A 1-year follow-up study on checkpoint inhibitor-induced colitis: results from a European consortium.

BACKGROUND: Data regarding the clinical outcome of patients with immune checkpoint inhibitor (ICI)-induced colitis are scant. We aimed to describe the 12-month clinical outcome of patients with ICI-induced colitis. MATERIALS AND METHODS: This was a retrospective, European, multicentre study. Endoscopy/histology-proven ICI-induced colitis patients were enrolled. The 12-month clinical remission rate, defined as a Common Terminology Criteria for Adverse Events diarrhoea grade of 0-1, and the correlates of 12-month remission were assessed. RESULTS: Ninety-six patients [male:female ratio 1.5:1; median age 65 years, interquartile range (IQR) 55.5-71.5 years] were included. Lung cancer (41, 42.7%) and melanoma (30, 31.2%) were the most common cancers. ICI-related gastrointestinal symptoms occurred at a median time of 4 months (IQR 2-7 months). An inflammatory bowel disease (IBD)-like pattern was present in 74 patients (77.1%) [35 (47.3%) ulcerative colitis (UC)-like, 11 (14.9%) Crohn's disease (CD)-like, 28 (37.8%) IBD-like unclassified], while microscopic colitis was present in 19 patients (19.8%). As a first line, systemic steroids were the most prescribed drugs (65, 67.7%). The 12-month clinical remission rate was 47.7 per 100 person-years [95% confidence interval (CI) 33.5-67.8). ICI was discontinued due to colitis in 66 patients (79.5%). A CD-like pattern was associated with remission failure (hazard ratio 3.84, 95% CI 1.16-12.69). Having histopathological signs of microscopic colitis (P = 0.049) and microscopic versus UC-/CD-like colitis (P = 0.014) were associated with a better outcome. Discontinuing the ICI was not related to the 12-month remission (P = 0.483). Four patients (3.1%) died from ICI-induced colitis. CONCLUSIONS: Patients with IBD-like colitis may need an early and more aggressive treatment. Future studies should focus on how to improve long-term clinical outcomes.

[Mechanism of action of quinapril in the treatment of primary arterial hypertension]. / Meccanismo d'azione del quinapril nel trattamento dell'ipertensione arteriosa primitiva.

The effects of a long-term therapy with quinapril on plasma renin activity, plasma aldosterone, atrial natriuretic peptide and left ventricular mass were analysed in patients with mild to moderate systemic hypertension. Fifteen patients (4 women) were treated for one year with quinapril 10 or 20 mg once daily, reducing hereby the systolic and diastolic blood pressure from 167.5 +/- 11.3 to 141 +/- 6.7 mmHg p < 0.001 and from 105.3 +/- 5 to 90 +/- 7 mmHg respectively, within the first two weeks. Blood pressure remained stable during the following 52 weeks. After 6 and 52 weeks of therapy, as expected, we observed an increase of plasma renin activity, plasma aldosterone decrease from 262.6 +/- 88.1 to 178.8 +/- 79.9 p = 0.01 and to 170.3 +/- 64.3 ng/ml p = 0.006 respectively. Atrial natriuretic peptide levels were not significantly altered. After 52 weeks of treatment left ventricular mass index decreased from 107.9 +/- 16.2 to 90.1 +/- 13.4 g/m2 p = 0.0001. It is concluded that treatment with quinapril for 1 year in addition to controlling blood pressure also reduced left ventricular mass probably by a favourable effect on renin-angiotensin-aldosterone system.

Cancer mortality among rice growers in Novara Province, northern Italy.

Some excess of non-Hodgkin lymphomas (NHL) and soft tissue sarcomas (STS) was reported in the literature among agricultural workers, mainly in relation to exposure to phenoxyacids and chlorophenols. In this study, information was analyzed for a cohort of rice growers that comprised 1,493 subjects, and for a follow-up that was more than 99% complete with regard to both traced subjects and known causes of deaths. A total of 960 subjects (65%) died during the observation period (1957-1992). Lower than expected standardized mortality ratios (SMRs) were found for all causes, for cardiovascular diseases (especially ischemic heart disease) and for all cancers. Slightly increased SMRs were found for some cancer sites (oral cavity, esophagus, liver, intestines, pancreas, bladder, STS, and NHL), although none of these was statistically significant in the overall analysis. An excess risk of close to statistical significance was found for NHL among workers with longer exposure during the period when phenoxyacid herbicide was in use (1950-1992). Thus, a prolonged follow-up is advisable. At present the study should be evaluated in the context of the data set suggesting a tendency toward an increased risk of NHL among farmers.

[24-hour ambulatory monitoring of arterial blood pressure and the sympathetic nervous system in hypertensive smokers]. / Monitoraggio ambulatoriale della pressione arteriosa nelle 24 ore e sistema adrenosimpatico nei fumatori ipertesi.

OBJECTIVE: To test the hypothesis that heavy smoking may interfere with the variation in ambulatory blood pressure (ABP) and sympathetic nervous system in essential hypertension. METHODS: We compared the office and 24-hour ABP of 48 untreated hypertensive smokers (> 20 cigarettes daily) with 90 non-smoking hypertensives matched for age, sex and body mass index. ABP was recorded using fully automatic SpaceLabs 90,207 units set to take a measurement every 15 minutes during the day (7.00 a.m.-10.00 p.m.) and every 20 minutes during the night (10.00 p.m.-7.00 a.m.). Urine collection for urinary sodium, potassium, epinephrine and norepinephrine excretion was performed during the 24-hour period of ABP monitoring. Catecholamines were measured by high pressure liquid chromatography. RESULTS: The office blood pressure readings of the smoking and non-smoking groups were 156.7/103.4 and 156.5/103.9 mmHg respectively. During the day-time period, ambulatory systolic and diastolic blood pressure was significantly higher in the smokers (146 +/- 12 vs 140.4 +/- 13 mmHg, p < 0.02; 96.4 +/- 8.15 vs 93.1 +/- 10 mmHg, p < 0.05 respectively). This difference was greater among patients under the age of 50 (145.9 +/- 13 vs 136.6 +/- 11 mmHg, p < 0.001 and 97.1 +/- 8.7 vs 92.3 +/- 9.9 mmHg, p < 0.02). Blood pressure during the night-time period did not differ between the two groups (130.5/81.3 vs 126.3/79.5). No differences were detected among the groups as far as urinary catecholamine excretion is concerned. CONCLUSION: Our data suggest that among hypertensive subjects, smokers maintain a higher day-time ambulatory systolic and diastolic blood pressure than non-smokers, particularly in the younger patients, even though casual blood pressure is similar.

Comparison of inter-observer reproducibility between conventional chest radiography and AMBER in the evaluation of silicosis.

The aims of this study were to test inter-observer and intraobserver agreement in the diagnosis of silicosis using conventional chest radiography and AMBER. One hundred and fifteen patients underwent chest x-rays and AMBER for the diagnosis of silicosis. Five readers blindly and independently evaluated the radiograms with standard ILO/UC classification scales. Reproducibility was assessed using ANOVA repeated measurements methods. AMBER showed a better technical quality of radiograms than conventional chest x-rays; interobserver reproducibility was high and similar (R = 0.75); intraobserver agreement between chest x-rays and AMBER was high ranging from 0.62 to 0.86 for the 5 readers. Notwithstanding the absence of standards for profusion classification, the interobserver reproducibility with AMBER was similar to that obtained with chest x-rays. Moreover, the intraobserver agreement in profusion scoring between AMBER and chest radiography was high, suggesting that AMBER and chest radiography provided similar information in the evaluation of silicosis.

[Transvaginal echography in patients with postmenopausal metrorrhagia]. / L'ecografia transvaginale in pazienti con metrorragia della postmenopausa.

Forty-one postmenopausal patients with abnormal uterine bleeding were scheduled for endometrial sampling in a week from the measurement of endometrial thickness by transvaginal ultrasonography. If the cut-off limit was 5 mm, the endometrial thickness was correlated with the presence of pathologic endometrium with a sensitivity of 87.5%, a specificity of 76%, a positive predictive value of 70% and a negative predictive value of 90.5%. Endometrial hyperplasia and polyp represented the two false negative cases. Waiting for a study on a sufficiently large series, the authors think that also an endometrial thickness of a few millimeters doesn't justify the non-recourse to endometrial biopsy in the presence of repeated haemorrhagic episodes or specific risk factors.

[Increase in absolute atmospheric pressure in hyperbaric chamber in cirrhosis with ascites: lack of natriuretic response and increase of atrial natriuretic peptide]. / Aumento della pressione atmosferica assoluta in camera iperbarica nella cirrosi con ascite: mancata risposta natriuretica e incremento del peptide natriuretico atriale.

In normal subjects increasing atmospheres of absolute pressure (ATA) on the cardiopulmonary system, in a hyperbaric chamber, results in a marked diuresis and an increase of circulating concentration of atrial natriuretic peptide (ANP). The present investigation was designed to determine the effect of ATA in a group of 5 sodium-retaining cirrhotic patients on hydro-saline balance, renin-angiotensin-aldosterone system and ANP. After seven days on a 10 mEq sodium intake, each patient was studied on both a control and experimental (4-hour stay at 2-ATA in hyperbaric chamber) day. On each day, measurement of the following were obtained: plasma ANP, plasma renin activity (PRA) and aldosterone, electrolytes, creatinine clearance, volume and sodium and potassium urinary excretion. The increasing ATA lacked to induce both diuresis, natriuresis and increase in ANP plasma concentration. In these patients baseline, pre-hyperbaric, mean levels of PRA, aldosterone and ANP were 15.5 +/- 11.5 ng/ml/h, 808.4 +/- 360 pg/ml, 86 +/- 10.1 pg/ml, respectively, and were significantly elevated compared with normal range for control subjects without sodium restriction. In conclusion, increasing pressure at 2-ATA, in a hyperbaric chamber is unable to elicit both diuresis and natriuresis as well as modification on ANP and renin-angiotensin-aldo-sterone system in sodium-retaining cirrhotic patients.

AgNORs in ductal breast cancer: correlation with ploidy and S-phase fraction by DNA flow cytometry.

Silver-binding nucleolar organizer regions (AgNORs) have been counted in sections of routinely processed paraffin embedded material. The AgNOR score has been correlated with proliferative activity of various neoplasms. An increase in the AgNOR score can be related to cellular growth fractions or DNA-ploidy. We have examined 301 invasive ductal breast carcinomas by this method. The AgNOR counts were also compared with DNA Ploidy and the S-phase fraction flow cytometry. A positive correlation has been found between the AgNOR score and the S-Phase fraction. These data show cell proliferation. We conclude that AgNOR counting may provide information on breast carcinoma in addition to that obtained from flow cytometric analysis.

[Atrial natriuretic peptide, left ventricular mass and renin-angiotensin-aldosterone system in essential arterial hypertension of a mild or moderate degree]. / Peptide natriuretico atriale, massa ventricolare sinistra e sistema renina-angiotensina-aldosterone nell'ipertensione arteriosa essenziale di grado lieve o moderato.

OBJECTIVE: The relationship between plasma atrial natriuretic peptide (ANP), renin-angiotensin-aldosterone system and left ventricular mass in essential hypertension was assessed. PATIENTS AND METHODS: Immunoreactive ANP in 10 normal subjects and 20 untreated patients with mild to moderate essential hypertension was compared with echocardiographic measurement of cardiac size, function and blood pressure. Venous plasma concentrations of ANP were also studied in relation to urinary sodium and potassium excretion, as well as the renin-angiotensin-aldosterone system. RESULTS: Plasma ANP was higher in hypertensive patients (25.3 +/- 13.3 pg/ml; p = 0.003) than normotensive subjects (11.1 +/- 2.7 pg/ml). In hypertensive patients, plasma ANP was inversely related to plasma renin activity (PRA) (r = -0.6; p = 0.009). No relationship was found between ANP and blood pressure, nor between the indices of left ventricular mass and function or urinary electrolytes. CONCLUSIONS: This study showed that circulating ANP is, in average, significantly increased in hypertensive patients, consistent with previous reports. Our data do not support a direct link between left ventricular mass and increased plasma ANP levels in hypertensive patients. Whether the inverse relationship between ANP and PRA in this pathologic state is a direct one or merely a secondary association has not been clearly established.

Cadmium in blood and urine after cessation of exposure.

A plant for the synthesis and packaging of cadmium oxide was operated for 32 months (1982-84) in a small chemical factory producing zinc and copper oxide. The cumulative exposure of 6 workers was from 12 to 190 days. Five years after cessation of exposure the blood cadmium levels in the exposed were, on average, 4-10 times higher than those of a reference group and the urinary cadmium levels were 1-6-times higher. In view of the long half-life of cadmium in the human body, the choice of normal reference values requires particular care since brief and sometimes forgotten exposures to cadmium may be a confounding factor to set reference values.

[Anesthetic gases and neuropsychological tests]. / Gas anestetici e test neuropsicologici.

The Authors observed, in a group of 15 subjects working in operating theatres and occupationally exposed to anesthetic gases, an increase of simple reaction average times and an increase of the latency of the wave V of the brainstem auditory evoked potentials. The small number of subjects doesn't allow to draw conclusions. Nevertheless the findings agree with first analogous studies. The Authors, therefore, think opportune to continue the research to acquire further evidence and to ascertain the validity of the current TLV.

Acute and short-term effects of nitrendipine and diltiazem at rest and during exercise in hypertensive patients.

The subjects were 30 patients with mild-to-moderate hypertension randomly assigned to receive 10 mg of nitrendipine twice daily or 60 mg of diltiazem thrice daily for 14 days. On days 1 and 14 the patients performed an effort test (to a maximum of 100 W) before and after drug administration. Both nitrendipine and diltiazem reduced systolic and diastolic blood pressure; after 14 days of treatment, the reductions in blood pressure were significantly greater in the nitrendipine-treated patients than in the diltiazem-treated patients. Blood pressures were reduced at maximum effort in both treatment groups before drug administration on day 14 compared with day 1. Two hours after drug administration on days 1 and 14, the reductions in effort blood pressures were significantly greater after nitrendipine than after diltiazem. No side effects were noted in either group. It is concluded that nitrendipine is safe and effective in patients with mild-to-moderate hypertension at rest and during exercise.

Absence of effects of ketanserin on renal prostacyclin and thromboxane A2 in essential hypertension.

The anti-hypertensive effect of ketanserin, a new antagonist of 5-HT2-serotonergic receptors, was evaluated in 10 patients with uncomplicated essential hypertension. At the end of 2 weeks of placebo wash-out and following 2 and 4 weeks of treatment with ketanserin (20 mg twice daily), blood pressure and heart rate were measured both in the supine and standing position. In addition, before and at the end of treatment, plasma renin activity (PRA), plasma concentration of aldosterone and the nocturnal urinary excretion of 6-keto-PGF1 alpha and TXB2, the two metabolites that largely reflect the renal synthesis of prostacyclin and thromboxane, respectively, were determined. The study was carried out in a metabolic ward where the intake of sodium was adjusted to 100-120 mmol day-1. Ketanserin significantly reduced blood pressure both in the supine and standing position with no significant change of heart rate. The treatment did not produce any variation of PRA, aldosterone, urinary excretion of 6-keto-PGF1 alpha or TXB2. These results indicate that ketanserin reduces blood pressure without interfering with the renin-angiotensin-aldosterone system or the renal synthesis of prostacyclin and thromboxane.

[Transluminal percutaneous angioplasty in renovascular hypertension caused by monolateral fibromuscular dysplasia]. / Angioplastica percutanea transluminale nell'ipertensione renovascolare da displasia fibromuscolare monolaterale.

The authors, following recent observation of two cases of renovascular hypertension, one related to single right renal artery stenosis and the other to fibromuscular dysplasia of the left renal artery, examine the value of the Captopril-Test and treatment with Percutaneous Transluminal Angioplasty (PTA), in the diagnosis and therapy of this form of hypertension. According to the latest experience, reported in the literature, the Captopril-Test yields valid information as regards the dependence of hypertension on the renin-angiotensin system, while PTA represents the primary procedure in the treatment of renovascular hypertension when some conditions are satisfied as in our cases.

[Effects of ketanserin on arterial pressure at rest and during physical exercise in essential arterial hypertension]. / Effetti della ketanserina sulla pressione arteriosa a riposo e durante esercizio fisico nell'ipertensione arteriosa essenziale.

The antihypertensive effect of ketanserin, a recent 5-hydroxytryptamine (5-HT) antagonist, which acts on the 5-HT2-subtype receptor, was evaluated in 10 patients of both sexes (age range 35-69 years) with mild to moderate essential hypertension. Blood pressure and heart rate were measured at rest, in supine and standing position at the end of two weeks of placebo washout and after 2, 4 and 8 weeks of treatment with ketanserin 20 mg twice daily as monotherapy, while the changes of blood pressure and heart rate during static (hand-grip) and dynamic (bicycle ergometer) exercise were evaluated at the end of placebo and of the fourth week of therapy. The treatment induced a highly significant reduction of supine and standing systolic and diastolic blood pressure during rest, without any significant change in heart rate. During dynamic exercise, the increase in systolic and diastolic blood pressure and heart rate was not blunted by ketanserin, while the drug reduced systolic blood pressure and heart rate increase, during static exercise, with no change of diastolic blood pressure. From these data it may be concluded that ketanserin lowers blood pressure in essential hypertension without any interference with cardiovascular reflexes related to standing or dynamic exercise, and reduces the increase of systolic blood pressure and heart rate during static exercise with favourable interference on myocardial oxygen consumption. This sparing effect on myocardial oxygen demand is particularly relevant in hypertensive patients with asymptomatic coronary disease engaged in normal daily physical activity which includes many forms of static exercise.

[Comparison of the efficacy of captopril and enalapril in single doses in the treatment of arterial hypertension. Evaluation by means of non-invasive ambulatory monitoring]. / Confronto dell'efficacia del captopril e dell'enalapril in monosomministrazione nel trattamento dell'ipertensione arteriosa. Valutazione con monitoraggio ambulatoriale non invasivo.

The study was designed to compare the efficacy of captopril and enalapril, both orally active inhibitors of angiotensin converting enzyme, in the treatment of primary hypertension when administered in a single daily dose. After placebo washout for two weeks, 20 hypertensive patients (I-II class, according to WHO), were admitted to active treatment, in a randomized sequence, with captopril (50 mg) and enalapril (20 mg) once a day in the morning (8 a.m.). Supine and erect blood pressure and heart rate were measured weekly, 24 hours after drug administration by using a mercury standard sphygmomanometer. In all patients ambulatory noninvasive blood pressure monitoring was performed after 4 weeks of treatment. The data confirmed the efficacy of both drugs in lowering blood pressure. However, while the antihypertensive effect of enalapril was prolonged throughout 24 hours, captopril was effective only for about 22 hours, a period longer than previously suggested on the basis of serum ACE inhibition, but not sufficient to cover the whole day. Therefore, if captopril therapy has to be used in a single daily dose an attempt should be made using an increased dosage or by employing the drug in some retarded pharmaceutical form. The need to prolong the antihypertensive effect of captopril to 24 hours is based on the clinical experience according to which the smaller the number of tablets to be taken the better the compliance. This is particularly true for cases of asymptomatic hypertension which nevertheless require lifelong therapy.