Socs3 ablation in kisspeptin cells partially prevents lipopolysaccharide-induced body weight loss.

Many cytokines have been proposed to regulate reproduction due to their actions on hypothalamic kisspeptin cells, the main modulators of gonadotropin-releasing hormone (GnRH) neurons. Hormones such as leptin, prolactin and growth hormone are good examples of cytokines that lead to Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway activation, consequently exerting effects in kisspeptin neurons. Different studies have investigated how specific components of the JAK/STAT signaling pathway affect the functions of kisspeptin cells, but the role of the suppressor of cytokine signaling 3 (SOCS3) in mediating cytokine actions in kisspeptin cells remains unknown. Cre-Loxp technology was used in the present study to ablate Socs3 expression in kisspeptin cells (Kiss1/Socs3-KO). Then, male and female control and Kiss1/Socs3-KO mice were evaluated for sexual maturation, energy homeostasis features, and fertility. It was found that hypothalamic Kiss1 mRNA expression is significantly downregulated in Kiss1/Socs3-KO mice. Despite reduced hypothalamic Kiss1 mRNA content, these mice did not present any sexual maturation or fertility impairments. Additionally, body weight gain, leptin sensitivity and glucose homeostasis were similar to control mice. Interestingly, Kiss1/Socs3-KO mice were partially protected against lipopolysaccharide (LPS)-induced body weight loss. Our results suggest that Socs3 ablation in kisspeptin cells partially prevents the sickness behavior induced by LPS, suggesting that kisspeptin cells can modulate energy metabolism in mice in certain situations.

Vasoactive intestinal peptide exerts an excitatory effect on hypothalamic kisspeptin neurons during estrogen negative feedback.

Hypothalamic kisspeptin neurons are the primary modulators of gonadotropin-releasing hormone (GnRH) neurons. It has been shown that circadian rhythms driven by the suprachiasmatic nucleus (SCN) contribute to GnRH secretion. Kisspeptin neurons are potential targets of SCN neurons due to reciprocal connections with the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) and the arcuate nucleus of the hypothalamus (ARH). Vasoactive intestinal peptide (VIP), a notable SCN neurotransmitter, modulates GnRH secretion depending on serum estradiol levels, aging or time of the day. Considering that kisspeptin neurons may act as interneurons and mediate VIP's effects on the reproductive axis, we investigated the effects of VIP on hypothalamic kisspeptin neurons in female mice during estrogen negative feedback. Our findings indicate that VIP induces a TTX-independent depolarization of approximately 30% of AVPV/PeN kisspeptin neurons in gonad-intact (diestrus) and ovariectomized (OVX) mice. In the ARH, the percentage of kisspeptin neurons that were depolarized by VIP was even higher (approximately 90%). An intracerebroventricular infusion of VIP leds to an increased percentage of kisspeptin neurons expressing the phosphoSer133 cAMP-response-element-binding protein (pCREB) in the AVPV/PeN. On the other hand, pCREB expression in ARH kisspeptin neurons was similar between saline- and VIP-injected mice. Thus, VIP can recruit different signaling pathways to modulate AVPV/PeN or ARH kisspeptin neurons, resulting in distinct cellular responses. The expression of VIP receptors (VPACR) was upregulated in the AVPV/PeN, but not in the ARH, of OVX mice compared to mice on diestrus and estradiol-primed OVX mice. Our findings indicate that VIP directly influences distinct cellular aspects of the AVPV/PeN and ARH kisspeptin neurons during estrogen negative feedback, possibly to influence pulsatile LH secretion.

Distinct effects of growth hormone deficiency and disruption of hypothalamic kisspeptin system on reproduction of male mice.

Growth hormone (GH) deficiency is a common cause of late sexual maturation and fertility issues. To determine whether GH-induced effects on reproduction are associated with alterations in hypothalamic kisspeptin system, we studied the male reproduction in two distinct GH deficiency mouse models. In the first model, mice present GH deficiency secondary to arcuate nucleus of the hypothalamus (ARH) lesions induced by posnatal monosodium glutamate (MSG) injections. MSG-induced ARH lesions led to significant reductions in hypothalamic Ghrh mRNA expression and consequently growth. Hypothalamic Kiss1 mRNA expression and Kiss1-expressing cells in the ARH were disrupted in the MSG-treated mice. In contrast, kisspeptin immunoreactivity remained preserved in the anteroventral periventricular and rostral periventricular nuclei (AVPV/PeN) of MSG-treated mice. Importantly, ARH lesions caused late sexual maturation and infertility in male mice. In our second mouse model, we studied animals profound GH deficiency due to a loss-of-function mutation in the Ghrhr gene (Ghrhrlit/lit mice). Interestingly, although Ghrhrlit/lit mice exhibited late puberty onset, hypothalamic Kiss1 mRNA expression and hypothalamic kisspeptin fiber density were normal in Ghrhrlit/lit mice. Despite presenting dwarfism, the majority of Ghrhrlit/lit male mice were fertile. These findings suggest that spontaneous GH deficiency during development does not compromise the kisspeptin system. Furthermore, ARH Kiss1-expressing neurons are required for fertility, while AVPV/PeN kisspeptin expression is sufficient to allow maturation of the hypothalamic-pituitary-gonadal axis in male mice.

Triiodothyronine (T3) upregulates the expression of proto-oncogene TGFA independent of MAPK/ERK pathway activation in the human breast adenocarcinoma cell line, MCF7

ABSTRACT Objective: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway Materials and methods: The cell line was treated with T3 at a physiological dose (10−9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%. Results: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA. Conclusion: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.

Triiodothyronine (T3) upregulates the expression of proto-oncogene TGFA independent of MAPK/ERK pathway activation in the human breast adenocarcinoma cell line, MCF7.

OBJECTIVE: To verify the physiological action of triiodothyronine T3 on the expression of transforming growth factor α (TGFA) mRNA in MCF7 cells by inhibition of RNA Polymerase II and the MAPK/ERK pathway. MATERIALS AND METHODS: The cell line was treated with T3 at a physiological dose (10-9M) for 10 minutes, 1 and 4 hour (h) in the presence or absence of the inhibitors, α-amanitin (RNA polymerase II inhibitor) and PD98059 (MAPK/ERK pathway inhibitor). TGFA mRNA expression was analyzed by RT-PCR. For data analysis, we used ANOVA, complemented with the Tukey test and Student t-test, with a minimum significance of 5%. RESULTS: T3 increases the expression of TGFA mRNA in MCF7 cells in 4 h of treatment. Inhibition of RNA polymerase II modulates the effect of T3 treatment on the expression of TGFA in MCF7 cells. Activation of the MAPK/ERK pathway is not required for T3 to affect the expression of TGFA mRNA. CONCLUSION: Treatment with a physiological concentration of T3 after RNA polymerase II inhibition altered the expression of TGFA. Inhibition of the MAPK/ERK pathway after T3 treatment does not interfere with the TGFA gene expression in a breast adenocarcinoma cell line.

STAT5 signaling in kisspeptin cells regulates the timing of puberty.

Previous studies have shown that kisspeptin neurons are important mediators of prolactin's effects on reproduction. However, the cellular mechanisms recruited by prolactin to affect kisspeptin neurons remain unknown. Using whole-cell patch-clamp recordings of brain slices from kisspeptin reporter mice, we observed that 20% of kisspeptin neurons in the anteroventral periventricular nucleus was indirectly depolarized by prolactin via an unknown population of prolactin responsive neurons. This effect required the phosphatidylinositol 3-kinase signaling pathway. No effects on the activity of arcuate kisspeptin neurons were observed, despite a high percentage (70%) of arcuate neurons expressing prolactin-induced STAT5 phosphorylation. To determine whether STAT5 expression in kisspeptin cells regulates reproduction, mice carrying Stat5a/b inactivation specifically in kisspeptin cells were generated. These mutants exhibited an early onset of estrous cyclicity, indicating that STAT5 transcription factors exert an inhibitory effect on the timing of puberty.

Camphene isolated from essential oil of Piper cernuum (Piperaceae) induces intrinsic apoptosis in melanoma cells and displays antitumor activity in vivo.

Natural monoterpenes were isolated from the essential oil of Piper cernuum Vell. (Piperaceae) leaves. The crude oil and the individual monoterpenes were tested for cytotoxicity in human tumor cell lineages and B16F10-Nex2 murine melanoma cells. In the present work we demonstrate the activity of camphene against different cancer cells, with its mechanism of action being investigated in vitro and in vivo in murine melanoma. Camphene induced apoptosis by the intrinsic pathway in melanoma cells mainly by causing endoplasmic reticulum (ER) stress, with release of Ca(2+) together with HmgB1 and calreticulin, loss of mitochondrial membrane potential and up regulation of caspase-3 activity. Importantly, camphene exerted antitumor activity in vivo by inhibiting subcutaneous tumor growth of highly aggressive melanoma cells in a syngeneic model, suggesting a promising role of this compound in cancer therapy.

Chemical composition and in vitro cytotoxic and antileishmanial activities of extract and essential oil from leaves of Piper cernuum.

Fractionation of the MeOH extract from leaves of Piper cernuum Vell. (Piperaceae) afforded six phenylpropanoid derivatives: 3',4'-dimethoxydihydrocinnamic acid (1), piplaroxide (2), methyl 4'-hydroxy-3',5'-dimethoxy cinnamate (3), 3',4',5'-trimethoxydihydrocinnamic acid (3), dihydropiplartine (5), and piplartine (6). The structures of isolated metabolites were characterized by NMR and MS spectral data analysis. The chemical composition of essential oil from the leaves was determined using GC/LREIMS followed by the determination of Kovats indexes. This procedure allowed the identification of nineteen terpenoids, with ß-elemene (7), bicyclogermacrene (8), germacrene D (9), and (E)-caryophyllene (10) as the main compounds. Compounds 1 and 3-6 displayed no in vitro cytotoxicity against cancer cell lineages B16F10-Nex2, U87, HeLa, HL-60, HCT, and A2058 while 2 showed moderate activity against B16F10-Nex2 and HL-60 lines. Otherwise, compounds 7-10 displayed high cytotoxic activity. Evaluation against non-tumorigenic HFF cells indicated a reduced selectivity of compounds 7-10 to tumoral cells. No antileishmanial activity on macrophages infected with L. (L.) amnazonensis was found for the crude MeOH extract and compounds 1-6. The crude essential oil and compounds 7-10 reduced parasitism and eliminated the majority of infected and non-infected cells at 50 µg/mL.

Hypertension and hepatitis C virus infection are strong risk factors for developing late renal dysfunction after living donor liver transplantation: significance of renal biopsy.

BACKGROUND: Late renal dysfunction (LRD) after liver transplantation develops due to several factors such as viral hepatitis, calcineurin inhibitor, diabetes mellitus, and hypertension. The aim of our study was to clarify the risk factors for LRD after living donor liver plantation (LDLT) by using simple criteria for LRD and paying special attention to the significance of renal biopsy. PATIENTS AND METHODS: Among the 98 recipients undergoing LDLT between March 2002 and June 2008, there were 77 patients who survived more than 1 year and had been followed at our clinic. LRD was simply defined as a postoperative serum creatinine level of 1.5/L or more at any point in time after 1 year from undergoing LDLT. The perioperative risk factors for developing LRD after LDLT were analyzed by uni- and multivariate analyses, and regardless of serum creatinine level, a renal biopsy was indicated when the patient developed clinical symptoms. RESULTS: Comparing the risk factors between 22 patients with LRD and 55 without LRD, univariate analysis revealed recipient's age, generation, hypertension, hepatitis C virus (HCV) antibody-positive, pretransplantation serum creatinine level, and graft-to-recipient weight ratio to be significant risk factors. By multivariate analysis, HCV and hypertension were selected as independent risk factors. Renal biopsy was indicated in the 4 patients with proteinuria, all of whom were positive for HCV. However, by histologic and/or electron micrographic analyses, only 1 patient was diagnosed with HCV-related membranous proliferative nephritis, 1 with diabetic nephropathy, and 2 with drug (tacrolimus) -induced renal dysfunction. CONCLUSION: Although HCV and hypertension were determined to be independent risk factors for LRD after LDLT, a renal biopsy should be performed when clinical symptoms develop regardless of creatinine levels to provide appropriate treatment.

Biliary complications in 108 consecutive recipients with duct-to-duct biliary reconstruction in living-donor liver transplantation.

BACKGROUND: Biliary complications remain the leading cause of postoperative complications after living-donor liver transplantation (LDLT) in patients undergoing duct-to-duct choledochocholedochostomy. The aim of this study was to analyze the causes of these complications. METHODS: One hundred eight patients who underwent LDLT with duct-to-duct biliary reconstruction at Mie University Hospital were enrolled in this study. The mean follow-up time was 58.4 months (range, 3-132). The most recent 18 donors underwent indocyanine green (ICG) fluorescence cholangiography for donor hepatectomy. The development of biliary complications was retrospectively analyzed. Biliary complications were defined as needing endoscopic or radiologic treatment. RESULTS: Biliary leakages and strictures occurred in 6 (5.6%) and 15 (13.9%) of the recipients, respectively, and 3 donors (2.7%) experienced biliary leakage. However, since the introduction of ICG fluorescence cholangiography, we have not encountered any biliary complications in either donors or recipients. Biliary leakage was an independent risk factor for the development of biliary stricture (P = .013). Twelve (80%) of the 15 recipients with biliary stricture had successful nonoperative endoscopic or radiologic management, and 3 patients underwent surgical repair with hepaticojejunosotomy. CONCLUSIONS: Biliary leakage was an independent factor for biliary stricture. ICG fluorescence cholangiography might be helpful to reduce biliary complications after LDLT in both donors and recipients.

Oral lesions in elderly patients of a community in Brazilian Northeast.

OBJECTIVE: To investigate the oral soft-tissue injuries in people aged 60 or older. METHODS: Cross-sectional research conducted with 262 elders aged 60-93 years (mean 69.84, SD ± 6.212) from the Dende community in Northeast, Brazil. Data were collected through an identification questionnaire and the Community Indicator in Oral Health. Data were computed by the Software SPSS, version 15. RESULTS: There was a predominance of female gender (64.1%), retired, low schooling and income of up to one minimum wage. It was detected a prevalence of soft-tissue injuries in 38.4% (n = 101) of the elders, distributed as follows: red spots 60(57.7%), blisters 20(19.2%), lesions and/or wound 16(15.4%), and white spot 8(7.7%). Among the elders, 40(15.3%) smoked and 20(7.6%) used alcohol. It was verified a statistical association between injuries and using prosthesis (p = 0.039), medicine (p = 0.023) and calculus (p = 0.016). CONCLUSION: The oral health of this population is precarious, and there is a high prevalence of oral lesions.

Living donor liver transplantation for the patients with portal vein thrombosis: use of an interpositional venous graft passed posteriorly to the pancreatic parenchyma without using jump graft.

BACKGROUND: It is difficult to reconstruct the portal vein (PV) using a long interpositional venous graft in living donor liver transplant (LDLT) patients with portal vein thrombosis (PVT), which involves the confluence of the superior mesenteric vein (SMV) and splenic vein (SV). We successfully performed LDLT for three patients with PVT using an interpositional vascular conduit passing posterior to the pancreas without a jump graft. METHODS: Three of 130 patients who underwent LDLT in our hospital between March 2002 and June 2011 required this technique. After indentifying the location of the SMV, SV and gastrocolic trunk, we ligated and cut the posterior superior pancreaticoduodenal vein and other short branches from the PV. The PV was drawn inferiorly to the pancreas and transected at the confluence of SMV and SV. The external iliac vein or internal jugular vein was sacrificed as a graft for anastomosis to the cut end of the SMV using 6-0 polypropylene running sutures. Then the venous graft was drawn superiorly to the pancreas by passing it posterior to the pancreas parenchyma for anastomosis to the liver graft PV. The interpositional vein was placed posterior to the pancreas where the PV used to be. RESULTS: All three patients displayed favorable postoperative courses with the Doppler ultrasound demonstrating good portal flow perioperatively. The postoperative portogram demonstrated patency of the vascular graft. CONCLUSION: This method is easy and helpful to treat portal vein thrombosis, by providing the shortest route between the PV of the donor and the SMV of the recipient.

Intracellular interferon-γ staining analysis of donor-specific T-cell responses in liver transplant recipients.

OBJECTIVE: Biomarkers that accurately reflect, detect, and/or predict detrimental immune responses to grafts are important in organ transplantation. We established a new detection method for alloreactive T cells on the basis of intracellular staining for interferon (IFN)-γ, using CD40-activated B cells as stimulators, and assessed temporal changes in alloreactive T-cell frequencies in patients who received liver transplantation. METHODS: Peripheral blood mononuclear cells and CD40-activated B cells were used as responder and stimulator cells, respectively. The responder cells were cultured with the stimulator cells for 7 days, restimulated for 5 hours, and flow cytometrically tested by intracellular staining for IFN-γ. RESULTS: The relative postoperative-preoperative ratio of donor-specific CD8+ T cells in the nonrejection group was significantly lower than that in the rejection group and found to be <1 in most individuals of the group throughout the postoperative periods, indicating an induction of donor-specific suppression of the CD8+ T-cell responses. In contrast, such differences were not found in the donor-specific CD4+ T cells. These results suggest that the relative postoperative-preoperative ratio of the donor-specific CD8+ T cells is a good indicator of graft rejection. CONCLUSION: We established a new flow cytometric method for the detection of alloreactive T cells by intracellular staining for IFN-γ, using CD40-activated B cells as stimulator cells. Using this system, we found that the relative postoperative-preoperative ratio of the donor-specific CD8+ T cells is a possible evaluative indicator of the risk for graft rejection.

Time trend in treatment-related deaths of patients with advanced non-small-cell lung cancer enrolled into phase III trials of systemic treatment.

PURPOSE: Despite recent improvements in supportive care, treatment-related death (TRD) remains a serious problem for lung cancer patients undergoing systemic chemotherapy. However, few studies have formally assessed possible changes in the TRD rate over the past two decades. PATIENTS AND METHODS: We searched phase III trials to address the role of systemic treatment of advanced non-small-cell lung cancer (NSCLC). Time trend was assessed using linear regression analysis. RESULTS: The overall incidence of TRD was calculated from 119 trials including 263 chemotherapy arms (46 477 patients), with information about the causes of deaths available for 197 arms (75%, 30 147 patients). Cisplatin-based regimens were the most frequently investigated. The crude TRD rate in the overall cohort of 119 trials was 1.26% and has been notably consistent over the investigated time (P = 0.762). The most common cause of death was febrile neutropenia, with no significant change in its incidence over the years (P = 0.139). In contrast, deaths due to renal toxicity decreased significantly (P = 0.042), whereas deaths due to pulmonary disorder increased significantly (P = 0.007). Among the pharmacological agents investigated, docetaxel (Taxotere) and epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) were associated with relatively high rates of deaths from pulmonary disorders, but EGFR-TKIs were not associated with death from any other cause. CONCLUSIONS: Despite of potential confounders in our results, the overall TRD rate has remained low, but not negligible, in phase III trials for advanced NSCLC, over the past two decades. Notably, the incidence and pattern of TRD stratified by cause have changed considerably.

Association between incremental gains in the objective response rate and survival improvement in phase III trials of first-line chemotherapy for extensive disease small-cell lung cancer.

BACKGROUND: The duration of, resources required for and cost of clinical trials could be reduced if a surrogate end point was to be used in place of survival. We assessed the extent to which the objective response rate (ORR) is predictive of mortality, how much difference in the ORR is needed to predict an obvious survival difference and what factors could affect the association between the two parameters during the first-line treatment of extensive disease (ED)-small-cell lung cancer (SCLC). METHODS: We used the ORRs and median survival times (MSTs) from 48 phase III trials of first-line chemotherapy involving 8779 randomised patients with ED-SCLC in a linear regression analysis. The MST difference was calculated as the difference in MST between the investigational and reference arms; the ORR difference was similarly defined. RESULTS: ORR difference between the treatment arms was modestly associated with the MST difference in the overall trials (R(2) = 0.3314). In contrast, the relationship was stronger among only trials in which prophylactic cranial irradiation was given to those having an objective response to the initial chemotherapy (R(2) = 0.6279). In this trial setting, large differences in ORR were needed to predict a survival advantage (1.2-day survival advantage per 2% increase in ORR). CONCLUSIONS: In the first-line treatment of ED-SCLC, a favourable relationship was detected between the two parameters in the selected trial setting. Large ORR differences were needed to predict a survival benefit, clearly suggesting the need for new chemotherapeutic agents.

Coexpression of an unusual form of the EWS-WT1 fusion transcript and interleukin 2/15 receptor betamRNA in a desmoplastic small round cell tumour.

BACKGROUND: The beta chain of the interleukin 2/15 receptor (IL-2/15Rbeta) is induced by the expression of the EWS-WT1. A case of desmoplastic small round cell tumour (DSRCT) expressing only an unusual EWS-WT1 treated by us is reported here. AIM: To characterise an unusual form of EWS-WT1. METHODS: Frozen tissue sections of the axillary tumour were examined using a laser-assisted microdissection technique and reverse transcriptase polymerase chain reaction. RESULTS: The novel fusion of exon 8 of EWS and the defective exon 10 of WT1 (-KTS) was detected. Although it was an unusual form, the coexpression of the present EWS-WT1, IL-2/15Rbeta and Janus kinase (JAK1) mRNA was detected in the tumour cells. IL-2 and signal transducers and activators of transcription (STAT5) mRNA were detected in both tumour and stromal cells. CONCLUSION: The induction of the IL-2/15 receptor signalling pathway may contribute to tumorigenesis in DSRCT through a paracrine or an autocrine system, even though the EWS-WT1 was an unusual form.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Significance of lymph node micrometastasis in pN0 hilar bile duct carcinoma.

AIMS: To examine micrometastasis in node-negative hilar bile duct carcinoma (HBDC) using an immunohistochemical method and evaluated the clinical significance. METHODS: Four hundred and twenty three regional lymph nodes from 28 patients with node-negative HBDC who had undergone a resection were immunostained with an antibody against cytokeratins eight and 18 (CAM 5.2). RESULTS: Lymph node micrometastasis was detected in 11 of the 28 patients and 14 of the 423 lymph nodes. Lymph node micrometastasis was significantly correlated with the pT classification (p=0.03), the histopathological grading (p=0.01) and venous invasion (p=0.05). The 5-year survival rate of the patients with lymph node micrometastasis was 21.8%, as opposed to 66.5% in the patients without micrometastasis. Patients with micrometastasis showed a significantly poorer survival rate than those without micrometastasis (p=0.02). CONCLUSION: The results suggest that immunohistochemically detected lymph node micrometastasis has an impact on the outcome in HBDC.

Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience.

BACKGROUND: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis. PATIENTS AND METHODS: We reviewed the clinical records of 365 Japanese patients with NSCLC who received gefitinib (250 mg/day). RESULTS: Of 324 (89%) patients assessable for response, 147 (45%) obtained disease stabilisation and 71 (22%) patients achieved an objective response. Overall survival in patients obtaining disease stabilisation was significantly longer than in patients with progressive disease (median survival time 12.1 versus 4.4 months; P <0.0001). In patients obtaining disease stabilisation, those who continued gefitinib treatment until disease progression tended to have longer overall and progression-free survival compared with those discontinuing gefitinib treatment (1-year survival rate 52.1% versus 36.6%, P = 0.08; 1-year progression-free survival rate 31.8% versus 5.2%, P = 0.001). Multivariate analysis showed discontinuing gefitinib was an independent risk factor for progression-free survival (hazard ratio 1.66; 95% confidence interval 1.07-2.56; P = 0.022) but not for overall survival. CONCLUSIONS: Our findings indicate the importance of achieving disease stabilisation with gefitinib treatment and continued gefitinib treatment in Japanese patients with disease stabilisation, although further studies are required to confirm these findings.

Addition of platinum compounds to a new agent in patients with advanced non-small-cell lung cancer: a literature based meta-analysis of randomised trials.

BACKGROUND: Single new agents reportedly produce promising response and survival effects, but platinum-based doublets remain the standard chemotherapy for advanced non-small-cell lung cancer (NSCLC). The aim of this study was to evaluate the effectiveness of platinum for advanced NSCLC by carrying out a meta-analysis of trials that compared platinum-based doublets with single new agent therapy alone. METHODS: We carried out a literature search to identify trials, conducted between 1994 and 2003, comparing a doublet of platinum plus a new agent with a new agent alone in previously untreated patients with advanced NSCLC. Outcomes analysed were response, survival and toxicity. RESULTS: Eight trials encompassing 2374 patients were identified. Platinum-based doublets produced an approximately two-fold higher overall (complete and partial) response rate than the new agent alone [odds ratio = 2.32; 95% confidence interval (CI)=1.68-3.20]. Platinum-based doublet therapy was also associated with a 13% prolongation of survival (hazard ratio = 0.87; 95% CI = 0.80-0.94, P <0.001). Despite significant increases in the frequencies of various toxic effects in patients receiving platinum-based doublets, no significant difference in treatment-related mortality was observed. CONCLUSION: This is the first published meta-analysis demonstrating the importance of combining platinum with single new agents in the treatment of advanced NSCLC.