Nivolumab with carboplatin, paclitaxel, and bevacizumab for first-line treatment of advanced nonsquamous non-small-cell lung cancer.

BACKGROUND: This international, randomized, double-blind phase III study (ONO-4538-52/TASUKI-52) evaluated nivolumab with bevacizumab and cytotoxic chemotherapy as first-line treatment for nonsquamous non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between June 2017 and July 2019, this study enrolled treatment-naïve patients with stage IIIB/IV or recurrent nonsquamous NSCLC without sensitizing EGFR, ALK, or ROS1 alterations. They were randomly assigned in a 1 : 1 ratio to receive nivolumab or placebo in combination with carboplatin, paclitaxel, and bevacizumab every 3 weeks for up to six cycles, followed by nivolumab/placebo with bevacizumab until progressive disease or unacceptable toxicity. The primary endpoint was progression-free survival (PFS) assessed by an independent radiology review committee (IRRC). RESULTS: Overall, 550 patients from Japan, Korea, and Taiwan were randomized; of these patients, 273 and 275 received the nivolumab and placebo combinations, respectively. In the present preplanned interim analysis with a median follow up of 13.7 months, the IRRC-assessed median PFS was significantly longer in the nivolumab arm than in the placebo arm (12.1 versus 8.1 months; hazard ratio 0.56; 96.4% confidence interval 0.43-0.71; P < 0.0001). The PFS benefit was observed across all patients with any programmed death-ligand 1 (PD-L1) expression levels including PD-L1-negative patients. The IRRC-assessed objective response rates were 61.5% and 50.5% in the nivolumab and placebo arms, respectively. The incidence of treatment-related adverse events of grade 3 or 4 was comparable between the two arms; treatment-related adverse events leading to death were observed in five and four patients in the nivolumab and placebo arms, respectively. CONCLUSION: The TASUKI-52 regimen should be considered a viable new treatment strategy for treatment-naïve patients with advanced nonsquamous NSCLC.

Osimertinib versus platinum-pemetrexed for patients with EGFR T790M advanced NSCLC and progression on a prior EGFR-tyrosine kinase inhibitor: AURA3 overall survival analysis.

BACKGROUND: In AURA3 (NCT02151981), osimertinib, a third-generation epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI), significantly prolonged progression-free survival and improved response in patients with EGFR T790M advanced non-small-cell lung cancer (NSCLC) and progression on prior EGFR-TKI treatment. We report the final AURA3 overall survival (OS) analysis. PATIENTS AND METHODS: Adult patients were randomized 2 : 1 to osimertinib (80 mg orally, once daily) or pemetrexed plus carboplatin/cisplatin (platinum-pemetrexed) intravenously, every 3 weeks (≤6 cycles). Patients could crossover to osimertinib on progression confirmed by blinded independent central review. OS and safety were secondary end points. RESULTS: A total of 279 patients were randomly assigned to receive osimertinib and 140 to platinum-pemetrexed (136 received treatment). At data cut-off (DCO; 15 March 2019), 188 patients (67%) receiving osimertinib versus 93 (66%) receiving platinum-pemetrexed had died. The hazard ratio (HR) for OS was 0.87 [95% confidence interval (CI) 0.67-1.12; P = 0.277]; the median OS was 26.8 months (95% CI 23.5-31.5) versus 22.5 months (95% CI 20.2-28.8) for osimertinib and platinum-pemetrexed, respectively. The estimated 24- and 36-month survival was 55% versus 43% and 37% versus 30%, respectively. After crossover adjustment, there was an HR of 0.54 (95% CI 0.18-1.6). Time to first subsequent therapy or death showed a clinically meaningful advantage toward osimertinib (HR 0.21, 95% CI 0.16-0.28; P < 0.001). At DCO, 99/136 (73%) patients in the platinum-pemetrexed arm had crossed over to osimertinib, 66/99 (67%) of whom had died. The most common adverse events possibly related to study treatment were diarrhea (32%; grade ≥3, 1%) and rash (grouped term; 32%; grade ≥3, <1%) in the osimertinib arm, versus nausea (47%; grade ≥3, 3%) in the platinum-pemetrexed arm. CONCLUSIONS: In patients with T790M advanced NSCLC, no statistically significant benefit in OS was observed for osimertinib versus platinum-pemetrexed, which possibly reflects the high crossover rate of patients from platinum-pemetrexed to osimertinib. CLINICAL TRIALS NUMBER: ClinicalTrials.gov NCT02151981; https://clinicaltrials.gov/ct2/show/NCT02151981.

Monitoring of somatic mutations in circulating cell-free DNA by digital PCR and next-generation sequencing during afatinib treatment in patients with lung adenocarcinoma positive for EGFR activating mutations.

Background: Analysis of circulating cell-free DNA (cfDNA) is under intensive investigation for its potential to identify tumor somatic mutations. We have now explored the usefulness of such liquid biopsy testing with both the digital polymerase chain reaction (dPCR) and next-generation sequencing (NGS) during treatment of patients with the epidermal growth factor receptor (EGFR) inhibitor afatinib. Patients and methods: Eligible patients had advanced lung adenocarcinoma with EGFR activating mutations and were treated with afatinib. Plasma samples were collected before and during (4 and 24 weeks) afatinib treatment as well as at disease progression. Tumor and plasma DNA were analyzed by dPCR and NGS. Results: Thirty-five patients were enrolled. The objective response rate and median progression-free survival (PFS) were 77.1% and 13.8 months, respectively. Tumor and plasma DNA were available for 32 patients. dPCR and NGS detected EGFR activating mutations in 81.3% and 71.9% of baseline cfDNA samples, respectively. In 19 patients treated with afatinib for ≥24 weeks, the number of EGFR mutant alleles detected in cfDNA by dPCR declined rapidly and markedly after treatment onset, becoming undetectable or detectable at only a low copy number (<10 copies per milliliter) at 4 weeks. Median PFS was slightly longer for patients with undetectable EGFR mutant alleles in cfDNA at 4 weeks than for those in whom such alleles were detectable (14.3 versus 10.0 months). A total of 45 somatic mutations was identified in baseline tumor DNA, and 30 (66.7%) of these mutations were identified in cfDNA by NGS. Allele frequency for somatic mutations in cfDNA determined by NGS changed concordantly during afatinib treatment with the number of EGFR mutant alleles determined by dPCR. Conclusions: Monitoring of cfDNA by dPCR is informative for prediction of afatinib efficacy, whereas that by NGS is reliable and has the potential to identify mechanisms of treatment resistance.

Measurement and comparison of individual external doses of high-school students living in Japan, France, Poland and Belarus-the 'D-shuttle' project.

Twelve high schools in Japan (of which six are in Fukushima Prefecture), four in France, eight in Poland and two in Belarus cooperated in the measurement and comparison of individual external doses in 2014. In total 216 high-school students and teachers participated in the study. Each participant wore an electronic personal dosimeter 'D-shuttle' for two weeks, and kept a journal of his/her whereabouts and activities. The distributions of annual external doses estimated for each region overlap with each other, demonstrating that the personal external individual doses in locations where residence is currently allowed in Fukushima Prefecture and in Belarus are well within the range of estimated annual doses due to the terrestrial background radiation level of other regions/countries.

Comparison of perioperative and short-term oncological outcomes after single- or multiport surgery for colorectal cancer.

AIM: The aim of this retrospective study was to compare the short-term surgical results of single-port surgery (SPS) with those of multiport surgery (MPS) for colorectal cancer. METHOD: We studied 673 consecutive patients who underwent SPS or MPS for colorectal cancer in our department from January 2008 to December 2013. The operative parameters and oncological outcome were analysed and compared between the SPS and the MPS groups retrospectively. RESULTS: The SPS and MPS groups did not differ significantly in terms of preoperative evaluation. The median operative time was significantly shorter with SPS than with MPS (176 min vs 193 min; P < 0.001). The two groups did not differ significantly in terms of postoperative complications. Length of hospital stay was significantly shorter with SPS than with MPS (8 days vs 10 days; P < 0.001). Oncological resection was similar in the two groups. The disease-free survival rates at 2 years according to the TNM stage did not differ significantly between the two groups (Stage I, 98.5% vs 94.7%; Stage II, 93.4% vs 90.7%; and Stage III, 70.8% vs 68.4%). CONCLUSION: Our experience demonstrates that SPS is safe and can provide oncological outcomes equal to those of MPS in patients with colorectal cancer.

Individual-level data on the relationships of progression-free survival, post-progression survival, and tumor response with overall survival in patients with advanced non-squamous non-small cell lung cancer.

The effects of first-line chemotherapy on overall survival (OS) might be confounded by subsequent therapies in patients with non-small cell lung cancer (NSCLC). We examined whether progression-free survival (PFS), post-progression survival (PPS), or tumor response could be valid surrogate endpoints for OS after first-line chemotherapies in advanced NSCLC by using individual-level data, given the lack of research in this area. Between April 2009 and June 2011, 50 patients with advanced non-squamous NSCLC treated with cisplatin and pemetrexed as first-line chemotherapy were analyzed. The relationships of PFS, PPS, and tumor response with OS were analyzed at the individual level. Spearman rank correlation analysis and linear regression analysis showed that PPS was strongly correlated with OS (r = 0.89, P < 0.05, R2 = 0.79), PFS was moderately correlated with OS (r = 0.67, P < 0.05, R2 = 0.39), and tumor shrinkage was weakly correlated with OS (r = 0.36, P < 0.05, R2 = 0.14). Performance status at the beginning of second-line treatment, the best response to second-line treatment, and number of regimens used after progression following first-line chemotherapy were significantly associated with PPS (P < 0.05). Analysis of individual-level data suggested that PPS could be used as a surrogate for OS in patients with advanced non-squamous NSCLC with unknown oncogenic driver mutations and therefore limited options for subsequent chemotherapy. Our findings also suggest that subsequent treatment after disease progression following first-line chemotherapy may greatly influence OS. These results should be validated in other larger populations.

Background rates of x-ray transition-edge sensor micro-calorimeters under a frequency domain multiplexing readout for solar axion-like particles' detection.

We report on the x-ray background rate measured with transition-edge sensors (TES) micro-calorimeters under frequency-domain multiplexing (FDM) readout as a possible technology for future experiments aiming at a direct detection of axion-like particles. Future axion helioscopes will make use of large magnets to convert axions into photons in the keV range and x-ray detectors to observe them. To achieve this, a detector array with high spectral performance and extremely low background is necessary. TES are single-photon, non-dispersive, high-resolution micro-calorimeters and represent a possible candidate for this application. We have been developing x-ray TES micro-calorimeters and an FDM readout technology in the framework of the space-borne x-ray astronomical observatories. We show that the current generation of our detectors is already a promising technology for a possible axion search experiment, having measured an x-ray background rate of 2.2(2) × 10-4 cm-2 s-1 keV-1 with a cryogenic demonstrator not optimized for this specific application. We then make a prospect to further improve the background rate down to the required value (<10-7 cm-2 s-1 keV-1) for an axion-search experiment, identifying no fundamental limits to reach such a level.

Performance and uniformity of a kilo-pixel array of Ti/Au transition-edge sensor microcalorimeters.

Uniform large transition-edge sensor (TES) arrays are fundamental for the next generation of x-ray space observatories. These arrays are required to achieve an energy resolution ΔE < 3 eV full width at half maximum (FWHM) in the soft x-ray energy range. We are currently developing x-ray microcalorimeter arrays for use in the future laboratory and space-based x-ray astrophysics experiments and ground-based spectrometers. In this contribution, we report on the development and the characterization of a uniform 32 × 32 pixel array with 140 × 30 µm2 Ti/Au TESs with the Au x-ray absorber. We report on extensive measurements on 60 pixels in order to show the uniformity of our large TES array. The averaged critical temperature is Tc = 89.5 ± 0.5 mK, and the variation across the array (∼1 cm) is less than 1.5 mK. We found a large region of detector's bias points between 20% and 40% of the normal-state resistance where the energy resolution is constantly lower than 3 eV. In particular, results show a summed x-ray spectral resolution ΔEFWHM = 2.50 ± 0.04 eV at a photon energy of 5.9 keV, measured in a single-pixel mode using a frequency domain multiplexing readout system developed at SRON/VTT at bias frequencies ranging from 1 MHz to 5 MHz. Moreover, we compare the logarithmic resistance sensitivity with respect to temperature and current (α and ß, respectively) and their correlation with the detector's noise parameter M, showing a homogeneous behavior for all the measured pixels in the array.

Frequency shift algorithm: Application to a frequency-domain multiplexing readout of x-ray transition-edge sensor microcalorimeters.

In the frequency-domain multiplexing (FDM) scheme, transition-edge sensors (TESs) are individually coupled to superconducting LC filters and AC biased at MHz frequencies through a common readout line. To make efficient use of the available readout bandwidth and to minimize the effect of non-linearities, the LC resonators are usually designed to be on a regular grid. The lithographic processes, however, pose a limit on the accuracy of the effective filter resonance frequencies. Off-resonance bias carriers could be used to suppress the impact of intermodulation distortions, which, nonetheless, would significantly affect the effective bias circuit and the detector spectral performance. In this paper, we present a frequency shift algorithm (FSA) to allow off-resonance readout of TESs, while preserving the on-resonance bias circuit and spectral performance, demonstrating its application to the FDM readout of an x-ray TES microcalorimeter array. We discuss the benefits in terms of mitigation of the impact of intermodulation distortions at the cost of increased bias voltage and the scalability of the algorithm to multi-pixel FDM readout. We show that with FSA, in the multi-pixel and frequencies shifted on-grid, the line noises due to intermodulation distortion are placed away from the sensitive region in the TES response and the x-ray performance is consistent with the single-pixel, on-resonance level.

A six-degree-of-freedom micro-vibration acoustic isolator for low-temperature radiation detectors based on superconducting transition-edge sensors.

Dilution and adiabatic demagnetization refrigerators based on pulse tube cryocoolers are nowadays used in many low temperature physics experiments, such as atomic force and scanning tunneling microscopy, quantum computing, radiation detectors, and many others. A pulse tube refrigerator greatly simplifies the laboratory activities being a cryogen-free system. The major disadvantage of a pulse tube cooler is the high level of mechanical vibrations at the warm and cold interfaces that could substantially affect the performance of very sensitive cryogenic instruments. In this paper, we describe the performance of a very simple mechanical attenuation system used to eliminate the pulse-tube-induced low frequency noise of the superconducting transition-edge sensors under development for the instruments of the next generation of infra-red and X-ray space observatories.

First Report of Spring Black Stem and Leaf Spot of Alfalfa in Washington State Caused by Phoma medicaginis.

Lesions were observed on leaves and stems of alfalfa (Medicago sativa L.) growing as weeds in Pullman, Washington in June of 2001. Lesions appeared similar to those described for spring black stem and leaf spot caused by Phoma medicaginis Malbr. & Roum. in Roum. var. medicaginis Boerema (synonyms Phoma herbarum Westend. var. medicaginis Fckl. and Ascochyta imperfecta Peck). Sporulation was induced by placing surface-disinfested pieces of infected tissue on 3% water agar (WA) for 24 h under fluorescent light with a 12-h photoperiod. Single-conidial isolations were made by streaking conidia on 3% WA and picking germinated conidia after 18 h. Isolates had cultural and conidial morphology similar to descriptions of P. medicaginis and isolate ATCC52798 when grown on V8 agar and PDA at room temperature (3). Distinction between P. medicaginis var. medicaginis and P. medicaginis var. macrospora was not attempted. Conidial suspensions (1 × 106 conidia/ml) of isolates AS1, AS2, AS3, and AS4 were spray inoculated to runoff onto 3-week-old plants. PI lines 536535 and 536534 of M. sativa subsp. sativa (4-trifolate stage) and PI lines 442896 and 577609 of M. truncatula (5- to 7-trifolate stage) from the USDA Western Region Plant Introduction Station, Pullman, Washington were inoculated, with at least two replicate plants inoculated per isolate. Plants were incubated in a dew chamber at 20°C in the dark for 24 h to promote infection and then transferred to a growth chamber at 18°C with a 12-h photoperiod. Lesions were apparent on M. sativa subsp. sativa plants 4 days postinoculation (dpi) and 7 dpi on M. truncatula plants. At 12 dpi, many dark brown lesions with chlorotic halos were noted on leaves of M. sativa subsp. sativa, occasionally killing the entire trifoliate leaf and progressing approximately 1 cm down the stem. According to the previously published 1-to-5 visual rating scale for this disease (4), disease scores on both genotypes of M. sativa subsp. sativa were 4 (susceptible), while disease ratings on M. truncatula were 1-2 (resistant) with a few dark brown lesions noted on leaves and stems generally restricted to less than 2 mm in diameter. DNA was extracted from isolates AS1 and AS4, and PCR was performed using gpd-1 and gpd-2 primers for the glyceraldehyde-3-phosphate dehydrogenase gene (G3PD) (1), and EF1-728F and EF1-986R primers for the translation elongation factor 1-alpha gene (EF) (2), resulting in amplification of an approximately 600-bp fragment from each primer set. Amplicons were direct-sequenced on both strands, and BLAST searches of the NCBI nucleotide database were conducted with consensus G3PD and EF sequences of both isolates AS1 and AS4. Closest matches obtained for the G3PD and EF sequences were P. medicaginis isolate ATCC52798 (Accession No. DQ525740) and P. medicaginis var. medicaginis CBS316.90 (Accession No. AY831548), respectively. The G3PD and EF sequences for these isolates have been deposited in GenBank database (Accession Nos. EU394712-EU394715). To our knowledge, this is the first confirmed report of spring black stem and leaf spot of alfalfa in Washington State supported by Koch's postulates, cultural morphology, and multigene sequencing. References: (1) M. L. Berbee et al. Mycologia 91:964, 1999. (2) I. Carbone and L. M. Kohn. Mycologia 91:553, 1999. (3) G. C. Kinsey. No. 1503 in: IMI Descriptions of Fungi and Bacteria. CABI Bioscience, Surrey, UK, 2002. (4) R. M. Salter and K. L. Leath. Spring blackstem and leafspot resistance. Online publication. North American Alfalfa Improvement Conference, Beltsville, MD, 1992.

[Endobronchial metastasis from renal cell carcinoma resected 9 years before; report of a case].

A 68-year-old man, who had undergone a left nephrectomy for a clear cell type renal cell carcinoma (RCC) in June 1995 and then received interferon therapy till March 1997, was admitted with dyspnea in June 2004. Chest X-ray showed atelectasis of the left lower lung lobe and chest computed tomography revealed a polypoid mass in the left lower bronchus. He was diagnosed with a pulmonary metastasis of a RCC by transbronchial biopsy. We considered it a slow growing type of RCC because of the long disease free interval (DFI). A left lower lobectomy with bronchoplasty was carried out. However, 6 month after the operation, a new lesion has occurred near the portion of the broncho-anastmosis and multiple metastases have developed in the right lung.

Overcorrection in vertical alveolar distraction osteogenesis for dental implants.

A decrease in bone height following alveolar distraction osteogenesis (DO) before implant placement is common, and can be severe when alveolar DO is performed soon after surgical intervention. The aim of this study was to investigate the decrease in bone height after vertical alveolar DO and determine the need for overcorrection with implant placement. Thirty-five patients (17 males and 18 females, mean age 43.9 years) underwent 38 procedures with successful placement of 141 dental implants. Alveolar ridge height was evaluated using digital orthopantomographic radiographs taken shortly after the end of distraction, at consolidation and before implant placement. The mean distraction was 9.7 mm. The total vertical alveolar bone decrease was 2.1mm (21%) during the consolidation period and 3.6mm (37%) at implant placement. Although the 20 sites with a healthy alveolus (surgery >6 months) had bone reductions of 1.5 and 2.5mm (15 and 25%) the 18 sites at which alveolar DO was performed within 6 months (mean 3.0) of surgical intervention had much greater bone loss of 2.7 and 4.8mm (28 and 50%), respectively ((**)P<0.01). These results indicate that any alveolar DO protocol should include a waiting period after the surgical intervention, as well as consider an overcorrection of more than 25% within the limits of the applied surgical protocol.

Host Specificity of Ascochyta spp. Infecting Legumes of the Viciae and Cicerae Tribes and Pathogenicity of an Interspecific Hybrid.

ABSTRACT Ascochyta spp. (teleomorphs: Didymella spp.) infect a number of legumes, including many economically important species, and the diseases they cause represent serious limitations of legume production worldwide. Ascochyta rabiei, A. fabae, A. pisi, A. lentis, and A. viciae-villosae are pathogens of chickpea (Cicer arietinum), faba bean (Vicia faba), pea (Pisum sativum), lentil (Lens culinaris), and hairy vetch (V. villosa), respectively. Inoculations in the greenhouse and in growth chambers demonstrated that A. fabae, A. lentis, A. pisi, A. rabiei, and A. viciae-villosae were host specific. Isolates caused no visible disease symptoms on "nonhost" plants (plants other than the hosts they were originally isolated from) but were recovered consistently from inoculated, surface-disinfested, nonhost tissues. Interspecific crosses of A. pisi x A. fabae and A. viciae-villosae x A. lentis produced pseudothecia with viable ascospores, and the hybrid status of the ascospore progeny was verified by the segregation of mating type and amplified fragment length polymorphism (AFLP) markers. Interspecific progeny were morphologically normal in culture but exhibited more phenotypic variation compared with progeny from intraspecific crosses. Mating type and the majority of AFLP markers segregated in Mendelian 1:1 ratios in both intraspecific and interspecific crosses. A total of 11 and 7% of AFLP markers showed segregation distortion among progeny from interspecific crosses and intraspecific crosses, respectively; however, this difference was not significant (P = 0.90). Only 30 of 114 progeny isolates from the A. fabae x A. pisi cross inoculated in the greenhouse caused lesions on pea and only 4 caused disease on faba bean. In all, 15 of 110 progeny isolates were pathogenic to pea and none were pathogenic to faba bean under growth chamber conditions. Although no obvious postzygotic, intrinsic isolating barriers were identified in any of the interspecific crosses, it appears that host specialization may act as both a prezygotic, ecological isolating barrier and a postzygotic, extrinsic, ecological isolating barrier in these fungi. Host specificity, coupled with low pathogenic fitness of hybrids, may be an important speciation mechanism contributing to the maintenance of hostspecific, phylogenetic lineages of these fungi.

The effect of fexofenadine on pruritus in a mouse model (HR-ADf) of atopic dermatitis.

Fexofenadine, a histamine H1-receptor antagonist, is approved for the treatment of pruritus associated with atopic dermatitis. The effects of fexofenadine on scratching behaviour, and plasma levels of histamine and eotaxin were assessed in a new model of atopic dermatitis. Mice fed a diet low in Mg2+ and Zn2+ (special diet S) were compared with mice on a normal diet (N) or diet S plus fexofenadine HCl for weeks 0-10 (S + F(0-10)), 0-5 (S + F(0-5)) or 6 - 10 (S + F(6-10)) (seven mice per group). Compared with group N, group S mice showed significantly greater scratching frequency, and plasma histamine and eotaxin concentrations; these three variables were significantly lower in group S + F(0-10) than in group S. Scratching frequency increased when fexofenadine was discontinued. Fexofenadine significantly reduced mast cell and eosinophil numbers. Histamine may be important in the pathological changes seen in this model of atopic dermatitis, suggesting that it might aid future development of antihistamines for the treatment of atopic dermatitis.

Suppression of transformed phenotypes of human fibrosarcoma cells by overexpression of recombinant fibronectin.

Loss of fibronectin (FN) from the cell surface has been shown to be closely associated with malignant transformation of cells. To elucidate the role of the FN matrix in the modulation of malignant phenotypes, we overexpressed a full-length cDNA encoding plasma-type FN in HT1080 human fibrosarcoma cells. The cells overexpressing FN adopted a more flattened morphology and deposited a moderately developed FN matrix both in vitro and in vivo, although the level of expression of integrin alpha5beta1 remained unchanged. FN-overexpressing cells exhibited a reduced cell motility on the substratum and grew poorly when injected s.c. into nude mice. Overexpression of FN also suppressed the ability of the tumor cells to proliferate in soft agar, whereas the suppression was reversed by inclusion in soft agar of the Arg-Gly-Asp (RGD)-containing peptide and adhesion-blocking antibodies against the central cell-binding domain of FN. Neither cell motility nor growth potential was altered by overexpression of a truncated form of FN lacking the central cell-binding domain. These results, taken together, indicate that increased deposition of FN in the pericellular matrix per se can suppress the motility and growth potential of tumor cells through interaction with RGD-recognizing integrins, most likely alpha5beta1.

Correlation of tissue and plasma RANTES levels with disease course in patients with breast or cervical cancer.

The beta-chemokine RANTES was measured in plasma in 43 patients with breast cancer and in 23 patients with cervical cancer, and the RANTES content in primary tumors, tumor metastatic to lymph nodes, and clinically normal skin or pelvic mucosa was measured. In addition, plasma levels were determined in all of the patients for the platelet-derived chemokine beta-thromboglobulin (beta-TG) and for IFN-gamma, interleukin (IL)-2, IL-4, IL-5, and IL-10, along with serum IgE levels and blood eosinophils. Plasma RANTES levels were found to be higher in order of stages IV, III, II, and I of each cancer except for stage I. A marked increase in plasma RANTES level (> 10,000 pg/ml) was found in 27% of patients with progressive malignancy but in none of those in clinical remission. The platelet RANTES content was correspondingly decreased in those patients with increased plasma RANTES levels. Beta-TG showed a pattern similar to RANTES both in plasma and platelets, but with much less dramatic differences between patients with different stages of disease. Other allergic parameters, IgE, eosinophils and plasma IFN-gamma, IL-2, -5, and -10, were not elevated in the cancer patients. The RANTES content was markedly elevated in the primary tumor and metastatic lesions (lymph node or skin) from all of the patients with breast or cervical cancer, irrespective of the plasma RANTES level. In addition, in patients with progressive breast or cervical cancer, but not in patients thought to be cured of these tumors, the RANTES content was markedly increased in clinically normal tissue taken from near the operative site several months postoperatively, as well as in intact skin or mucosa taken perioperatively near the excised tumor. This study suggests an as-yet-undefined but important role played by RANTES in carcinogenesis, as well as the possibility that a RANTES assay in tissue surrounding a tumor or postoperative tumor site may help predict prognosis in these patients.

[Gingival metastasis of pulmonary pleomorphic carcinoma; report of a case].

A 71-year-old male was admitted to the hospital complaining of cough. The chest X-ray and computed tomography (CT) revealed a large tumor in the right lower lung, which was diagnosed as poorly differentiated adenocarcinoma. As the tumor grew rapidly and caused obstructive pneumonia, right middle and lower lobectomy was performed even if right gingival tumor was suspected as metastasis from lung tumor. The patient complicated with aspiration pneumonia after operation and died on the 20th postoperative day. The prognosis of lung cancer with gingival metastasis is very poor. Early detection and appropriate therapy is necessary.

Protective role of copper, zinc superoxide dismutase against UVB-induced injury of the human keratinocyte cell line HaCaT.

On the basis of our recent observation that copper, zinc-superoxide dismutase and manganese-superoxide dismutase change differently following a single exposure to ultraviolet-B irradiation in the human keratinocyte cell line HaCaT, we have examined the possible role of endogenous copper,zinc-superoxide dismutase or manganese-superoxide dismutase against ultraviolet-B-induced reactive-oxygen- species-mediated keratinocyte injury in vitro. To evaluate the individual defensive roles of copper, zinc-superoxide dismutase and manganese-super-oxide dismutase, we treated HaCaT cells with diethyldithiocarbamate, a chelating agent of ionic copper that inactivates copper,zinc-superoxide dismutase activities, tumor necrosis factor alpha, which enhances manganese-superoxide dismutase levels, or transforming growth factor beta1, which inhibits manganese-superoxide dismutase levels. After the treatment with each reagent, HaCaT cells in the three different conditions were exposed to a single dose of ultraviolet-B irradiation. We assessed ultraviolet-B-induced cytotoxicity by measuring both lactate dehydrogenase leakage and cell viability using trypan blue dye exclusion assay. The lactate dehydrogenase leakage in the supernatant from damaged HaCaT cells whose copper,zinc-superoxide dismutase levels were inactivated by diethyldithiocarbamate was significantly increased and the cell viability was significantly decreased in comparison with untreated groups at 8 and 24 h after ultraviolet-B irradiation. On the other hand, the lactate dehydrogenase release and cell viability for HaCaT cells whose manganese-superoxide dismutase levels were enhanced by tumor necrosis factor alpha or inhibited by transforming growth factor beta1 showed no significant difference from untreated groups. Furthermore, increased production of intracellular peroxides in HaCaT cells treated with diethyldithiocarbamate was observed by flow cytometric analysis at 8 h after ultraviolet-B irradiation. These results suggest that copper,zinc-superoxide dismutase may play a primary protective role against ultraviolet-B-induced injury of the human keratinocyte cell line HaCaT.