CNS response to osimertinib in patients with T790M-positive advanced NSCLC: pooled data from two phase II trials.

Background: Central nervous system (CNS) metastases are common in patients with non-small-cell lung cancer (NSCLC). Osimertinib has shown systemic efficacy in patients with CNS metastases, and early clinical evidence shows efficacy in the CNS. To evaluate osimertinib activity further, we present a pre-specified subgroup analysis of CNS response using pooled data from two phase II studies: AURA extension (NCT01802632) and AURA2 (NCT02094261). Patients and methods: Patients with T790M-positive advanced NSCLC, who had progressed following prior epidermal growth factor receptor-tyrosine kinase inhibitor treatment, received osimertinib 80 mg od (n = 411). Patients with stable, asymptomatic CNS metastases were eligible for enrolment; prior CNS treatment was allowed. Patients with ≥1 measurable CNS lesion (per RECIST 1.1) on baseline brain scan by blinded independent central neuroradiology review (BICR) were included in the evaluable for CNS response set (cEFR). The primary outcome for this CNS analysis was CNS objective response rate (ORR) by BICR; secondary outcomes included CNS duration of response, disease control rate (DCR) and progression-free survival (PFS). Results: Of 128 patients with CNS metastases on baseline brain scans, 50 were included in the cEFR. Confirmed CNS ORR and DCR were 54% [27/50; 95% confidence interval (CI) 39-68] and 92% (46/50; 95% CI 81-98), respectively. CNS response was observed regardless of prior radiotherapy to the brain. Median CNS duration of response (22% maturity) was not reached (range, 1-15 months); at 9 months, 75% (95% CI 53-88) of patients were estimated to remain in response. Median follow-up for CNS PFS was 11 months; median CNS PFS was not reached (95% CI, 7, not calculable). The safety profile observed in the cEFR was consistent with the overall patient population. Conclusions: Osimertinib demonstrated clinically meaningful efficacy against CNS metastases, with a high DCR, encouraging ORR, and safety profile consistent with that reported previously. ClinicalTrials.gov number: NCT01802632; NCT02094261.

Single-photon avalanche diodes in 0.18-µm high-voltage CMOS technology.

We have designed and fabricated high-performance single-photon avalanche diodes (SPADs) by using 0.18-µm high-voltage CMOS technology. Without any technology customization, the SPADs have low dark-count rate, high photon-detection probability, low afterpulsing probability, and acceptable timing jitter and breakdown voltage. Our design provides a low-cost and high-performance SPAD for various applications.

Platelet factor 4 upregulates matrix metalloproteinase-1 production in gingival fibroblasts.

BACKGROUND AND OBJECTIVE: Periodontitis is a highly prevalent chronic inflammatory disease that causes tooth loss, morbidity and confers an increased risk for systemic disease. Tissue destruction during periodontitis is due in large part to collagen-degrading matrix metalloproteinases (MMPs) released by resident cells of the periodontium in response to proinflammatory cytokines. Platelets are immune-competent blood cells with a newly recognized role in chronic inflammation; however, their role in the pathogenesis of periodontitis is undefined. Consequently, the objective of this study was to assess the effect of platelet factor 4 (PF4), a major platelet-derived cytokine, on MMP-1 (collagenase) expression in human gingival fibroblasts (HGFs). MATERIAL AND METHODS: HGFs were cultured in the presence or absence of recombinant PF4. Pro-MMP-1 secretion was quantified by enzyme-linked immunosorbent assay analysis of the cell culture supernatants. MMP-1 transcription was quantified by real-time polymerase chain reaction. Regulation of MMP-1 production by the p44/42 MAP kinase (MAPK) signaling pathway was examined in the presence or absence of PF4. RESULTS: Exposure to PF4 caused a ~ 2-3-fold increase in MMP-1 transcription and secretion from cultured HGFs. PF4 treatment also enhanced phosphorylation of p44/42 MAPK, which has been previously shown to induce MMP-1 expression in fibroblasts. Blockade of p44/42 MAPK signaling with the cell-permeant inhibitors PD98059 and PD184352 abrogated PF4-induced pro-MMP-1 transcription upregulation and release from cultured HGFs. CONCLUSION: We conclude that PF4 upregulates MMP-1 expression in HGFs in a p44/42 MAPK-dependent manner. These findings point to a previously unidentified role for platelets in the pathogenesis of periodontal diseases.

A randomized, double-blind, placebo-controlled, phase III trial of erlotinib with or without a c-Met inhibitor tivantinib (ARQ 197) in Asian patients with previously treated stage IIIB/IV nonsquamous nonsmall-cell lung cancer harboring wild-type epidermal growth factor receptor (ATTENTION study).

BACKGROUND: A previous randomized phase II study demonstrated that the addition of a c-Met inhibitor tivantinib to an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor erlotinib might prolong progression-free survival (PFS) in patients with previously treated, nonsquamous nonsmall-cell lung cancer (NSCLC). On a subset analysis, the survival benefit was greater in patients with wild-type EGFR (WT-EGFR) than in those with activating EGFR mutations. Herein, this phase III study compared overall survival (OS) between Asian nonsquamous NSCLC patients with WT-EGFR who received erlotinib plus tivantinib (tivantinib group) or erlotinib plus placebo (placebo group). METHODS: A total of 460 NSCLC patients were planned to be randomized to the tivantinib or placebo group. Primary end point was OS. Secondary end points were PFS, tumor response, and safety. Tissue was collected for biomarker analysis, including c-Met and HGF expression. RESULTS: Enrollment was stopped when 307 patients were randomized, following the Safety Review Committee's recommendation based on an imbalance in the interstitial lung disease (ILD) incidence between the groups. ILD developed in 14 patients (3 deaths) and 6 patients (0 deaths) in the tivantinib and the placebo groups, respectively. In the enrolled patients, median OS was 12.7 and 11.1 months in the tivantinib and the placebo groups, respectively [hazard ratio (HR) = 0.891, P = 0.427]. Median PFS was 2.9 and 2.0 months in the tivantinib and the placebo groups, respectively (HR = 0.719, P = 0.019). The commonly observed grade ≥ 3 adverse events in the tivantinib group were neutropenia (24.3%), leukopenia (18.4%), febrile neutropenia (13.8%), and anemia (13.2%). CONCLUSIONS: This study was prematurely terminated due to the increased ILD incidence in the tivantinib group. Although this study lacked statistical power because of the premature termination and did not demonstrate an improvement in OS, our results suggest that tivantinib plus erlotinib might improve PFS than erlotinib alone in nonsquamous NSCLC patients with WT-EGFR. TRIAL REGISTRATION NUMBER: NCT01377376.

Randomised clinical trial: gut microbiome biomarkers are associated with clinical response to a low FODMAP diet in children with the irritable bowel syndrome.

BACKGROUND: A low fermentable oligosaccharides, disaccharides, monosaccharides and polyols (FODMAP) diet can ameliorate symptoms in adult irritable bowel syndrome (IBS) within 48 h. AIM: To determine the efficacy of a low FODMAP diet in childhood IBS and whether gut microbial composition and/or metabolic capacity are associated with its efficacy. METHODS: In a double-blind, crossover trial, children with Rome III IBS completed a 1-week baseline period. They then were randomised to a low FODMAP diet or typical American childhood diet (TACD), followed by a 5-day washout period before crossing over to the other diet. GI symptoms were assessed with abdominal pain frequency being the primary outcome. Baseline gut microbial composition (16S rRNA sequencing) and metabolic capacity (PICRUSt) were determined. Metagenomic biomarker discovery (LEfSe) compared Responders (≥50% decrease in abdominal pain frequency on low FODMAP diet only) vs. Nonresponders (no improvement during either intervention). RESULTS: Thirty-three children completed the study. Less abdominal pain occurred during the low FODMAP diet vs. TACD [1.1 ± 0.2 (SEM) episodes/day vs. 1.7 ± 0.4, P < 0.05]. Compared to baseline (1.4 ± 0.2), children had fewer daily abdominal pain episodes during the low FODMAP diet (P < 0.01) but more episodes during the TACD (P < 0.01). Responders were enriched at baseline in taxa with known greater saccharolytic metabolic capacity (e.g. Bacteroides, Ruminococcaceae, Faecalibacterium prausnitzii) and three Kyoto Encyclopedia of Genes and Genomes orthologues, of which two relate to carbohydrate metabolism. CONCLUSIONS: In childhood IBS, a low FODMAP diet decreases abdominal pain frequency. Gut microbiome biomarkers may be associated with low FODMAP diet efficacy. ClinicalTrials.gov identifier: NCT01339117.

Age-related changes in dynamic compressive properties of trochanteric soft tissues over the hip.

Hip fracture risk increases dramatically with age, and 90% of fractures are due to falls. During a fall on the hip, the soft tissues overlying the hip region (skin, fat, and muscle) act as shock absorbers to absorb energy and reduce the peak force applied to the underlying bone. We conducted dynamic indentation experiments with young women (aged 19-30; n=17) and older women (aged 65-81; n=17) to test the hypothesis that changes occur with age in the stiffness and damping properties of these tissues. Tissue stiffness and damping were derived from experiments where subjects lay sideways on a bed with the greater trochanter contacting a 3.8cm diameter indenter, which applied sinusoidal compression between 5 to 30Hz with a peak-to-peak amplitude of 1mm. Soft tissue thickness was measured using ultrasound. On average, stiffness was 2.9-fold smaller in older than young women (5.7 versus 16.8kN/m, p=0.0005) and damping was 3.5-fold smaller in older than young women (81 versus 282Ns/m, p=0.001). Neither parameter associated with soft tissue thickness. Our results indicate substantial age-related reductions in the stiffness and damping of soft tissues over the hip region, which likely reduce their capacity to absorb and dissipate energy (before "bottoming out") during a fall. Strategies such as wearable hip protectors or compliant flooringmay compensate for age-related reductions in the shock-absorbing properties of soft tissues and decrease the injury potential of falls.

Randomised controlled trial on the effectiveness of home-based walking exercise on anxiety, depression and cancer-related symptoms in patients with lung cancer.

BACKGROUND: Although exercise has been addressed as an adjuvant treatment for anxiety, depression and cancer-related symptoms, limited studies have evaluated the effectiveness of exercise in patients with lung cancer. METHODS: We recruited 116 patients from a medical centre in northern Taiwan, and randomly assigned them to either a walking-exercise group (n=58) or a usual-care group (n=58). We conducted a 12-week exercise programme that comprised home-based, moderate-intensity walking for 40 min per day, 3 days per week, and weekly exercise counselling. The outcome measures included the Hospital Anxiety and Depression Scale and the Taiwanese version of the MD Anderson Symptom Inventory. RESULTS: We analysed the effects of the exercise programme on anxiety, depression and cancer-related symptoms by using a generalised estimating equation method. The exercise group patients exhibited significant improvements in their anxiety levels over time (P=0.009 and 0.006 in the third and sixth months, respectively) and depression (P=0.00006 and 0.004 in the third and sixth months, respectively) than did the usual-care group patients. CONCLUSIONS: The home-based walking exercise programme is a feasible and effective intervention method for managing anxiety and depression in lung cancer survivors and can be considered as an essential component of lung cancer rehabilitation.

A phase II study of erlotinib in combination with bevacizumab versus chemotherapy plus bevacizumab in the first-line treatment of advanced non-squamous non-small cell lung cancer.

BACKGROUND: Molecularly targeted agents for non-small cell lung cancer (NSCLC) can provide similar efficacy to chemotherapy without chemotherapy-associated toxicities. Combining two agents with different modes of action could further increase the efficacy of these therapies. The TASK study evaluated the efficacy and safety of the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib in combination with the anti-angiogenic agent bevacizumab as first-line therapy in unselected, advanced non-squamous NSCLC patients. METHODS: Patients were recruited from December 2007 to September 2008. Planned sample size was 200 patients, a total of 124 patients were randomized. Patients were randomized using a minimization algorithm 1:1 to receive bevacizumab (iv 15 mg/kg day 1 of each 21-day cycle) plus chemotherapy (gemcitabine/cisplatin or carboplatin/paclitaxel standard doses, 4-6 cycles) (BC arm) or bevacizumab plus erlotinib (p.o. 150 mg/day; BE arm) until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival (PFS). If the hazard ratio (HR) of PFS for BE relative to BC was above 1.25 at the pre-planned interim analysis in favor of BC, the study would be re-evaluated. Secondary endpoints included overall survival, response rate and safety. RESULTS: All randomized patients (n = 63 BE; n = 61 BC) were evaluated for the efficacy analyses. At the updated interim analysis, median PFS was 18.4 weeks (95% confidence interval [CI] 17.0-25.1) versus 25.0 weeks (95% CI 20.6-[not reached]) for BE versus BC, respectively (HR for death or disease progression, BE relative to BC, 2.05, p = 0.0183). The incidence of death was 19% for BE treatment compared with 11.5% for BC treatment. The HR for PFS at the updated interim analysis was above 1.25, therefore patients on the BE arm were permitted to change arms or switch to another drug and the study was terminated. Adverse events reported were as expected. CONCLUSIONS: The TASK study did not show a benefit in terms of PFS for the combination of erlotinib with bevacizumab in unselected first-line advanced non-squamous NSCLC compared with chemotherapy plus bevacizumab.

Survivin SNP-carcinogen interactions in oral cancer.

UNLABELLED: In Taiwan, oral cancer is causally associated with environmental carcinogens. Survivin is an anti-apoptotic protein and is generally considered a marker of malignancy. The current study explored the combined effect of survivin gene polymorphisms and environmental carcinogens on the risk and clinico-pathological development of oral cancer. Five single-nucleotide polymorphisms (SNPs) of survivin genes from 439 male patients with oral cancer and 424 male control participants (who did not have cancer) were analyzed. The survivin -31GG, +9194 GG, and +9809 TT homozygotes exhibited higher risk for oral cancer compared with the corresponding ancestral genotype, after adjustment for related confounders. The survivin -31, +9194, and +9809 SNPs combined with betel quid chewing and/or tobacco consumption could robustly elevate susceptibility to oral cancer. The distribution frequency of the -31 G: +9194 A: +9809 T haplotype was significantly higher in oral cancer patients than in control participants. These results suggest that survivin gene polymorphisms and their interactions with environmental carcinogens may increase susceptibility to oral cancer in Taiwanese men. ABBREVIATIONS: AOR, adjusted odds ratio; CI, confidence intervals; PCR, polymerase chain-reaction; SNP, single-nucleotide polymorphisms.

A randomised phase II study of weekly paclitaxel or vinorelbine in combination with cisplatin against inoperable non-small-cell lung cancer previously untreated.

Phase II studies have suggested that weekly paclitaxel has a higher response rate and better toxicity profile than the conventional schedule of once every 3 or 4 weeks. Our aim was to evaluate the efficacy of weekly paclitaxel plus cisplatin (PC) vs vinorelbine plus cisplatin (VC) in chemonaïve non-small-cell lung cancer (NSCLC) patients. From October 2000 to May 2002, 140 patients were enrolled. The treatment dose was P 66 mg m(-2) intravenous infusion (i.v.) on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, or V 23 mg m(-2) i.v. on days 1, 8, and 15, and C 60 mg m(-2) i.v. on day 15, every 4 weeks. In all, 281 cycles of PC and 307 cycles of VC were given to the patients in the PC and VC arms, respectively. There were 26 partial responses and one complete response (overall 38.6%) in the PC arm, and no complete responses, but 27 partial responses (overall 38.6%) in the VC arm. Myelosuppression was more common in the VC arm (P<0.001). Peripheral neuropathy and myalgia were significantly more common in the PC arm (P<0.001). The median time to disease progression was 6 months in the PC arm and 8.4 months in the VC arm (P=0.0344). The median survival time was 11.7 months in the PC arm and 15.4 months in the VC arm (P=0.297). We concluded that weekly PC is not suggested for NSCLC patients due to the relatively shorter progression-free survival and more common nonhaematological toxicities. British Journal of Cancer (2004) 90, 359-365. doi:10.1038/sj.bjc.6601526 www.bjcancer.com

Pleural effusion and serum soluble fas-ligand levels are elevated in different clinical conditions.

Fas ligand (FasL) plays an important role in the regulation of apoptosis. Soluble FasL (sFasL) is produced by a cleavage of FasL from the cell surface by metalloproteinase. Whether or not sFasL exists or is elevated in the pleural effusion of different etiologies is unknown. The present study is designed to determine pleural effusion and serum sFasL levels under different clinical conditions, and ascertain if there exists a significant difference in the levels found in different clinical conditions, and whether this difference can be used as a tool for differential diagnosis. Soluble FasL levels in the pleural effusion and serum of 103 patients, including 37 with malignant pleural effusion, 24 with uncomplicated parapneumonic effusion, 8 with bacterial empyema, 16 with tuberculous pleurisy, and 18 with transudate effusion (8 with congestive heart failure and 10 with viral liver cirrhosis), were analyzed with ELISA assays. Pleural effusion from patients with bacterial empyema (median 79.4 pg/ml) and TB pleurisy (median 31.9 pg/ml) contained significantly higher amounts of sFasL than the pleural effusion from all other conditions studied (p <0.001). Viral liver cirrhosis had a significantly higher serum sFasL level (median 53.6 pg/ml, p = 0.025, when compared with other patients). Patients with congestive heart failure had the lowest serum sFasL levels when compared with other patients (p = 0.014). There was no significant correlation between pleural effusion sFasL levels and other parameters, such as effusion LDH, cell count, neutrophil, and lymphocyte percentage. In conclusion, soluble FasL is a useful marker for the differentiation of bacterial empyema and TB pleurisy from other disease entities. In addition, the elevation of serum sFasL levels in viral liver cirrhosis can also be used to differentiate cirrhosis from congestive heart failure, in which both effusions are transudate.

Gemcitabine and cisplatin in a multimodality treatment for locally advanced non-small cell lung cancer.

The role of new cytotoxic agents like gemcitabine has not yet been proven in the neoadjuvant settings. We designed a phase II study to test the feasibility of using gemcitabine and cisplatin before local treatment for stage III non-small cell lung cancer patients. Patients received three cycles of induction chemotherapy of gemcitabine (1000 mg m(-2), days 1, 8, 15) and cisplatin (90 mg m(-2), day 15) every 4 weeks before evaluation for operability. Operable patients underwent radical resection. Inoperable patients and patients who had incomplete resection received concurrent chemoradiotherapy with daily low dose cisplatin. All patients who did not progress after local treatment received three more cycles of adjuvant chemotherapy of gemcitabine and cisplatin. Fifty-two patients received induction treatment. Two patients had complete response and 31 patients had partial response (response rate 63.5%) after induction chemotherapy. Thirty-six patients (69%) were operable. Eighteen patients (35%) had their tumours completely resected. Two patients had pathological complete response. Median overall survival was 19.1 months, projected 1-year survival was 66% and 2-year survival was 34%. Three cycles of gemcitabine and cisplatin is effective and can be used as induction treatment before surgery for locally advanced non-small cell lung cancer patients.

Paclitaxel plus carboplatin, compared with paclitaxel plus gemcitabine, shows similar efficacy while more cost-effective: a randomized phase II study of combination chemotherapy against inoperable non-small-cell lung cancer previously untreated.

BACKGROUND: Paclitaxel (Taxol) plus carboplatin (PC) has shown activity in the treatment of advanced non-small-cell lung cancer (NSCLC). Non-platinum-containing combination chemotherapy, such as paclitaxel plus gemcitabine (PG), has also demonstrated reasonable efficacy. Our aim here was to evaluate the clinical efficacy and cost-effectiveness of PC versus PG in chemo-naive. advanced NSCLC patients. PATIENTS AND METHODS: Ninety (68 male, 22 female) patients were enrolled from August 1999 to August 2000. The performance status was one in 29 patients and two in 16 patients of the PC group, and one in 24 patients and two in 21 patients of the PG group. Seventeen patients had stage IIIb disease and 28 patients stage IV disease in the PC group: 18 patients had stage IIIb disease and 27 patients stage IV disease in the PG group (New International Staging System). Treatment consisted of P 175 mg/m2 and C at AUC = 7 (predicted using measured clearances and the Calvert formula) intravenous infusion (i.v.) on day 1, or P 175 mg/m2 i.v. on day 1 and G 1000 mg/m2 i.v. on days 1 and 8, every 3 weeks. RESULTS: In all, 175 cycles of PC and 184 cycles of PG were given in the PC and PG groups, respectively. The median treatment cycle was four cycles in both groups. All the patients were assessable for toxicity and response measurement. There were three complete responses and 15 partial responses (overall 40%) in the PC group, and no complete response, but 18 partial responses (overall 40%) in the PG group. WHO grades 3/4 leukopenia, anemia and thrombocytopenia occurred in six (13.3%), seven (15.5%) and five patients (11.1%) in the PC group; and in four (8.9%), six (13.3%) and 0 patients in the PG group, respectively. Two patients in each group suffered from grade 3 peripheral neuropathy. Other non-hematological toxicities were mild and few. Median survival time was 14.1 months in the PC group and 12.6 months in the PG group. One-year survival was 50.7% in the PC group and 53.3% in the PG group. The PG group had a higher total expense and expended more days undergoing treatment than the PC group (P = 0.034 and 0.069, respectively). CONCLUSIONS: Both PC and PG combination chemotherapy produce a similar efficacy in the treatment of NSCLC. However, PC is more cost-effective than PG.

Human masticatory muscle activity and jaw position under experimental stress.

The purpose of the present study was to determine whether stress induced a consistent pattern of increased electromyographic (EMG) activity in different masticatory muscles, and whether stress produced changes in jaw position. Thirty-five dental students at Taipei Medical College volunteered for this study. Mental arithmetic was used to create a stress condition and relaxation instruction was used to help relax the subjects. Subjects were asked to evaluate the stress they felt under each experimental condition with a visual analogue scale (VAS). Surface electrodes were used to monitor the EMG activities of the right masseter, right posterior temporalis and suprahyoid muscles. A kinesiograph was used to observe the jaw position. Data collected before mental arithmetic or relaxation monitored the baseline level. The VAS means were significantly increased during the stress condition and significantly decreased following relaxation, compared with the baseline. There was also a significant increase in EMG activity of all three muscles during mental arithmetic compared with baseline; different patterns of increased EMG activity were noticed in the three muscles under a continuous stress condition. Under stress, the incidence of tooth contact at intercuspal position was also increased.

Genetic analysis of conservation and variation of lipooligosaccharide expression in two L8-immunotype strains of Neisseria meningitidis.

Neisseria meningitidis strains A1 and M978 both express the lipooligosaccharide (LOS) L8 immunotype [Gu et al., J. Clin. Microbiol. 30 (1992) 2047-2053]. Under different growth conditions, strain A1 did not change its LOS profile whereas strain M978 produced variable LOS profiles on SDS-PAGE. To understand the genetic basis of LOS conservation and variation, their lgt locus encoding glycosyltransferases responsible for the biosynthesis of the alpha-chain of LOS was analyzed. Strain A1 possessed only two genes, lgtA and lgtH, at the lgt locus. The lgtA gene was inactivated due to a frameshift mutation; thus strain A1 expressed only L8 LOS. In contrast, strain M978 contained five genes lgtZ, lgtC, lgtA, lgtB and lgtE at this locus, thus it had a potential to express L1, L3,7 in addition to the L8 LOS. The data showed that strain A1 is a better reference strain for the L8 immunotype because of the stability of L8 LOS expression resulting from its unique lgt locus. In addition, these two strains had two new genetic organizations, lgtAH and lgtZCABE, compared to the reported gene organization at the lgt locus in N. meningitidis.

Interleukin-7 and interleukin-12 have different effects in rescue of depressed cellular immunity: comparison of malignant and tuberculous pleural effusions.

The present study attempts to determine the role of interleukin-7 (IL-7) and IL-12 in recovering the functions of the lymphocytes of malignant effusion, in terms of cytokine production, proliferation, and cytolytic activity, compared with lymphocytes from tuberculous pleural effusion. Effusion-associated lymphocytes (EAL) were isolated from tuberculous (tEAL) and malignant (mEAL) pleural effusions. The EAL proliferate response was measured after 3 days in culture. Interferon-gamma (IFN-gamma) production and cytotoxicity against K-562 cells or autologous tumor cells were assessed after 6 days in culture. It was found that the mEAL had depressed proliferation, IFN-gamma production, and cytolytic activity, as compared with tEAL. Stimulation with IL-12 plus IL-2, but not with IL-7 plus IL-2, fully restored the IFN-gamma production of mEAL to that of tEAL levels. In contrast, the proliferate response of mEAL was enhanced significantly more with IL-7 plus IL-2 than with IL-12 plus IL-2. Both the IL-7 plus IL-2 and IL-12 plus IL-2 stimulation of mEAL showed a significant increase in cytolytic activity against autologous tumor cells, although the cytolytic activity against K-562 cells did not increase. These results suggest that tEAL had a higher cellular activity than mEAL. This depressed cellular function of mEAL could be reversed with cytokines. However, different cytokines had different effects on mEAL; for example, IL-7 had a better effect in the stimulation of lymphocyte proliferation compared with IL-12, which had a better effect in driving the lymphocytes to the T helper 1 (TH1) pathway and a higher IFN-gamma production. Both IL-7 and IL-12, in the presence of IL-2, can restore the immunosuppressed cytolytic activity of the lymphocytes of malignant pleural effusion against autologous tumor.

Overexpression of dihydrodiol dehydrogenase as a prognostic marker of non-small cell lung cancer.

By using mRNA differential display to examine specimens of non-small cell lung cancer (NSCLC), we have identified overexpression of dihydrodiol dehydrogenase (DDH) that was not detected in the corresponding normal lung tissue. Normally DDH is associated with catalysis of polycyclic aromatic hydrocarbons (PAHs) in the liver; in NSCLC cells, DDH expression would implicate an association with disease progression. In this study we investigated the prognostic significance of DDH expression in patients with NSCLC. By using immunohistochemistry, we measured DDH expression in 381 patients with NSCLC. The relationship between DDH expression and clinicopathological parameters (age, gender, smoking history, mitotic index, histological type, stage, cell differentiation, and lymphovascular invasion) was analyzed by chi2 analysis. Survival curves were plotted with the method of Kaplan-Meier, and statistical difference of survivals between different groups was compared by a log-rank test. Our results showed that DDH overexpression could be detected in 317 (83.2%) of 381 pathological sections and in 77.9% (60 of 77) of metastatic lymph nodes. Expression of DDH was confirmed by immunoblotting. Compared with patients with DDH overexpression in tumors, patients with low DDH expression had significantly lower incidence of early tumor recurrence and distant organ metastasis (46.7 versus 29.7%; P = 0.045). Interestingly, survival was also significantly better in patients with low DDH expression than in those with DDH overexpression (P = 0.0017). Using univariate analysis, we correlated three important factors, DDH overexpression, tumor stages, and gender, with poor prognosis for NSCLC patients. Nevertheless, biological function and involvement of DDH in the disease progression of NSCLC require additional studies.

Efficient off-resonance correction for spiral imaging.

A new spiral imaging technique incorporates the acquisition of a field map into imaging interleaves. Variable density spiral trajectories are designed to oversample the central region of k-space, and interleaves are acquired at two different echo times. A field map is extracted from this data and multifrequency reconstruction is used to form an off-resonance corrected image using the entire dataset. Simulation, phantom, and in vivo results indicate that this technique can be used to achieve higher image and/or field map spatial resolution compared to conventional techniques. Magn Reson Med 45:521-524, 2001.

An analysis of cytokine status in the serum and effusions of patients with tuberculous and lung cancer.

The present study was designed to ascertain whether or not the pleural effusion and serum cytokine levels (granulocyte-macrophage colony-stimulating factor [GM-CSF], interleukin-10 [IL-10], and interferon-gamma [IFN gamma]) in lung cancer patients differ from tuberculous (TB) pleural effusion, in which a strong cellular immune reaction is found; and, whether cytokine levels are a prognostic factor in lung cancer patients with malignant effusion. A total of 202 lung cancer patients with malignant pleural effusion and 26 patients with TB pleural effusion were studied consecutively between 1995 and 1998. Serum and effusion cytokine levels were analyzed with ELISA assays. The results showed that pleural effusion GM-CSF and IL-10 levels were significantly higher than serum levels in both cancer and TB patients. Pleural effusion IFN gamma levels were significantly higher than serum levels in TB patients. IFN gamma levels in both pleural effusion and serum were significantly higher in TB patients than in those with cancer. No significant difference was found, between TB and cancer patients, in the serum or pleural effusion levels of either IL-10 or GM-CSF. The ratio of pleural effusion IFN gamma to serum IFN gamma, effusion IFN gamma to effusion IL-10, and effusion IL-10 to serum IL-10, were all significantly higher in TB than in cancer patients, suggesting a higher cellular activity and T-helper 1 (Th1) reaction in TB pleural effusion than in malignant effusions, which were predominantly Th2 type. Survival analysis showed no significant difference in lung cancer patients with different levels of these cytokines. It was concluded that lung cancer patients with malignant pleural effusion had poorer immune profiles than those with TB pleurisy, both locally and systemically; and the cytokine profiles were not prognostic factors for lung cancer patients with malignant pleural effusion.