A perivascular niche in the bone marrow hosts quiescent and proliferating tumorigenic colorectal cancer cells

Disseminated tumor cells (dTCs) can frequently be detected in the bone marrow (BM) of colorectal cancer (CRC) patients, raising the possibility that the BM serves as a reservoir for metastatic tumor cells. Identification of dTCs in BM aspirates harbors the potential of assessing therapeutic outcome and directing therapy intensity with limited risk and effort. Still, the functional and prognostic relevance of dTCs is not fully established. We have previously shown that CRC cell clones can be traced to the BM of mice carrying patient-derived xenografts. However, cellular interactions, proliferative state and tumorigenicity of dTCs remain largely unknown. Here, we applied a coculture system modeling the microvascular niche and used immunofluorescence imaging of the murine BM to show that primary CRC cells migrate toward endothelial tubes. dTCs in the BM were rare, but detectable in mice with xenografts from most patient samples (8/10) predominantly at perivascular sites. Comparable to primary tumors, a substantial fraction of proliferating dTCs was detected in the BM. However, most dTCs were found as isolated cells, indicating that dividing dTCs rather separate than aggregate to metastatic clones—a phenomenon frequently observed in the microvascular niche model. Clonal tracking identified subsets of self-renewing tumor-initiating cells in the BM that formed tumors out of BM transplants, including one subset that did not drive primary tumor growth. Our results indicate an important role of the perivascular BM niche for CRC cell dissemination and show that dTCs can be a potential source for tumor relapse and tumor heterogeneity.     

Results of radical treatment of stage IIIa non-small-cell carcinoma of the lung

From 1979 to 1987, 907 patients with non-oat cell carcinoma of the lung were subjected to thoracotomy: of these, 685 (75.5%) underwent radical resection of the lung tumour. The 230 stage IIIa patients were studied in this paper. These were divided into three groups. First group: 93 patients with only local parietal or mediastinal spread without involvement of the mediastinal lymph nodes (T3N0-1M0); the 5-year survival of this group was 35% (44.1% when the ribs and muscles were not affected). A second group of 118 patients had tumour spreading to the mediastinal lymph nodes, but without local involvement (T1-2N2M0): this group had a 5-year survival of 22.3%. The 5-year survival was better in patients without metastases in the subcarinal lymph nodes than in patients with them (23.76% versus 12.89%). Skipping of lymphatic levels was frequent: 37% of patients with metastasis to mediastinal lymph nodes did not have metastases in the lymph nodes of the lung; 10% of tumours removed by lobectomy had metastases in the lymph nodes of the residual lobe. The third group with parietal and lymphatic mediastinal invasion (T3N2M0) had a poor survival (13.5% at 5 years). The author concludes that it is possible to achieve an acceptable 5-year survival in selected cases with metastasis to mediastinal lymph nodes: when the CT scan demonstrated mediastinal lymph nodes larger than 1.5 cm, mediastinoscopy was carried out and, if positive, the patient was judged inoperable.     

The factor of magnification in mammography

The last generation of mammographic equipment allows mammography to be performed with direct magnification techniques, thanks to such technical features as microfocus, high focus-film distance, high-power generators. The authors compared the diagnostic yield of two different equipment sets, with 1.4x and 2x magnification respectively, and verified the utility of magnification radiography. A significant reduction was obtained in questionable diagnoses (42 to 18) in a group of 63 patients, with no evidence of substantial differences in the diagnostic yield of the images obtained with different magnification ratios. An objective analysis of the system resolution power privileges 2x magnification ratio, which however implies an increase in the average dose to the breast. The use of faster recording systems reduces the dose by 50%, though maintaining good image quality.     

Testosterone and postnatal ontogenesis of hypothalamic mu ([3H]dihydromorphine) opioid receptors in the rat.

Brain opioids modulate the activity of the hypothalamo-pituitary complex by binding to specific receptors which have been subdivided at least into 3 subclasses (mu, kappa, delta, etc). mu-Receptors and their ligands seem to be particularly involved in the control of gonadotropin and prolactin release. It is known that the neuroendocrine system, as well as the brain opioid systems and their receptors, are not fully mature at birth; it is also known that the postnatal maturation of many brain machineries is under the control of androgens secreted by the developing testes. Consequently, it has been investigated whether the presence or the absence of testosterone at time of birth may induce changes of the binding characteristics of hypothalamic mu-opioid receptors. The experiments have been performed by evaluating the maximal binding capacity (Bmax, an index of the number of receptors), and the affinity constant (Ka) of the specific mu-ligand dihydromorphine in hypothalamic plasma membrane preparations derived from normal male rats, normal female rats, male rats orchidectomized 2 days after birth and female rats treated 2 days after birth with 1.25 mg of testosterone propionate. Animals belonging to the 4 groups were killed at days 16, 26 and 60 of age. The results obtained show that, at 16 days of age, in the 4 groups of rats the number of hypothalamic mu receptors is identical. At 26 days a significant increase in the number of mu-receptors occurs in normal female animals, while their levels remain similar to those found at 16 days in the other 3 groups of animals. At 60 days of age, the number of mu-receptors in normal females remains elevated, while the number of mu-receptors increases to reach normal female levels in the hypothalamus of neonatally castrated males. At 60 days, there were no changes in normal males or in androgenized females. The variations here reported took place without any change of the Ka of dihydromorphine for the mu-receptors. These data show a sexual dimorphism of hypothalamic mu-receptors and suggest that their ontogenetic development may be linked to the presence or the absence of androgens at time of birth.     

Determinants of left ventricular systolic function recovery after an acute coronary syndrome.

INTRODUCTION: Ischemic heart disease is a major cause of heart failure in western societies. However, the factors that may influence left ventricular function (LVF) recovery after an acute coronary syndrome (ACS) are still unclear. OBJECTIVE: To identify variables that may influence LVF evolution one year after ACS. METHODS: 104 patients hospitalized with ACS between 7/1/2001 and 12/31/2002 and with systolic dysfunction--defined as an echocardiographic ejection fraction (EF) < or = 45%--were randomly allocated to a planned coronary follow-up program (FUP) or a general cardiology clinic (GC); patients from both groups were also randomly referred to a structured cardiac rehabilitation program (CRP). EF was re-assessed at one year. We compared differences between patients who recovered left ventricular function (EF > 45%; group 1) and those who did not (group 2). RESULTS: One year after discharge, 44.2% of the patients had recovered function. There were no significant differences between the groups in gender (77.7 vs. 76.5% male), age (56 vs. 59 years), hypertension, diabetes, dyslipidemia, smoking habits or family history. A previous history of cardiovascular events was more frequent in group 2 (11.1% vs. 35.3%, p = 0.03). Cardiac catheterization was performed before discharge in 88.8% and 88.2% in groups 1 and 2 respectively (p = NS); no differences were found in coronary anatomy between the two groups. Angioplasty was performed in 54.2% in group 1 and 50% in group 2 (p = NS). There were no differences in the use of angiotensin-converting enzyme inhibitors (83.3% vs. 87.5%), beta-blockers (87.5% vs. 87.5%), nitrates (37.5% vs. 33.3%), aspirin (95.8% vs. 95.8%), statins (79.1% vs. 75%) or diuretics (20.8% vs. 45.8%). There was no significant difference in LVF recovery between patients randomized to FUP or GC (38.5% vs. 54.5%). 87.5% of patients who completed the CRP had normal EF at one year compared to 32.7% of patients not referred to the program (p = 0.009). Although EF improved in both groups, this improvement was greater in patients who completed a CRP (EF 8% vs. 5%, p = 0.003). CONCLUSION: A previous cardiovascular event and completion of a CRP were the only variables that influenced LVF recovery. Thus, enrollment in a CRP, in addition to standard therapy, could be an important therapeutic measure in patients with systolic dysfunction after ACS; our data suggest that these programs should be more widely used.     

Multiple sources of calcium for contraction of the human urinary bladder muscle.

1. KCl, carbachol, neurokinin A and endothelin produced concentration-dependent contractions of mucosa-free muscle strips from the dome of the human urinary bladder. The maximal response to carbachol or neurokinin A exceeded that to KCl, while the maximal response to endothelin approached that to KCl. 2. Nifedipine (1 microM) abolished the response to KCl, reduced the response to carbachol or neurokinin A but had no effect on the response to endothelin. Bay K 8644 (1 microM) markedly potentiated the response to KCl but had little or no effect on the response produced by the other stimulants. 3. Superfusion of the strips with a nominally calcium (Ca)-free medium containing EDTA (1 mM) for 30 min markedly reduced the response to carbachol, neurokinin A and endothelin, although a small response was still evident at high concentrations. Likewise, after a prolonged (60 min) superfusion of the strips with a high K (80 mM) Ca-free medium plus EDTA (1 mM) these three agonists still produced a small contractile response. 4. The nifedipine (1 microM) resistant response to carbachol, neurokinin A or endothelin was markedly depressed by LaCl3 (1 mM). In contrast, the nifedipine-(1 microM) resistant response to carbachol was not modified by NiCl2 (0.1 mM) or omega-conotoxin (0.1 microM). 5. Caffeine produced divergent effects depending upon the temperature of incubation: a relaxation at 37 degrees C and a concentration-dependent (2.5-20 mM) contraction at 25 degrees C. The latter was markedly inhibited by procaine (3 mM) but unaffected by nifedipine (1 microM). 6. After a prolonged (60 min) superfusion with a high K, Ca-free medium containing EDTA the response to carbachol (100 microM) was abolished by previous exposure to procaine (3 mM). Conversely, the response to endothelin (1 microM) was unaffected by procaine. The response to endothelin in these experimental conditions was also resistant to LaCl3 (1 mM). 7. These findings indicate that multiple sources of Ca are mobilized for contraction of the human bladder muscle by different stimulants. Dihydropyridine- and voltage-sensitive Ca channels provide the major if not the sole source of Ca for the response to KCl, play some role in the response to muscarinic (carbachol) or NK-2 tachykinin receptor stimulation but are not involved in the response to endothelin. Carbachol, neurokinin A and endothelin all mobilize a Ca pool (either extracellular or located at membrane level) which is LaCl3-sensitive but nifedipine-resistant. Neither T- nor N-type channels appear to be involved in the response to carbachol.(ABSTRACT TRUNCATED AT 400 WORDS)     

Oral contraceptive use and invasive cervical cancer

The relationship between oral contraceptive use and the risk of invasive cervical cancer was investigated using data from a hospital-based case-control study conducted in the greater Milan area, Northern Italy. A total of 367 women under 60 years of age with a histologically confirmed diagnosis of invasive cervical cancer was compared with a group of 323 controls admitted for a spectrum of acute conditions, non-gynaecological, hormonal or neoplastic and apparently unrelated to oral contraceptive use. Cases had used oral contraceptives more frequently than controls, the age-adjusted relative risk (RR) being 1.53 (95% confidence interval 0.99-2.36). The risk increased with duration of use: compared with never users the age-adjusted RR was 1.48 for up to two years and 1.83 for more than two years (chi 2(1) = 5.28, p = 0.02). Allowing for major identified potential confounding factors, including sexual and reproductive habits, by means of multiple logistic regression, did not explain the association (multivariate RR 1.85 for ever use, 1.05 for up to two years and 2.47 for more than two years). When the interaction between oral contraceptive use and parity or sexual habits was analysed, the effects of various factors appeared independent: the point estimate for multiparous oral contraceptive users versus nulliparous never users was 8.01. There was no consistent influence on risk of invasive cervical cancer of age at first use, whereas the RRs were slightly greater for women who had first used oral contraceptives less than ten years before or had last used them less than five years before diagnosis: these findings, however, were far from significant.     

Effects of intravenous L-acetylcarnitine on retinal oscillatory potentials

L-acetylcarnitine is a compound with cholinergic properties and putative action on the visual system and the glucose metabolism. Ten healthy, emmertropic volunteers (age range: 21 to 28 years) were studied. Each subject was administered 5, 10, and 30 mg/kg acute intravenous doses of L-acetylcarnitine and matching placebo. Retinal oscillatory potentials to full-field flash stimulation were recorded before and 30, 60, and 120 min after administration. A systematic reduction of the implicit time of the P2 and N2 oscillatory potential components was observed after administration of the 10 and 30 mg/kg doses: significant changes were not evident at the 5 mg dose or after placebo. The latency reduction was significantly correlated with the postdrug increment of the L-acetylcarnitine plasma concentration. No other systematic modification in latency of amplitude was observed.The results were presented in part at the XXV I.S.C.E.V. Symposium, Sarasota (Florida), April 26–30, 1987.     

Correlation with age and sex of flash-evoked electroretinogram and retinal oscillatory potentials recorded with skin electrodes

Electroretinograms and retinal oscillatory potentials to full-field flash stimulation were recorded by dermal electrodes in a population of subjects (1 to 84 yrs) balanced for age and sex (119 females, 133 males), without evidence or history of ocular and/or relevant systemic diseases. The electroretinogram latencies and b-wave amplitude increased, while the a-wave amplitude decreased linearly with age. The oscillatory potential amplitude initially increased, to decrease approximately at the age of 50, with an inverted U-shaped distribution.Presented in part at the XXV ISCEV Symposium, Sarasota (Florida), April 26–30, 1987.