by pulsed-field gel electrophoresis (PFGE) were unique, supporting the hypothesis that the L. longbeachae infections occurred sporadically.

MDM2 promoter polymorphism and p53 codon 72 polymorphism in chronic myeloid leukemia: the association between MDM2 promoter genotype and disease susceptibility, age of onset, and blast-free survival in chronic phase patients receiving imatinib.

The genetic or functional inactivation of the p53 pathway plays an important role with regards to disease progression from the chronic phase (CP) to blast phase (BP) and imatinib treatment response in chronic myeloid leukemia (CML). Two functional single nucleotide polymorphisms (SNPs), p53 R72P and MDM2 SNP309, are associated with alternation of p53 activity, however the association regarding CML susceptibility and BP transformation under imatinib treatment is unclear. The MDM2 SNP309 genotype was determined by polymerase chain reaction-restriction fragment length polymorphism and confirmed by direct sequencing from 116 CML patients, including 104 in the CP at diagnosis, and 162 healthy Taiwanese controls. The p53 R72P polymorphism was examined in all CML patients. The SNP309 G/G genotype was associated with an increased risk of CML susceptibility (OR: 1.82, 95% CI: 1.03-3.22, P = 0.037), and an earlier age of disease onset (log-rank P = 0.005) compared with the T/T + T/G genotypes. Higher MDM2 mRNA expression was found in G/G genotype compared with T/T (P = 0.034) and T/T + T/G (P = 0.056) genotypes. No associations were found between the p53 R72P genotypes and clinical parameters and survival outcomes. Among 62 CP patients receiving imatinib as first-line therapy, the G/G genotype was associated with a shorter blast-free survival (log-rank P = 0.048) and more clonal evolution compared with the T/T + T/G genotypes. In patients with advanced diseases at diagnosis, the G/G genotype was associated with a poor overall survival (log-rank P = 0.006). Closely monitoring CML patients harboring the G/G genotype and further large-scale studies are warranted.

Outcome of allotransplants in patients with chronic-phase chronic myeloid leukemia following imatinib failure: prognosis revisited.

BACKGROUND: The outcome of allotransplants in patients with chronic -phase (CP) chronic myeloid leukemia (CML) who progressed to accelerated phase (AP) or blast phase (BP) following imatinib failure, especially those without preceding suboptimal response, remains unclear. PATIENTS AND METHODS: One hundred and five patients with newly-diagnosed CML-CP were retrospectively reviewed. Sixty-six patients received first-line imatinib therapy, 26 received interferon followed by imatinib, and 13 received front-line allotransplants. RESULTS: No significant differences were found in overall survival (p=0.57) and blast-free survival (p=0.25) between different first-line therapies. Among 66 imatinib-treated patients, 18 (27.3%) developed imatinib failure, 14 (21.2%) progressed to AP/BP, including eight without preceding suboptimal response. Compared to front-line allotransplant, patients with imatinib failure had a significantly worse overall survival after allotransplants (p=0.015), mainly due to an increase of treatment-related mortality. CONCLUSION: Early recognition of imatinib-treated patients who should receive an allotransplant is important rather than waiting until imatinib failure with disease progression.

Higher lipocalin 2 expression may represent an independent favorable prognostic factor in cytogenetically normal acute myeloid leukemia.

Abstract Several molecular markers, such as NPM1, FLT3 and CEBPA, have been incorporated into both the World Health Organization and European LeukemiaNet classifications as routine assessments for the diagnosis and evaluation of prognostic significance in acute myeloid leukemia (AML). Lipocalin 2 (LCN2) is related to cancer development and is believed to be associated with the outcome of cytogenetically normal (CN)-AML. In the present study, we analyzed the prognostic effects and interactions of LCN2 expression (by molecular analysis, quantitative real-time polymerase chain reaction [qRT-PCR]) with neucleophosmin 1, fms-related tyrosine kinase 3 (FLT3) and CCAAT/enhancer-binding protein alpha mutations in 85 patients with CN-AML receiving intensive induction chemotherapy. Our results indicate that patients with higher LCN2 mRNA expression in the bone marrow (LCN2high), especially in combination with wild type FLT3-ITD, had better prognoses. FLT3-ITD compensated LCN2-overexpression-enhanced oxidative stress-induced apoptosis in cell line studies. In conclusion, LCN2high was associated with better prognosis, and FLT3 status had an adjuvant effect on overall survival.

Herpes zoster is associated with an increased risk of subsequent lymphoid malignancies - a nationwide population-based matched-control study in Taiwan.

BACKGROUND: Infectious agents have been shown to contribute to the development of lymphoid malignancies. The different distribution of lymphoid malignancies in Asian and Western populations suggests possibly different etiologies in Asian populations. Herpes zoster infection, commonly seen in immunocompromised persons, has been reported to be associated with lymphoid malignancies in retrospective case-control studies from Western populations, but the results are controversial and large-scale prospective studies from Asian populations are lacking. METHODS: A nationwide population-based matched-controlled prospective study on Taiwanese patients was performed using the National Health Insurance Research Database from 1996 to 2007. Herpes zoster and malignancies were defined by compatible ICD-9-CM (International Classification of Disease, 9th Revision, Clinical Modification) codes. Patients who had been diagnosed with any malignancies before herpes zoster, with known viral infections including human immunodeficiency virus, and duration from herpes zoster to diagnosis of malignancies less than 6 months were excluded. RESULTS: Of 42,498 patients with herpes zoster prior to the diagnosis of any malignancies, the cumulative incidence for lymphoid malignancies was 0.11% (n = 48), compared with 0.06% (n = 106) in 169,983 age- and gender-matched controls (univariate hazard ratio (HR): 1.82, 95%CI: 1.29-2.55). The most common lymphoid malignancy was non-Hodgkin's lymphoma (60.4%, n = 29), followed by multiple myeloma (27.1%, n = 13). Risk for developing lymphoid malignancies is significantly higher in herpes zoster patients (log rank P = 0.005). After adjusting for presence of any comorbidities in Charlson comorbidity index, time-dependent covariate for herpes group, and income category using Cox proportional hazard regressions, herpes zoster patients had an increased risk of developing lymphoid malignancies (adjusted HR: 1.68, 95%CI: 1.35-2.42, P = 0.0026), but did not have an increased risk of developing non-lymphoid malignancies (adjusted HR: 1.00, 95%CI: 0.91-1.05, P = 0.872). CONCLUSION: Preceding herpes zoster infection is an independent risk marker for subsequent lymphoid malignancies in Taiwanese subjects. Further studies are warranted for pathogenesis exploration and preventive strategies in Asian populations.

Induction of cellular senescence by doxorubicin is associated with upregulated miR-375 and induction of autophagy in K562 cells.

BACKGROUND: Cellular senescence is a specialized form of growth arrest that is generally irreversible. Upregulated p16, p53, and p21 expression and silencing of E2F target genes have been characterized to promote the establishment of senescence. It can be further aided by the transcriptional repression of proliferation-associated genes by the action of HP1γ, HMGA, and DNMT proteins to produce a repressive chromatin environment. Therefore, senescence has been suggested to functions as a natural brake for tumor development and plays a critical role in tumor suppression and aging. METHODOLOGY/PRINCIPAL FINDINGS: An in vitro senescence model has been established by using K562 cells treated with 50 nM doxorubicin (DOX). Since p53 and p16 are homozygously deleted in the K562 cells, the DOX-induced senescence in K562 cells ought to be independent of p53 and p16-pRb pathways. Indeed, no change in the expression of the typical senescence-associated premalignant cell markers in the DOX-induced senescent K562 cells was found. MicroRNA profiling revealed upregulated miR-375 in DOX-induced senescent K562 cells. Treatment with miR-375 inhibitor was able to reverse the proliferation ability suppressed by DOX (p<0.05) and overexpression of miR-375 suppressed the normal proliferation of K562 cells. Upregulated miR-375 expression was associated with downregulated expression of 14-3-3zeta and SP1 genes. Autophagy was also investigated since DOX treatment was able to induce cells entering senescence and eventually lead to cell death. Among the 24 human autophagy-related genes examined, a 12-fold increase of ATG9B at day 4 and a 20-fold increase of ATG18 at day 2 after DOX treatment were noted. CONCLUSIONS/SIGNIFICANCE: This study has demonstrated that in the absence of p53 and p16, the induction of senescence by DOX was associated with upregulation of miR-375 and autophagy initiation. The anti-proliferative function of miR-375 is possibly exerted, at least in part, by targeting 14-3-3zeta and SP1 genes.