Lung Cancer Mortality and Styrene Exposure in the Reinforced-Plastics Boatbuilding Industry: Evaluation of Healthy Worker Survivor Bias.

The evidence for styrene's being a human lung carcinogen has been inconclusive. Occupational cohorts within the reinforced-plastics industry are an ideal population in which to study this association because of their relatively high levels of exposure to styrene and lack of concomitant exposures to other known carcinogens. However, healthy worker survivor bias (HWSB), where healthier workers stay employed longer and thus have higher exposure potential, is a likely source of confounding bias for exposure-response associations, in part due to styrene's acute effects. Through December 31, 2016, we studied a cohort of 5,163 boatbuilders exposed to styrene in Washington State who were employed between 1959 and 1978; prior regression analyses had demonstrated little evidence for an exposure-response relationship between styrene exposure and lung cancer mortality. Based on estimates of necessary components of HWSB, we found evidence for a potentially large HWSB. Using g-estimation of a structural nested model to account for HWSB, we estimated that 1 year of styrene exposure at more than 30 parts per million accelerated time to lung cancer death by 2.29 years (95% confidence interval: 1.53, 2.94). Our results suggest possibly strong HWSB in our small cohort and indicate that large, influential studies of styrene-exposed workers may suffer from similar biases, warranting a reassessment of the evidence of long-term health effects of styrene exposure.

The patient's perspective on treatment with dacomitinib: patient-reported outcomes from the Phase III trial ARCHER 1050.

Aim: Patient-reported symptoms, functioning and overall quality of life (QoL) were compared between dacomitinib and gefitinib in ARCHER 1050. Patients & methods: Patients (n = 448) with advanced EGFR mutation-positive non-small-cell lung cancer completed the EORTC-QLQ-C30 questionnaire and its lung-specific module, LC-13. Mean scores over time were analyzed using a mixed model for repeated measures. Results: Both treatments showed early improvement in disease-related symptoms that was maintained during treatment. Treatment-related diarrhea and sore mouth decreased following dose reduction with dacomitinib. There were no clinically meaningful changes in functioning and overall QoL in either treatment group. Conclusion: Longer treatment duration, enabled by dose reduction, allowed patients on dacomitinib to improve treatment-related symptoms and maintain functioning and overall QoL for longer than gefitinib.

Number of Teeth and All-Cause and Cancer Mortality in a Japanese Community: The Takayama Study.

BACKGROUND: The association between the number of teeth and mortality among community-dwelling people has been examined in many epidemiological studies. However, few Japanese studies have included cancer mortality as an endpoint. We prospectively investigated the association between number of remaining teeth and all-cause and cancer mortality in a Japanese community. METHODS: This study included participants in the Takayama Study who were aged 35-70 years old at baseline in 1992. Information on the number of remaining teeth was obtained from 11,273 participants via questionnaire at the second survey in 2002. The response rate was 66.9%. Deaths and their causes were ascertained during 11.8 years of follow-up. RESULTS: A total of 1,098 deaths (435 cancer-related and 235 cardiovascular-related) were identified during the follow-up period. After adjusting for covariates, participants with 0 to 9 teeth were at moderate but significantly increased risk of all-cause mortality (hazard ratio [HR] 1.19; 95% confidence interval [CI], 1.03-1.39) and cancer mortality (HR 1.31; 95% CI, 1.03-1.67) compared to those with 20 or more teeth. With regard to cancer site, a significant association was observed for lung cancer (HR for 0-9 teeth vs. 20 or more teeth, 1.75; 95% CI, 1.08-2.83). This association was somewhat strengthened among never-smokers (HR 3.56; 95% CI, 1.02-12.45). CONCLUSIONS: We observed that a lower number of remaining teeth was significantly associated with increased risk from all-cause and lung cancer mortality. Further studies on the number of teeth and lung and other types of cancer are needed.

Combination of DESI2 and endostatin gene therapy significantly improves antitumor efficacy by accumulating DNA lesions, inducing apoptosis and inhibiting angiogenesis.

DESI2 is a novel pro-apoptotic gene. We previously reported that DESI2 overexpression induces S phase arrest and apoptosis by activating checkpoint kinases. This work was to test whether the combination of endostatin, an endogenous antiangiogenic inhibitor, with DESI2 could improve the therapy efficacy in vitro and in vivo. The recombinant plasmid co-expressing DESI2 and endostatin was encapsulated with DOTAP/Cholesterol cationic liposome. Mice bearing CT26 colon carcinoma and LL2 lung cancer were treated with the DNA-liposome complex. We found that, in vitro, the combination of DESI2 and endostatin more efficiently inhibited proliferation of CT26, LL2, HCT116 and A549 cancer cells via apoptosis, as assessed by MTT assay, colony-formation assays, flow cytometric analysis, hoechst staining and activation of caspase-3, respectively. In addition, DESI2 overexpression caused up-regulation of RPS7, a substrate of DESI2 deubiquitination. Furthermore, siRNA targeting RPS7 partially abrogated, whereas RPS7 overexpression enhanced DESI2-induced inhibition of cell proliferation. Importantly, the combination also caused DNA lesions accumulation, which further promotes apoptosis. Mechanistic rationale suggested that endostatin first inhibits DNA-PKcs kinase, and partly abrogated DESI2-induced phosphorylation of DNA-PKcs, leading to increase of DNA damage, then contributes to DESI2-induced apoptosis. In vivo, the combined gene therapy more significantly inhibited tumor growth and efficiently prolonged the survival of tumor bearing mice than mono therapy. The improved antitumor effect was associated with inhibition of cell proliferation via apoptosis, as analyzed by TUNEL assay and PCNA immunostaining. The combination also inhibited angiogenesis, as assessed by alginate-encapsulated tumor cell assay and CD31 staining. Our data suggest that the combined gene therapy of DESI2 and endostatin can significantly enhance the antitumor activity as a DNA lesions accumulator, apoptosis inducer and angiogenesis inhibitor. The present study may provide a novel method for the treatment of cancer.

Surgical outcome of pulmonary artery reconstruction using the expanded polytetrafluoroethylene patch in patients with lung cancer.

PURPOSE: Pulmonary artery reconstruction is sometimes utilized as an alternative to pneumonectomy in lung cancer surgery. We herein report our experience of pulmonary artery reconstruction using an expanded polytetrafluoroethylene (ePTFE) patch based on the surgical results and long-term outcome. METHODS: Clinical records of lung cancer patients who underwent patch plasty were reviewed retrospectively. RESULTS: Between 2003 and 2017, pulmonary artery patch plasty were performed in 21 patients [18 males, 3 females; mean age 65 (range 47-79) years]. Induction chemoradiotherapy was performed in three patients. Bronchoplasty was performed in five patients. The pathologic stages were stage I in 3 patients, stage II in 6 and stage III in 12. Pneumonectomy, lobectomy and segmentectomy were performed in 2, 18 and 1 patient, respectively. The left upper lobe was the most frequent origin of lung cancer (15 patients). There was no reconstruction-related morbidity or mortality. The overall survival rate at 5 years was 64.1% with a mean follow-up of 39.5 months, and the survival rates for N0-1 and N2-3 were 80.8% and 28.6%, respectively. CONCLUSION: Patch angioplasty using the ePTFE sheet is a reliable procedure in radical surgery for lung cancer.

Multicenter phase II study on cisplatin, pemetrexed, and bevacizumab followed by maintenance with pemetrexed and bevacizumab for patients with advanced or recurrent nonsquamous non-small cell lung cancer: MAP study.

BACKGROUND: We evaluated the safety and efficacy of induction chemotherapy with bevacizumab followed by maintenance chemotherapy with bevacizumab for advanced non-small cell lung cancer (NSCLC) in this multicenter phase II study. METHODS: Chemotherapy-naïve patient with stage IIIB-IV or recurrent nonsquamous NSCLC were eligible. We planned approximately four cycles of induction cisplatin (75 mg/m2), pemetrexed (500 mg/m2), and bevacizumab (15 mg/kg) followed by maintenance with pemetrexed (500 mg/m2) and bevacizumab (15 mg/kg) until disease progression. Progression-free survival (PFS) was the primary endpoint. RESULTS: Forty patients received a median of four induction chemotherapy cycles. Of them, 35 (87.5%) patients received a median of nine maintenance chemotherapy cycles. The objective response was 70.6%, and the disease control rate was 97.1%. The median PFS was 10.8 (95% CI, 9.0-12.6), and overall survival was 48.0 (95% CI, 32.9-63.1) months. Median PFS of 23 patients with epidermal growth factor receptor (EGFR) mutations and of 16 patients without EGFR mutations were 12.9 (95% CI, 9.4-16.3) and 7.9 (95% CI, 1.1-14.7) months, respectively. Toxicities graded ≥3 included neutropenia (15%), anemia (15%), hypertension (7.5%), anorexia (7.5%), fatigue (7.5%), thromboembolic events (5%), jaw osteonecrosis (5%), nausea (2.5%), oral mucositis (2.5%), tumor pain (2.5%), hyponatremia (2.5%), and gastrointestinal perforation (2.5%). Treatment-related deaths were not found. CONCLUSIONS: In patients with advanced or recurrent nonsquamous NSCLC, induction chemotherapy with cisplatin, pemetrexed, and bevacizumab followed by maintenance chemotherapy with pemetrexed and bevacizumab is safe and effective regardless of their EGFR mutation status. TRIAL REGISTRATION: UMIN Clinical Trial Registry: UMIN000005569 . Registered date: May 8, 2011.

Dual Functional LipoMET Mediates Envelope-type Nanoparticles to Combinational Oncogene Silencing and Tumor Growth Inhibition.

The success of small interfering RNA (siRNA)-mediated gene silencing for cancer therapy is still limited because of its instability and poor intracellular internalization. Traditional cationic carriers cannot adequately meet the need for clinical application of siRNA. We herein report a dual-functional liposome containing a cholesterol derivative of metformin, i.e., LipoMET, which takes advantage of the fusogenic activity as well as intrinsic tumor apoptosis inducing ability of biguanide moiety to achieve a combinational anti-oncogenic effect. In this study, the vascular endothelial growth factor (VEGF)-specific siRNAs were first electrostatically condensed into a ternary nanocomplex composed of polycation and hyaluronate, which was subsequently enveloped by LipoMET through membrane fusion. In comparison with common cationic control group, the resulting envelope-type nanoparticles (PH@LipoMET nanoparticles [NPs]) showed the ability of rapid cellular internalization and effective endosomal escape of siRNA during intracellular trafficking studies. Systemic administration of the targeted LipoMETs was capable of inducing apoptosis and tumor growth inhibition in the NCI-H460 xenograft model. When carrying VEGF-specific siRNAs, PH@LipoMET NPs remarkably downregulated the expression of VEGF and led to even more tumor suppression in vivo. Thus, LipoMET originated envelope-type nanoparticles may serve as a potential dual-functional siRNA delivery system to improve therapeutic effect of oncogene silencing.

Cancer mortality update with an exposure response analysis among styrene-exposed workers in the reinforced plastics boatbuilding industry.

BACKGROUND: There is sparse and inconsistent evidence of an association between styrene exposure and cancer. METHODS: This study examines mortality patterns in a previously studied cohort of 5201 workers employed in two Washington boat-building facilities, extending follow-up 5 years. Standardized mortality ratios (SMR) were calculated using state rates as referent. Cox regression calculated rate ratios (RR) per year employed in styrene-exposed exposed jobs. RESULTS: No excess deaths from lymphohematopoietic cancers (LHCs) were observed (SMR: 0.99, 95%CI: 0.74-1.30) when compared to the referent population; however, the relative risk increased with duration of employment in internal analyses. Conversely, lung cancer mortality was significantly elevated (SMR: 1.24, 95%CI: 1.08-1.41), but there was no evidence of a dose-response relationship. CONCLUSION: We found evidence that occupational exposure to styrene was associated with increased LHC risk, while no such association was observed for lung cancer.

[Mortality study in a cohort of workers employed in the hot working processing of plastics and rubber]. / Studio di mortalità in una coorte di esposti nella lavorazione a caldo di materie plastiche e gomma.

OBJECTIVES: to study mortality rates among workers in companies manufacturing thermoplastic and rubber articles (excluding tyres). DESIGN: cohort study. SETTING AND PARTICIPANTS: the cohort includes 4,543 workers employed up to 2000 in 131 companies in the Province of Bologna (Emilia-Romagna Region, Northern Italy) exposed to emissions from hot processing of plastics (3,937) and rubber (606). MAIN OUTCOME MEASURES: general- and cause-specific Standardized Mortality Rates (SMR), with 95% confidence intervals; entire reference population resides in the Emilia-Romagna Region. RESULTS: excess mortality for all causes (116 Obs; SMR: 1.20; 95%CI 1.00-1.44) and for lung cancer (18 Obs; SMR: 1.67; 95%CI 1.05-2.65) in men of the rubber factories. Increased mortality rates for oesophageal cancers in women (3 Obs; SMR: 5.41; 95%CI 1.74-16.8) and in men (6 Obs; SMR: 2.16; 95%CI 0.97-4.81), for malignant tumours of pancreas (16 Obs; SMR: 1.65; 95%CI 1.01- 2.70), rectum (11 Obs; SMR: 2.17; 95%CI 1.20-3.92) and kidney (11 Obs; SMR: 1.98; 95%CI 1.10-3.58) in men occupied in plastic processing. CONCLUSION: in this study, we observed an excess of mortality rates for lung cancer in men of rubber factories and for malignant tumours of the digestive tract, pancreas, and kidney in workers employed in the production of plastic articles. Nevertheless, these results must be interpreted with caution, because exposures to non-occupational risk factors, like tobacco smoke or other occupational exposures outside the companies concerned, are not known. The results suggest to continue epidemiological surveillance.

Cancer mortality in cohorts of workers in the European rubber manufacturing industry first employed since 1975.

BACKGROUND: Increased cancer risk has been reported among workers in the rubber manufacturing industry employed before the 1960s. It is unclear whether risk remains increased among workers hired subsequently. The present study focused on risk of cancer mortality for rubber workers first employed since 1975 in 64 factories. PATIENTS AND METHODS: Anonymized data from cohorts of rubber workers employed for at least 1 year from Germany, Italy, Poland, Sweden, and the UK were pooled. Standardized mortality ratios (SMRs), based on country-specific death rates, were reported for bladder and lung cancer (primary outcomes of interest), for other selected cancer sites, and for cancer sites with a minimum of 10 deaths in men or women. Analyses stratified by type of industry, period, and duration of employment were carried out. RESULTS: A total of 38 457 individuals (29 768 men; 8689 women) contributed to 949 370 person-years. No increased risk of bladder cancer was observed [SMR = 0.80, 95% confidence interval (CI) 0.46; 1.38]. The risk of lung cancer death was reduced (SMR = 0.81, 95% CI 0.70; 0.94). No statistically significant increased risk was observed for any other cause of death. A reduced risk was evident for total cancer mortality (SMR = 0.81, 95% CI 0.76; 0.87). Risks were lower for workers in the tyre industry compared with workers in the general rubber goods sector. Analysis by employment duration showed a negative trend with SMRs decreasing with increasing duration of employment. In an analysis of secondary end points, when stratified by type of industry and period of first employment, excess risks of myeloma and gastric cancer were observed each due, essentially, to results from one centre. CONCLUSION: No consistent increased risk of cancer death was observed among rubber workers first employed since 1975, no overall analysis of the pooled cohort produced significantly increased risk. Continued surveillance of the present cohorts is required to confirm the absence of long-term risk.

Mortality among styrene-exposed workers in the reinforced plastic boatbuilding industry.

BACKGROUND: We updated mortality through 2011 for 5203 boat-building workers potentially exposed to styrene, and analysed mortality among 1678 employed a year or more between 1959 and 1978. The a priori hypotheses: excess leukaemia and lymphoma would be found. METHODS: Standardised mortality ratios (SMRs) and 95% CIs and standardised rate ratios (SRRs) used Washington State rates and a person-years analysis programme, LTAS.NET. The SRR analysis compared outcomes among tertiles of estimated cumulative potential styrene exposure. RESULTS: Overall, 598 deaths (SMR=0.96, CI 0.89 to 1.04) included excess lung (SMR=1.23, CI 0.95 to 1.56) and ovarian cancer (SMR 3.08, CI 1.00 to 7.19), and chronic obstructive pulmonary disease (COPD) (SMR=1.15, CI 0.81 to 1.58). Among 580 workers with potential high-styrene exposure, COPD mortality increased 2-fold (SMR=2.02, CI 1.08 to 3.46). CONCLUSIONS: COPD was more pronounced among those with potential high-styrene exposure. However, no outcome was related to estimated cumulative styrene exposure, and there was no change when latency was taken into account. We found no excess leukaemia or lymphoma mortality. As in most occupational cohort studies, lack of information on lifestyle factors or other employment was a substantial limitation although we excluded from the analyses those (n=3525) who worked <1 year. Unanticipated excess ovarian cancer mortality could be a chance finding. Comparing subcohorts with potential high-styrene and low-styrene exposure, COPD mortality SRR was elevated while lung cancer SRR was not, suggesting that smoking was not the only cause for excess COPD mortality.

Mortality among workers exposed to toluene diisocyanate in the US polyurethane foam industry: Update and exposure-response analyses.

BACKGROUND: Mortality among 4,545 toluene diisocyante (TDI)-exposed workers was updated through 2011. The primary outcome of interest was lung cancer. METHODS: Life table analyses, including internal analyses by exposure duration and cumulative TDI exposure, were conducted. RESULTS: Compared with the US population, all cause and all cancer mortality was increased. Lung cancer mortality was increased but was not associated with exposure duration or cumulative TDI exposure. In post hoc analyses, lung cancer mortality was associated with employment duration in finishing jobs, but not in finishing jobs involving cutting polyurethane foam. CONCLUSIONS: Dermal exposure, in contrast to inhalational exposure, to TDI is expected to be greater in finishing jobs and may play a role in the observed increase in lung cancer mortality. Limitations include the lack of smoking data, uncertainty in the exposure estimates, and exposure estimates that reflected inhalational exposure only. Am. J. Ind. Med. 59:630-643, 2016. Published 2016. This article is a U.S. Government work and is in the public domain in the USA.

Nanomedicine for Treatment of Lung Cancer.

Lung cancer is the second most common cancer and the primary cause of cancer-related death in both men and women in the United States and rest of the world. Due to diagnosis at an advanced stage, it is associated with a high mortality in a majority of patients. In recent years, enormous advances have occurred in the development and application of nanotechnology in the detection, diagnosis, and therapy of cancer. This progress has led to the development of the emerging field of "cancer nanomedicine." Nanoparticle-based therapeutic systems have gained immense popularity due to their bioavailability, in vivo stability, intestinal absorption, solubility, sustained and targeted delivery, and therapeutic effectiveness of several anticancer agents. Currently, a plethora of nanocarrier formulations are utilized including lipid-based, polymeric and branched polymeric, metal-based, magnetic, and mesoporous silica. In lung cancer, nanoparticle-based therapeutics is paving the way in the diagnosis, imaging, screening, and treatment of primary and metastatic tumors. The application and expansion of novel nanocarriers for drug delivery is an exciting and challenging research filed, in particular for the delivery of emerging cancer therapies. Some of the current progress and challenges in nanoparticle-based drug delivery systems for lung cancer treatment are discussed.

Cause-specific mortality in Finnish ferrochromium and stainless steel production workers.

BACKGROUND: Although stainless steel has been produced for more than a hundred years, exposure-related mortality data for production workers are limited. AIMS: To describe cause-specific mortality in Finnish ferrochromium and stainless steel workers. METHODS: We studied Finnish stainless steel production chain workers employed between 1967 and 2004, from chromite mining to cold rolling of stainless steel, divided into sub-cohorts by production units with specific exposure patterns. We obtained causes of death for the years 1971-2012 from Statistics Finland. We calculated standardized mortality ratios (SMRs) as ratios of observed and expected numbers of deaths based on population mortality rates of the same region. RESULTS: Among 8088 workers studied, overall mortality was significantly decreased (SMR 0.77; 95% confidence interval [CI] 0.70-0.84), largely due to low mortality from diseases of the circulatory system (SMR 0.71; 95% CI 0.61-0.81). In chromite mine, stainless steel melting shop and metallurgical laboratory workers, the SMR for circulatory disease was below 0.4 (SMR 0.33; 95% CI 0.07-0.95, SMR 0.22; 95% CI 0.05-0.65 and SMR 0.16; 95% CI 0.00-0.90, respectively). Mortality from accidents (SMR 0.84; 95% CI 0.67-1.04) and suicides (SMR 0.72; 95% CI 0.56-0.91) was also lower than in the reference population. CONCLUSIONS: Working in the Finnish ferrochromium and stainless steel industry appears not to be associated with increased mortality.

[Clinical Analysis of Surgical treatment of long bone metastases].

OBJECTIVE: To evaluate the safety and efficacy of microwave ablation combined with curettage in the treatment of long bone metastases. METHODS: From April 2010 to June 2015, 38 patients with long bone metastases were adopted, who all underwent microwave ablation combined with curettage with 40 lesions involved in Department of Orthopaedic Oncology, Beijing Jishuitan Hospital. There were 22 males and 16 females with an average age of 58.3 years (range from 32 to 83 years). Solitary metastases were found in 9 cases and multiple metastases in 29 patients. Primary malignancies included: 15 cases of lung cancer, 7 cases of renal carcinoma, 4 cases of breast cancer, 3 cases of liver cancer, 1 case of thyroid carcinoma, 1 case of endometrial carcinoma, 1 case of cervical carcinoma, 1 case of esophageal carcinoma and 6 cases of carcinoma of unknown primary. The operative sites included the femur (n=21), the humerus (n=12) and the tibia (n=7). There were 23 cases of pathologic fractures which included: 12 in femur, 10 in humerus and 1 in tibia. Curettage after in situ microwave ablation was performed in 40 lesions. Reconstructions were carried out in all lesions: bone cement filling alone in 1 lesion and bone cement filling with metal implants in the other 39 lesions. RESULTS: The mean follow-up was 6.9 months (range; 1-65 months). During the follow-up, 22 patients died and 16 patients were alive. The 6-month overall survival (OS) was 73.7%, and the 1-year and 2-year OS were 48.6% and 28.1% respectively. The postoperative survival time was 7.1 months on average (range 2-40 months) in the 22 patients who finally died. The occurrence of pathological fracture had a significant effect on the OS (χ(2)=5.606, P=0.018). The local recurrence rate was 10% (4/40), which occurred at 6.8 months after the operation on average (range 2-14 months). No complications occurred in the perioperative period, and there were no complications such as internal fixation failure or pathological fracture noticed during the follow-up period. The scores of VAS, KPS and ECOG were significantly improved after operation. The mean MSTS score was 22 points (range 17-28 points) in 33 evaluable locations and the rate of excellent and good was 72.7%. CONCLUSIONS: Microwave ablation combined with curettage appears to be a safe and effective approach in the surgical treatment of long bone metastases, which can relieve local pain and control the local development of bone metastases.

Muramyl tripeptide-phosphatidyl ethanolamine encapsulated in liposomes (L-MTP-PE) in the treatment of osteosarcoma.

Bacille Calmette-Guerin (BCG) has been used for decades as an immune stimulant to treat cancer. Early work by Fidler and Kleinerman identified muramyl dipeptide (MDP) as a critical component of the BCG cell wall which retained most of the immunostimulatory properties of the native BCG. Addition of a peptide to MDP resulted in muramyl tripeptide (MTP) which allowed incorporation into liposomal membranes. The resulting pharmaceutical, liposomal muramyl tripeptide phosphatidyl ethanolamine (L-MTP-PE or mifamurtide) showed activity in preclinical models of human cancers. Phase I studies documented the safety of the compound for human administration. These trials did not reach a maximally tolerated dose (MTD), and the dose chosen for phase II trials was a biologically optimized dose, not an MTD. Phase II studies showed decreased risk of further recurrence in patients who received mifamurtide after surgical ablation of metastatic osteosarcoma. A phase III prospective randomized trial demonstrated a statistically significant reduction in the risk of death from osteosarcoma when MTP was added to systemic chemotherapy for the treatment of localized osteosarcoma. The same trial allowed treatment of patients who presented with initially metastatic disease. While the overall and event-free survival was improved in patients with metastatic osteosarcoma who received L-MTP-PE, the sample size was small and the improvement did not achieve conventional statistical significance. From 2008 to 2012, patients with metastatic and recurrent osteosarcoma were given L-MTP-PE in an expanded access trial, and the results suggest a decreased risk of subsequent recurrence and death with the inclusion of L-MTP-PE in the treatment strategy for these high-risk patients.

RESILIENT Part 2: A Randomized, Open-Label Phase III Study of Liposomal Irinotecan Versus Topotecan in Adults With Relapsed Small Cell Lung Cancer.

PURPOSE: The phase III RESILIENT trial compared second-line liposomal irinotecan with topotecan in patients with small cell lung cancer (SCLC). PATIENTS AND METHODS: Patients with SCLC and progression on or after first-line platinum-based chemotherapy were randomly assigned (1:1) to intravenous (IV) liposomal irinotecan (70 mg/m2 every 2 weeks in a 6-week cycle) or IV topotecan (1.5 mg/m2 daily for 5 consecutive days, every 3 weeks in a 6-week cycle). The primary end point was overall survival (OS). Key secondary end points included progression-free survival (PFS) and objective response rate (ORR). RESULTS: Among 461 randomly assigned patients, 229 received liposomal irinotecan and 232 received topotecan. The median follow-up was 18.4 months. The median OS was 7.9 months with liposomal irinotecan versus 8.3 months with topotecan (hazard ratio [HR], 1.11 [95% CI, 0.90 to 1.37]; P = .31). The median PFS per blinded independent central review (BICR) was 4.0 months with liposomal irinotecan and 3.3 months with topotecan (HR, 0.96 [95% CI, 0.77 to 1.20]; nominal P = .71); ORR per BICR was 44.1% (95% CI, 37.6 to 50.8) and 21.6% (16.4 to 27.4), respectively. Overall, 42.0% and 83.4% of patients receiving liposomal irinotecan and topotecan, respectively, experienced grade ≥3 related treatment-emergent adverse events (TEAEs). The most common grade ≥3 related TEAEs were diarrhea (13.7%), neutropenia (8.0%), and decreased neutrophil count (4.4%) with liposomal irinotecan and neutropenia (51.6%), anemia (30.9%), and leukopenia (29.1%) with topotecan. CONCLUSION: Liposomal irinotecan and topotecan demonstrated similar median OS and PFS in patients with relapsed SCLC. Although the primary end point of OS was not met, liposomal irinotecan demonstrated a higher ORR than topotecan. The safety profile of liposomal irinotecan was consistent with its known safety profile; no new safety concerns emerged.

Diurnal cortisol rhythm as a predictor of lung cancer survival.

BACKGROUND: Poorly coordinated diurnal cortisol and circadian rest-activity rhythms predict earlier mortality in metastatic breast and colorectal cancer, respectively. We examined the prognostic value of the diurnal cortisol rhythm in lung cancer. METHODS: Lung cancer patients (n=62, 34 female) were within 5 years of diagnosis and had primarily non small-cell lung cancer, with disease stage ranging from early to advanced. Saliva collected over two days allowed calculation of the diurnal cortisol slope and the cortisol awakening response (CAR). Lymphocyte numbers and subsets were measured by flow cytometry. Survival data were obtained for 57 patients. Cox Proportional Hazards analyses were used to test the prognostic value of the diurnal cortisol rhythm on survival calculated both from study entry and from initial diagnosis. RESULTS: The diurnal cortisol slope predicted subsequent survival over three years. Early mortality occurred among patients with higher slopes, or relatively "flat" rhythms indicating lack of normal diurnal variation (Cox Proportional Hazards p=.009). Cortisol slope also predicted survival time from initial diagnosis (p=.012). Flattened profiles were linked with male gender (t=2.04, df=59, p=.046) and low total and cytotoxic T cell lymphocyte counts (r=-.39 and -.30, p=.004 and .035, respectively). After adjustment for possible confounding factors, diurnal slope remained a significant, independent predictor of survival. CONCLUSIONS: Flattening of the diurnal cortisol rhythm predicts early lung cancer death. Data contribute to growing evidence that circadian disruption accelerates tumor progression.

Negative argininosuccinate synthetase expression in melanoma tumours may predict clinical benefit from arginine-depleting therapy with pegylated arginine deiminase.

BACKGROUND: Arginine-depleting therapy with pegylated arginine deiminase (ADI-PEG20) was reported to have activity in advanced melanoma in early phase I-II trial, and clinical trials are currently underway in other cancers. However, the optimal patient population who benefit from this treatment is unknown. METHODS: Advanced melanoma patients with accessible tumours had biopsy performed before the start of treatment with ADI-PEG20 and at the time of progression or relapse when amenable to determine whether argininosuccinate synthetase (ASS) expression in tumour was predictive of response to ADI-PEG20. RESULTS: Twenty-seven of thirty-eight patients treated had melanoma tumours assessable for ASS staining before treatment. Clinical benefit rate (CBR) and longer time to progression were associated with negative expression of tumour ASS. Only 1 of 10 patients with ASS-positive tumours (ASS+) had stable disease, whereas 4 of 17 (24%) had partial response and 5 had stable disease, when ASS expression was negative (ASS-), giving CBR rates of 52.9 vs 10%, P=0.041. Two responding patients with negative ASS expression before therapy had rebiopsy after tumour progression and the ASS expression became positive. The survival of ASS- patients receiving at least four doses at 320 IU m(-2) was significantly better than the ASS+ group at 26.5 vs 8.5 months, P=0.024. CONCLUSION: ADI-PEG20 is safe and the drug is only efficacious in melanoma patients whose tumour has negative ASS expression. Argininosuccinate synthetase tumour positivity is associated with drug resistance and tumour progression.

Cohort study of workers employed in an Italian tire manufacturing plant, 1962-2004.

PURPOSE: To investigate mortality and bladder cancer incidence among workers of a tire manufacturing plant where antioxidants severely contaminated by beta-naphthylamine were never used. METHODS: Mortality follow-up was performed of 9,501 workers first hired between 1962 when the plant started operations and 2000. Person-years of observation from 1962 to 2004, expected deaths, and standardized mortality ratios (SMR) were calculated. Follow-up for bladder cancer incidence from 1988 to 2003 was carried out, and standardized incidence ratios (SIR) were calculated. Multivariable (Poisson) analyses of bladder cancer incidence and mortality by duration of employment (DOE) and time since first employment (TSFE) were performed. RESULTS: Among men, SMRs were significantly reduced for all causes, all cancers, lung cancer, cardiovascular, and ischemic heart diseases. Bladder cancer mortality and leukemia mortality were close to expectation but increased with TSFE. Seventy-two incident cases of bladder cancer were observed (SIR = 1.15; 95 % confidence interval 0.90-1.44), and multivariable analysis suggested a possible increase in rate ratios with DOE. Among women, mortality was close to expectation, but the limited number of observed deaths prevented detailed analyses. CONCLUSIONS: No significant cancer excess was observed. A suggestion of increased risks of bladder cancer and leukemias after extended TSFE was present in men, deserving consideration as exposure to carcinogens possibly occurred early in plant operation. Furthermore, this cohort of workers is still relatively young and less than 10 % have died. There was, thus, limited power to detect small increases in risk at rare cancer sites. Further epidemiological surveillance of this cohort is planned.