Chromogranin A in heart failure; a novel neurohumoral factor and a predictor for mortality.

BACKGROUND: In chronic heart failure, several hormonal systems are activated with diagnostic and prognostic implications. We tested the hypotheses that serum Chromogranin-A (CgA) -- a 49 kDa acid protein present in the secretor granules of neuroendocrine cells -- is increased in chronic heart failure and that CgA levels are a predictive factor for mortality. METHOD AND RESULTS: In 160 patients with chronic heart failure, we measured serum CgA and other neuroendocrine hormones. The results showed that CgA is increased in chronic heart failure and the increase is related to the clinical severity of the syndrome: CgA levels in New York Heart Failure (NYHA) class II (median 146.9 ng x ml(-1), inter-quartiles 108.3-265.5) were significantly higher (P<0.05) than in class I (median 109.7 ng x ml(-1), inter-quartiles 96.7-137.6), and significantly lower (P<0.05) than in class III (median 279.0 ng x ml(-1), inter-quartiles 203.6-516.1). Class IV patients showed the highest serum levels of CgA (median 545.0 ng. ml(-1), inter-quartiles 231.8-1068.3), being statistically significantly different from class III patients (P<0.001). The association between survival and some recognized variables of prognostic significance, including CgA was also studied. The results showed that ejection fraction, noradrenaline, atrial natriuretic peptide, NYHA class and CgA were significant univariate prognosticators; however, in the multivariate analysis by the Cox proportional-hazard model, CgA and NYHA class were the only independent predictive factors for mortality (P<0.005, RR=1.22, 95% CI=1.06-1.41 and P=0.04, RR=1.58, 95% CI=1.02-2.46, respectively). CONCLUSIONS: CgA is a pro-hormone, precursor of several active fragments likely to exert biological effects in chronic heart failure. CgA serum levels are increased in patients with chronic heart failure and are a predictive factor for mortality.     

Physical rehabilitation in coronary patients who have suffered from episodes of cardiac failure.

The effects of bicycle training for 5 weeks were evaluated in 12 patients after myocardial infarction with left ventricular dysfunction (left ventricular ejection fraction < 40%) and at least one episode of cardiac failure in the past. The patients were divided into two groups of six according to the Weber classification: Group B (VO2/kg/min: 16-20) and Group C (VO2/kg/min: 10-15). Cardiopulmonary and hemodynamic parameters were evaluated during a maximal exercise test and a simultaneous catheterization of the right side of the heart before and after the training. An increase in the capacity for work was recorded in Group B (p < 0.02), while Group C remained unchanged. A statistically significant increase in minute ventilation (p < 0.05) and VO2/kg/min (p < 0.0006) was recorded in Group B. Group C showed an increase in the mean pulmonary arterial pressure (p < 0.03). All of the other parameters remained unchanged after training. We conclude that physical rehabilitation improves the tolerance to exercise in patients with a mildly depressed cardiac function (Group B) but not in patients with a very depressed cardiac function (Group C).     

Reversion of a fungal genetic code alteration links proteome instability with genomic and phenotypic diversification

Many fungi restructured their proteomes through incorporation of serine (Ser) at thousands of protein sites coded by the leucine (Leu) CUG codon. How these fungi survived this potentially lethal genetic code alteration and its relevance for their biology are not understood. Interestingly, the human pathogen Candida albicans maintains variable Ser and Leu incorporation levels at CUG sites, suggesting that this atypical codon assignment flexibility provided an effective mechanism to alter the genetic code. To test this hypothesis, we have engineered C. albicans strains to misincorporate increasing levels of Leu at protein CUG sites. Tolerance to the misincorporations was very high, and one strain accommodated the complete reversion of CUG identity from Ser back to Leu. Increasing levels of Leu misincorporation decreased growth rate, but production of phenotypic diversity on a phenotypic array probing various metabolic networks, drug resistance, and host immune cell responses was impressive. Genome resequencing revealed an increasing number of genotype changes at polymorphic sites compared with the control strain, and 80% of Leu misincorporation resulted in complete loss of heterozygosity in a large region of chromosome V. The data unveil unanticipated links between gene translational fidelity, proteome instability and variability, genome diversification, and adaptive phenotypic diversity. They also explain the high heterozygosity of the C. albicans genome and open the door to produce microorganisms with genetic code alterations for basic and applied research.     

Postoperative radiotherapy in the treatment of adenocarcinoma of the endometrium in pathological stage I

We report on 49 patients with pathologic stage I endometrial adenocarcinoma who underwent postoperative whole-pelvis irradiation (RT) (45-50 Gy in 5-6 weeks) from November 1981 to December 1988. RT was performed when one or more of the following unfavorable prognostic factors were discovered: myometrial infiltration greater than 1/3 (42 cases, or 85.7%), poorly-differentiated tumor (10, or 20.4%), tubaric angles involvement (4; or 8.2%), pelvic nodal metastases (1, or 2.0%). Five-year actuarial disease-free survival was 91.4%. After an average follow-up of 58 months, we observed recurrent disease in 4 patients (8.2%) (3 cases with distant metastases, 6.1%; 1 case with vaginal relapse, 2.0%). All recurrences were observed within 18 months from treatment and occurred only in patients with both myometrial infiltration greater than 1/3 and poorly or moderately differentiated tumor. The patient with vaginal relapse had a complete response after endocavitary curietherapy, but died later on from lung metastases. None of the treated patients experienced severe complications related to the treatment. Our results are comparable with those of the most recent literature, and confirm the good tolerance and efficacy of postoperative RT to prevent loco-regional relapses in early stage endometrial cancer with unfavorable prognostic factors.     

Vasodilator stress echocardiography for risk stratification of medically stabilized unstable angina.

AIMS: The aims of this study were to assess the safety, feasibility and prognostic value of dipyridamole-atropine stress echo in patients with medically stabilized unstable angina. METHODS: The initial population consisted of 173 patients consecutively admitted at two different Coronary Care Units with class IIIB unstable angina. Of these, 56 were excluded: five had poor acoustic window, 24 did not stabilize with medical therapy and underwent urgent coronary angiography, 26 evolved in non-Q wave myocardial infarction and one patient died. The remaining 117 patients underwent dipyridamole-atropine stress echo after 48 h without symptoms or electrocardiographic evidence of myocardial ischaemia. RESULTS: No complications or side effects occurred. An ischaemic response was found in 61 patients. During follow-up (10+/-9 months), three cardiac deaths, eight infarctions, 13 unstable anginas, and seven late (>3 months from stress testing) revascularizations occurred. There were 22 events (36%) in patients with, and nine events (16%) in patients without, inducible ischaemia (P=0.01). At Cox analysis peak-stress wall-motion score index (HR=5.5; 95% CI, 1.9 to 15.5; P=0.0015), and admission ST-segment depression (HR=4.2; 95% CI, 1.7 to 10.7; P=0.0022) were independent predictors of spontaneous events (cardiac death, infarction, unstable angina). The 12-month event-free survival was 69% for ischaemic and 83% for non-ischaemic group (P=0.03). In considering major events as end-points (spontaneous events, and late revascularization), again multivariate prognostic indicators were peak-stress wall-motion score index (HR=14.2; 95% CI, 2.6 to 76.6; P=0.0021), and admission ST-segment depression (HR=3.1; 95% CI, 1.4 to 6.9; P=0.0055). The 12-month event-free survival rate was 58% for ischaemic and 81% for non-ischaemic group (P=0.002). With an interactive stepwise procedure, stress echo findings were found to provide incremental prognostic contribution to that of clinical data alone. CONCLUSIONS: With proper selection of patients, dipyridamole-atropine stress echo is extremely safe and feasible in patients with medically stabilized unstable angina, and can be useful in identification of subjects at risk for future cardiac events.     

Results of radiotherapy in a series of 250 carcinomas of the mucosal surface of the cheek (author's transl)]

This paper presents the results of a retrospective clinical study of 250 cases of monocentric carcinoma of the mucosal surface of the cheek, i.e. all the primaries treated by radiotherapy at our Institute between January 1948 and December 1965. Neoplastic lesions found at follow-up were regarded as marginal recurrences if in the proximity of the treated area and as secondary tumors in other cases. From 1948 to 1957 conventional radium therapy was the usual treatment for the primary tumor whereas from 1958 to 1965 cobalt teletherapy was given most frequently. Surgery was reserved for lymph node metastases when present on clinical examination. In our experience radiotherapy is effective in cancers of the mucosal surface of the cheek, for it checked local spread in 50.9% of cases, however treated and regardless of initial clinical appearance, whereas in the T1-T2 cases the local failure rate dropped to 35.8%. The higher the T level the greater are the difficulties confronting radiotherapy; for more extensive lesions appropriate combination therapy (radiosurgical) in line with the well-defined rules explained in the text is useful. In our experience radiotherapy yields good long term results regardless of T level and even in the more unfavorable cases. Our study confirms the low rate of lymph spread of these carcinomas: over half of the patients were N0 before treatment; only 56.7% of the patients receiving surgical treatment on the neck had histologically positive lymph nodes; there were very few neck recurrences at follow-up; the presence of suspect or frankly metastatic nodes on clinical examination, being movable and homolateral (N1), did not worsen the prognosis. However, considering the techniques used for irradiation of the primary, some patients received a substantial dose to the neck; hence radiotherapy probably played its part in the low rate of neck metastases.     

The value of radiotherapy in the treatment of vaginal carcinoma.

Herein we report the retrospective survey of 48 consecutive unselected cases of vaginal carcinoma, mainly treated with radiotherapy in our Institute from 1959 to 1970. In this series irradiation was delivered almost always with a single and continuous application of sources of radium 226. Radiumtherapy treatment varied according to the extension in surface of the neoplasm, the clinical stage and especially the vaginal step involvement, considering the length of the organ. Despite the very good immediate response, failures of treatment locally or in paravaginal and pelvic areas were frequently observed, and success of the treatment after a brief follow-up was poor. The actuarial survival was 41.6% and 33.3% at 3 and 5 years, respectively. Stage I cases showed at the follow-up better therapeutic results (48.6% survival at 5 years) than stage II and III cases (28.3%). The poorest results were observed in neoplasms extended to the whole vagina, and all these patients died within 4 years of the beginning of treatment. This report stresses that radiotherapy of vaginal carcinomas demands individualization and a properly planned therapeutic program that combines external irradiation with renewed techniques of low dose rate and continuous irradiation with radioactive sources.     

Clinical results of lymphography in cancer of the uterine cervix. A retrospective study of 542 consecutive, unselected patients

From 1961 to 1976, 542 patients were evaluated with foot lymphography for cancer of the cervix at the Istituto Nationale Tumori of Milan. A group of 341 patients had lymphangiography as part of the initial diagnostic work-up. The overall incidence of positive examinations was 25% (9% stage I, 29% stage II, 46% stage III, 50% stage IV). In the 115 patients who had pelvic surgery the overall diagnostic accuracy of lymphography was 88%, with 2 false positive and 12 false negative reports. A second group of 90 patients was evaluated in the follow-up without clinical evidence of disease, and the incidence of metastases was 17%. Finally, group of 111 patients was studied for recurrence, and in this group the incidence of metastases was 51%. As regards site of involvement, the external iliac chains were involved in 93 to 96% of the cases, the common iliac in 34 to 79%, and the para-aortic in 17 to 36% in the different clinical conditions. The highest incidence of para-aortic metastases was found in the clinically initial stages (I and II) and in the recurrences. The lymphographic involvement of the retroperitoneal nodes was usually limited to a single region (41%) or two regions (37%). Only in 22% of the positive cases was a diffuse involvement of the retroperitoneal node chains evident.