Phase I-II study of gemcitabine and paclitaxel in pretreated patients with stage IIIB-IV non-small cell lung cancer

Gemcitabine and paclitaxel are among the most active new agents in non-small cell lung cancer (NSCLC) and are worth considering for second-line chemotherapy. In this phase I–II study, we combined gemcitabine and paclitaxel for second-line treatment of advanced NSCLC. Gemcitabine doses were kept fixed at 1000 mg/m² on day 1 and 8, and paclitaxel doses were escalated from 90 mg/m² on day 1 of the 21-day cycle. Thirty-seven patients were treated at six different dose levels. Grade 4 neutropenia was dose-limiting toxicity (DLT), since it occurred in two out of six patients treated at paclitaxel 240 mg/m²; the paclitaxel dose level just below (210 mg/m²) was selected for phase II evaluation. Non-hematologic toxicity was mild. One complete response (CR) (3%) and 13 partial responses (PR) (36%) were observed in 36 evaluable patients for an overall response rate of 39% (95% C.I., 23–57%). Median duration of response was 35 weeks (range, 8–102). All of the observed objective responses occurred in the 19 patients who had previously responded to the first-line therapy. Median survival was 40 weeks (range, 8–108 weeks). The combination of gemcitabine and paclitaxel is a feasible, well-tolerated, and active scheme for second-line treatment of advanced NSCLC; further evaluation, at least in selected patients, such as those previously responding to first-line chemotherapy, is definitely warranted.     

Impact of dose and volume on lymphedema

Lymphedema represents one of the major problem of morbidity in breast cancer therapy. Approximately 15-30% of patients show more or less severe lymphedema of the arm, following cancer therapy. Main pathogenetic mechanisms, risk factors, main grading criteria and scales as LENT-SOMA, CTCv2, CTCAE v3 are presented. A close correlation has been documented between the extent of axillary dissection and the association with radiotherapy in determining an increased risk of lymphedema. Details of surgery and radiotherapy are relevant in the definition of the risk of edema of the arm. Because the axillary area does not correspond to an organ, evaluable parameters as V20 and Dmean available for other organs are not applicable. There is some evidence of a correlation between the irradiation volume and the development of lymphedema. Data of the impact of the dose and its fractionation on the development of lymphedema are contrasting. The monitoring system of late toxicity used by the authors is presented.     

A contiguous stretch of methionine residues mediates the energy-dependent internalization mechanism of a cell-penetrating peptide

Recently we characterized an unusual switch in the internalization mechanism of the monomeric and dimeric forms of the cell-penetrating peptide RDLWEMMMVSLACQY. Here, we observed both energy-dependent and energy-independent modes of peptide uptake by the target B-lymphocytes WI-L2-729HF2, suggesting that higher-order structure might modulate the action of this novel cell-penetrating peptide. In the present work, we propose a possible internalization mechanism for the dimeric peptide which involves an initial interaction with the cell membrane, followed by an energy-dependent internalization process which requires the contiguous Met(6-8) sequence.     

DNA fragmentation and DNA repair synthesis induced in rat and human thyroid cells by four rat thyroid carcinogens

Four chemicals that are known to induce in rats thyroid follicular-cell adenomas and carcinomas were assayed for their ability to induce DNA damage and DNA repair synthesis in primary cultures of human thyroid cells. Significant dose-dependent increases in the frequency of DNA single-strand breaks and alkali-labile sites, as measures by the Comet assay, were obtained after a 20-h exposure to the following subtoxic concentrations of the four test compounds: 2,4-diaminoanisole (DAA) from 0.10 to 1.0 mM, 4,4'-methylene-bis(N,N-dimethyl)benzenamine (MDB) from 0.32 to 1.8 mM, propylthiouracil (PTU) from 1.8 to 5.6 mM, and 4,4'-thiodianiline (THA) from 0.032 to 0.18 mM. Under the same experimental conditions, DNA repair synthesis, as evaluated by quantitative autoradiography, was present in thyreocytes exposed to DAA but absent after treatment with MDB, PTU, and THA. Consistent with their thyroid-specific carcinogenic activity, all the four chemicals, administered p.o. in rats in a single dose corresponding to 1/2 LD50, induced a statistically significant degree of DNA fragmentation in the thyroid, whereas any substantial evidence of DNA lesions was absent in liver, kidney, and lung, which, with the exception of liver tumors caused by THA, are not targets of the carcinogenic activity of the four test compounds. These findings indicate that the DNA damage observed in thyroid cells was consistent with the carcinogenicity of the four test compounds, and suggest that DAA, MDB, PTU, and THA might be carcinogenic to thyroid in humans.     

Temporal clusters of Salmonella serovars in humans in Alberta, 1990-2001

BACKGROUND: Temporal clusters of salmonellosis are believed to occur but have not been quantitatively explored, thus, our objectives were to describe trends, seasonal patterns, and clusters of salmonellosis in humans in Alberta by examining isolates reported through passive surveillance systems. METHODS: Cases of salmonellosis reported through Notifiable Disease Records between January 1990 and December 2001 were obtained from Alberta Health and Wellness. Least squares regression was used to characterize the distribution (long-term trends and seasonal patterns) of isolates. A cluster detection test was used to determine if and when isolates of specific serovars aggregated in time, over and above the background distribution. Comparisons were made to temporal patterns in Alberta livestock and to known outbreaks in humans. RESULTS: S. Typhimurium, Enteritidis, Hadar, Heidelberg, and Thompson were the five most common serovars of the 9,188 isolates reported. The annual number of isolates was relatively stable over time, with a distinct summertime seasonal pattern. Clusters were observed in 23 of 32 serovars examined. More clusters occurred in September and October than in other months, and in 1998 through 2001 than in the early to mid-1990s. Also, more clusters were of short duration than long. INTERPRETATION: Short-duration clusters likely indicate a point source of infection, while long-duration clusters may indicate exposure to a persistent common source or the occurrence of secondary infections. A sharp increasing trend and a large cluster of S. Heidelberg may have public health implications. Surveillance activities focussed on similarities between common serovars, trends, and temporal clusters in humans and animals, and studies on factors associated with autumn clusters may be useful in preventing outbreaks in humans.     

Concentration of elements in serum of patients affected by multiple sclerosis with first demyelinating episode: a six-month longitudinal follow-up study

Twenty-six chemical elements and oxidative status were determined in serum of 12 patients with first demyelinating episode and brain magnetic resonance imaging compatible with the disease at different time points. Quantifications of Al, Ba, Be, Bi, Ca, Cd, Co, Cr, Cu, Fe, Hg, Li, Mg, Mn, Mo, Ni, Pb, Sb, Si, Sn, Sr, V, Tl, W, Zn and Zr, as well as of serum oxidative status and antioxidant capacity were carried out. The results were compared with values obtained from healthy subjects living in the same geographic area. Concentration variability, expressed as coefficient of variation (CV), was evaluated over a six months longitudinal follow-up. The CV was higher for Li and Pb, while showed minimal variation for Ca, Cu, Mg and Zn--elements strictly body regulated. Significant difference (p < or = 0.05) in mean concentrations of Ba, Ca, Cd, Cr, Li, Mn, Mo, Ni, Sb, Si, Sn and Zr between patients at time 0 and controls was also found.     

Combination Chemotherapy for Marrow Relapse in Children and Adolescents with Acute Lymphocytic Leukaemia

38 children with acute lymphocytic leukaemia (ALL) in haematologic relapse were retreated with vincristine, daunomycin and prednisone (VPD) together with intrathecal methotrexate and prednisone, followed by asparaginase in those patients not in complete remission after 4 weeks. The overall complete remission (CR) rate was 79%; asparaginase was needed to achieve CR in 7 of the 30 responding patients. The median duration of second remission was only 36 weeks, but 6 out of 15 children receiving the COAP-POMP-CART consolidation regimen remain in continuous second remission after 37–260 weeks; 3 of them are currently off all therapy. It is concluded that a prolonged second remission can be achieved in children with ALL in bone marrow relapse by combining intensive chemotherapy with the prevention of meningeal leukaemia.     

What are the effects of maternal and pre-adult environments on ageing in humans, and are there lessons from animal models?

An open issue in research on ageing is the extent to which responses to the environment during development can influence variability in life span in animals, and the health profile of the elderly in human populations. Both affluence and adversity in human societies have profound impacts on survivorship curves, and some of this effect may be traceable to effects in utero or in infancy. The Barker Hypothesis that links caloric restriction in very early life to disruptions of glucose-insulin metabolism in later life has attracted much attention, as well as some controversy, in medical circles. It is only rarely considered by evolutionary biologists working on phenotypic plasticity, or by biogerontologists studying model organisms such as C. elegans or Drosophila. One crucial mechanism by which animals can respond in an adaptive manner to adverse conditions, for example in nutrition or infection, during development is phenotypic plasticity. Here we begin with a discussion of adaptive plasticity in animals before asking what such phenomena may reveal of relevance to rates of ageing in animals, and in humans. We survey the evidence for effects on adult ageing of environmental conditions during development across mammalian and invertebrate model organisms, and ask whether evolutionary conserved mechanisms might be involved. We conclude that the Barker Hypothesis is poorly supported and argue that more work in human populations should be integrated with multi-disciplinary studies of ageing-related phenomena in experimental populations of different model species that are subjected to nutritional challenges or infections during pre-adult development.