Impact of age and gender on the efficacy and safety of upfront therapy with panitumumab plus FOLFOX followed by panitumumab-based maintenance: a pre-specified subgroup analysis of the Valentino study.

BACKGROUND: The safety and efficacy outcome of elderly metastatic colorectal cancer (mCRC) patients fit enough to receive combination chemotherapy plus biological agents is an issue of growing interest. Also, gender-specific differential toxicity and efficacy of anti-epidermal growth factor receptor (EGFR)-based upfront treatments need to be explored. PATIENTS AND METHODS: Valentino was a multicenter, randomized, phase II trial, investigating two panitumumab-based maintenance strategies following first-line panitumumab plus FOLFOX in RAS wild-type mCRC patients. We carried out a subgroup analysis, aimed at assessing the differences in efficacy, safety and quality of life (QoL) according to age (<70 versus ≥70 years) and gender (male versus female). Efficacy endpoints were progression-free survival (PFS), overall survival (OS) and overall response rate (ORR); safety endpoints were rates of any grade and grade 3/4 adverse events (AEs). RESULTS: No significant differences in terms of PFS, OS and ORR were observed between patients aged <70 or ≥70 years and the effect of the maintenance treatment arm on survival outcomes was similar in the two subgroups. The safety profile of both induction and maintenance treatment and the impact on QoL were similar in elderly and younger patients. No significant differences in PFS, OS, ORR or clinical benefit rate were observed according to gender. A significantly higher rate of overall grade 3/4 AEs (P = 0.008) and of grade 3/4 thrombocytopenia (P = 0.017), any grade and grade 3/4 neutropenia (P < 0.0001) and any grade conjunctivitis (P = 0.033) was reported in female as compared to male patients. Conversely, we reported a significantly higher incidence of any grade skin rash (P = 0.0007) and hypomagnesemia (P = 0.029) in male patients. CONCLUSIONS: The upfront choice of an anti-EGFR-based doublet chemotherapy followed by a maintenance strategy represents a valuable option in RAS wild-type mCRC irrespective of gender and age, though a careful evaluation of patients to maximize the risk/benefit ratio is warranted.

Temozolomide and irinotecan (TEMIRI regimen) as salvage treatment of irinotecan-sensitive advanced colorectal cancer patients bearing MGMT methylation.

Background: Non-randomized studies showed that temozolomide (TMZ) achieves an average 10% response rate in heavily pretreated metastatic colorectal cancer (mCRC) patients with promoter methylation of the DNA repair gene O6-methylguanine-DNA methyltransferase (MGMT). In this phase II trial, irinotecan and temozolomide (TEMIRI) combination regimen was assessed in irinotecan-sensitive, MGMT methylated/microsatellite stable (MSS) pretreated mCRC patients. Patients and methods: Key inclusion criteria were centrally confirmed MGMT methylation by methylation-specific PCR, MSS mCRC, progression after at least two prior chemotherapy regimens for advanced disease and irinotecan-free interval >3 months. TEMIRI (TMZ 150 mg/m2 on days 1-5 plus irinotecan 100 mg/m2 on days 1, 15 q28 days) was administered for six cycles, followed by maintenance with TMZ. The primary end point was overall response rate (ORR). Exploratory translational analyses included MGMT immunohistochemistry (IHC) and methyl-BEAMing (MB). Results: Between December 2014 and June 2017, 25 patients were enrolled. The primary end point was met, since six patients achieved a partial response [ORR 24%, 95% confidence interval (CI) 11% to 43%]. At a median follow-up of 15.6 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.4 and 13.8 months, respectively. Only four (16%) patients had ≥ grade 3 (CTCAE 4.0) adverse events. All patients whose cancer was MGMT-positive IHC were non-responders. Consistently, patients with MGMT-negative/low tumors had a significantly longer mPFS than others (6.9 versus 2.0 months; hazard ratio = 0.29, 95% CI 0.02-0.41; P = 0.003) and a non-significant trend for longer mOS. MB testing showed similar accuracy. Conclusions: TEMIRI regimen is a safe and active option in pre-treated, irinotecan-sensitive mCRC patients with MGMT methylation.

Congenital hypothyroidism and pericardial effusion.

A group of infants, affected by congenital hypothyroidism diagnosed through the neonatal screening program, was investigated with echocardiography to detect the presence of pericardial effusion. We studied the relationship between the effusion and the etiology of hypothyroidism, established through thyroid scintiscanning. Our data show a high prevalence of effusion in hypothyroid patients, without other clinical signs of cardiac involvement as well as a relationship between the etiology of hypothyroidism and the presence of effusion. This seems to be much more frequent in those forms which can imply a more severe hormonal defect, particularly during fetal life (agenesis/dyshormonogenesis). Furthermore, the high prevalence of pericardial effusion suggests to start the L-T4 replacement therapy with lower dosages as commonly advised, in order to avoid a cardiac involvement.

[Cardiac echinococcosis: 2 cases treated surgically]. / Echinococcosi cardiaca: due casi trattati chirurgicamente.

Cardiac hydatid disease represents 0.02-2% of the possible locations of the parasite. In these last few years we have seen an increase in the percentage of cardiac hydatid disease treated with surgery. The Authors report on two patients who underwent surgery for the excision of cardiac hydatid cysts. The Authors agree that in spite of the rarity of cardiac hydatid disease it should be investigated routinely by two-dimensional echocardiography in the presence of hepatic or pulmonary hydatid disease in order to prevent the possible spread of the parasite throughout the body.

[Autologous blood transfusion in elective heart surgery: prospective study of 189 consecutive patients]. / L'autoemotrasfusione in cardiochirurgia elettiva: studio prospettico in 189 pazienti consecutivi.

Blood autotransfusion has entered a new phase in blood transfusion technique, since it represents an important alternative in eliminating the risks connected with blood transfusion: viral hepatitis, AIDS, blood transfusion reactions, and alloimmunization. Transfusion requirements during cardiac surgical procedures have steadily decreased; nowadays most adult patients require no transfusion during surgery. Patients (pts) receiving bank-blood may develop infectious diseases (hepatitis, AIDS, etc.). We have studied how to avoid the risk of infections with homologous blood transfusions. We present our experience of day-hospital pre-operative autologous blood collection. One-hundred-eighty-nine patients undergoing primary myocardial revascularization or valvular replacement were submitted to the drainage of 350 ml of blood three times every four days before surgery. The blood was centrifuged at once, to separate red cells from plasma. Surgeries were performed 21 days after the first drainage; iron therapy was recommended. After surgery pts received blood only if haematocrit was lower than 28%. The following data were recorded: no. of pts who received homologous blood; blood loss and homologous total blood volume used for each pt. Average blood loss was 1230 cc for ischemic pts and 701 cc for valvular pts. Non-A non B hepatitis occurred in 3/189 pts (1.5%). All of them had received homologous blood transfusions. Our data show clearly that autotransfused pts had a better post-operative period; less bank-blood and fewer transfusions have been used. No pt had collateral effects such as angina or hypotension from blood drawing. Our data show that severe cardiac diseases do not represent an absolute contraindication to heavy blood drainage.(ABSTRACT TRUNCATED AT 250 WORDS)

Focal lymphocytic myocarditis in acquired immunodeficiency syndrome (AIDS): a correlative morphologic and clinical study in 26 consecutive fatal cases.

In 26 consecutive cases with acquired immunodeficiency syndrome (AIDS) the main cardiac findings were Kaposi's sarcoma in 2 cases, microfocal myocardial abscess in 1, subendocardial infarct necrosis in 2, contraction band necrosis in 13, lymphocytic myocarditis in 9, intramyocardial lymphocytic infiltrates without myocell necrosis in 7 and epicardial lymphocytic infiltrates in 4. No patient had congestive heart failure. However, two-dimensional echocardiography performed in eight patients demonstrated functional abnormalities in six (fractional shortening ranging from 18 to 30%, globular shape, hypokinesia, mild ventricular dilation). Four of these six patients had lymphocytic myocarditis and two had lymphocytic infiltrates in the myocardium and epicardium without myocell necrosis. No lymphocytic infiltrates were seen in the two cases with a normal echocardiogram. Quantitative analysis indicated that involvement of the heart by lymphocytic myocarditis is inadequate in itself to explain dysfunction. It remains to be established 1) whether lymphocytic myocarditis is a possible indication of a more widespread molecular disorder, and 2) what its eventual relation with dilated cardiomyopathy will be.

Echocardiography detects myocardial damage in AIDS: prospective study in 102 patients.

Few data are available about cardiac involvement in AIDS. We examined 102 consecutive patients with AIDS diagnosed clinically and serologically (Walter Reed Stage 5 and 6), by means of TM and cross-sectional echocardiography with the aim of detecting cardiac abnormalities. None of the patients had overt clinical signs of heart failure. Fifty-five (54%) patients showed persistent tachycardia, diminished left ventricular (LV) wall thickness (mean 7.6 +/- 0.2 mm) and decreased percentage LV fractional shortening (27 +/- 5). In 42 (41%) there was a globular and poorly contracting LV. Thirty-nine (38%) patients had pericardial effusion which was moderate in 30 and small in nine. In four patients, valvular endocarditic vegetation was shown--on the tricuspid valve in three, on the aortic valve in one: all of them were drug addicts; in three (2.9%) patients a cardiac mass was found which proved to be a localization of Kaposi's sarcoma in two. Twenty-five (24.5%) patients died; necropsy showed cardiac chamber dilation, and thin LV walls in 18. On microscopic examination, myocardial fibrosis and lymphocyte infiltration with cell necrosis were observed. We conclude that cardiac abnormalities are common in AIDS. Impairment in LV contractility as assessed from fractional shortening appears to be the most common echocardiographic finding, followed by LV wall thinning, pericardial effusion and eventually by LV cavity dilation. This evolution is suggestive of myocardial damage and supports the hypothesis that dilated cardiomyopathy may be a cardiac complication of AIDS.

[Effect of the sympathetic activation and its inhibition on left ventricular mechanics in mitral prolapse. Echocardiographic study in 35 patients]. / Effetto dell'attivazione simpatica e della sua inibizione sulla meccanica ventricolare sinistra nel prolasso della mitrale. Studio ecocardiografico in 35 pazienti.

Mitral valve prolapse (MVP) is characterized by arrhythmias, atypical anginal chest pain and left ventricular (LV) wall motion abnormalities. The role of autonomic nervous system (ANS) as the origin of these disturbances is still debated. The aim of the study was to determine the possible interference between left ventricle (LV) mechanics and ANS. 35 consecutive patients with MVP (24 female, 11 male) (mean age 30 +/- 9 years), matched with a homogeneous control group, were examined by means of 2D-Echo during resting conditions and during sympathetic activation induced by passive orthostatism (90 degrees Tilting). At rest, no significant difference was found between the two groups regarding heart rate (HR), LV volume (LVV), ejection fraction (EF). Tilting produced a significant increase in HR (p less than 0.1) and LVV reduction (p less than .01) in both groups; on the other hand, EF did not change significantly. At 2D-Echo, LV abnormal wall motion at rest in 10/35 (29%) MVP, increasing to 17/35 (49%) was found during Tilting. This abnormality consisted in LV wall reduced systolic thickening and motion, localized in the antero-apical region in 11 patients (54%) and in the posterior wall in 6 patients (36%). Thirteen MVP patients with LV abnormal contraction patterns were re-examined after two weeks of beta-adrenergic blockade (200 mg Metoprolol orally per day). In all of them, LV abnormalities disappeared while LVV and EF remained unchanged. These data stress the role of the ANS in inducing LV abnormalities in patients with MVP.

Echocardiographic diagnosis of congenital bicuspid aortic valve in gonadal dysgenesis.

Among the gonadal dysgenesis, Turner's syndrome (T.S.) is often associated with cardiovascular malformations, mainly of the aorta. In order to assess noninvasively the incidence of those abnormalities we have evaluated 36 consecutive female patients (pts) with gonadal dysgenesis, mean age 13.3 +/- 2 years, range 3-24 years, without a prior history of cardiovascular disease, by clinical examination chromosomal karyotyping, 12 leads electrocardiography (ECG), and by Time Motion (TM) and Two-Dimensional (2D) Echocardiography (Echo). The following parameters were considered: presence of an auscultatory systolic ejection click (SEC); evidence of a bicuspid aortic valve (BAV); aortic valve stenosis (AVS); aortic valve eccentricity index (AVEI); left ventricle wall hypertrophy (LVWH). 9 pts out 36 (25%) presented a BAV at the 2D Echo; 8 pts out of 36 (22%) presented a SEC, 3/9 (33%) mild AVS, 2/9 (22%) displayed AVEI on TM study and 3/9 (33%) had LVWH. These findings indicate that an isolated BAV is present in a high percentage of pts with gonadal dysgenesis, more than before suspected. Echocardiography shows to be particularly useful and reliable in the assessment of that abnormality.

[Contrast echocardiography in the diagnosis of tricuspid insufficiency. Evaluation before and after cardiosurgical intervention in 24 patients]. / L'ecocontrastografia nella diagnosi dell'insufficienza tricuspidale. Valutazione prima e dopo intervento cardiochirurgico in 24 pazienti.

26 patients (pts) (8 males and 18 females), mean age 50 +/- 9 years, with rheumatic valve (MV) disease, candidates to MV replacement, were examined by contrast echocardiography (CE) before and after surgery. This was done in order to assess pre and postoperatively the presence of associated tricuspid regurgitation (TR) and to evaluate the short and long-term results of the operation on the TR itself. For assessing TR, the systolic presence, intensity and persistence of the microbubbles of the contrast medium injected into an antecubital vein, were observed within the inferior vena cava (IVC). We used synchronous time motion (TM) and two dimensional (2D) echocardiography from subcostal view. TR was classified as follows: severe (massive systolic opacification and persistence of the microbubbles in the IVC for at least 20 seconds); moderate (moderate systolic opacification lasting less than 20 seconds); mild (slight systolic opacification lasting less than 10 seconds); insignificant TR (sporadic appearance of the contrast medium into the IVC). On the average, the examination was carried out 48 hours before surgery, 15 days after and, in pts undergoing De Vega tricuspid valvuloplasty, 14 months after the operation. At pre-operative examination, massive TR was found in 16 pts, only 6 of whom showed clinical signs of TR. The findings were confirmed at surgery in 15 pts who underwent not only MV replacement but also tricuspid repair. In the other pts, agreement was found between CE and surgery as far as moderate TR was concerned, meanwhile mild CE TR was not confirmed at surgery. Sensitivity (SN) was 100%, specificity (SP) 38%, positive predictive value (PPV) 78%, negative predictive value (NPV) 100%. Excluding CE mild TR, SP and PPV raised to 75% and 95% respectively, meanwhile SN and NPV remained 100%. Short term post-operative follow-up CE performed on 13 out of the 15 pts with tricuspid repair showed no signs of TR in 7 and slight signs in 6. Furthermore, in those pts undergoing simple MV replacement, CE showed a marked reduction of the contrast echographic effect. Long term post-operative follow-up CE performed in the 13 pts with tricuspid repair showed no signs of TR in 9, slight signs in 3. Moreover in two pts massive TR due to late mitral prosthesis detachment was diagnosed by means of CE and confirmed at cardiac catheterization and surgery.(ABSTRACT TRUNCATED AT 400 WORDS)

Ambulatory blood pressure monitoring (24 h), basal blood pressure and left ventricular echocardiographic findings in young adults.

Left ventricular (LV) echocardiography and ambulatory monitoring of blood pressure (BP) were performed in 50 normal 20-year-old subjects previously followed longitudinally for 4 years with annual measurements of basal BP (BBP). The relationship of basal, casual and mean 24-h non-invasive ambulatory BP (ABP) with echo findings, blood chemistries and body fatness was evaluated. Subjects with mean BBP on the 4 years above the 85th percentile showed significantly higher blood levels of urea and glucose and of body fat than subjects below this BP level. Left ventricular echo measurements did not differ in the two groups. Left ventricular diameters and volumes were not correlated with basal, casual or ambulatory BP. Interventricular septum (IVS), LV posterior wall (LVPW) and LV mass were correlated with ambulatory systolic but not with basal or casual BP. A significant increase of wall thickness and LV mass was associated with a mean 24-h ambulatory systolic BP (ASBP) above 129 mmHg. It is concluded that random BP and ABP tend to identify hypertensive subjects with different features.

Chlorpropamide-alcohol flushing in non insulin-dependent diabetes: prevalence of small and large vessel disease and or risk factors for angiopathy.

One hundred and eight non insulin-dependent diabetics were tested for alcohol flushing after chlorpropamide administration (CPAF test). The overall prevalence of patients who flushed at the first challenge was 32%. However, nearly half of them still flushed after alcohol administration, when placebo was given instead of chlorpropamide, so that the prevalence of 'true' flushers was only 17%. Even though the distribution of retinal lesions was similar in 'true' flushers and in non flushers, severe loss of visual acuity was confined to the non flushers and aspecific flushers. The frequency of pathological ECG findings and of peripheral pulse reduction or abolition was significantly higher in the non flushers and aspecific flushers. Blood pressure, serum lipids and hemostatic parameters were similar in the two groups, and therefore do not explain the differences in prevalence of lesions. This study confirms the previous findings of a lower prevalence of large vessel lesions in flushers; however, the prevalence of 'true' CPAF phenomenon in our out-patient population appears to be much lower than previously reported.

[Echocardiographic study of left ventricular performance during sitting bicycle exercise (author's transl)]. / L'ecocardiografia da sforzo nello studio computerizzato della funzione ventricolare sinistra.

Twelve healthy volunteers, mean age 25.4 +/- 4.18 years, performed sitting bicycle ergometer graded exercise to exhaustion. Recordings of left ventricular echocardiographic dimension, heart rate, arterial blood pressure, were obtained at rest and at two minutes intervals during exercise and recovery. Echocardiographic tracings were digitized and the values of three complexes were combined and means determined for the overall analysis. Heart rate increased from 76.92 +/- 15.09 to 154.91 +/- 12.13 (p less than 0.001) at peak exercise and decreased to 98.50 +/- 11.60 (P less than 0.001) at six minutes recovery. Similarly behaved blood pressure. End diastolic Echo dimension varied significantly from 46.50 +/- 4.66 mm to 51.44 +/- 5.38 mm (P less than 0.005) at peak exercise and to 45.91 +/- 4.52 mm (P less than 0.005) at six minutes recovery, but resulted unchanged at lower levels of exercise. It started to return towards resting values, from two to four minutes of recovery. End systolic dimension did not change significantly at any heart rate. Shortening fraction increased progressively and significantly at every step of exercise, decreasing in the same way during recovery: rest 38.42 +/- 3.62%; peak exercise 44.28 +/- 5.32% (P less than 0.005); end recovery 39.28 +/- 5.89% (P less than 0.001). So did respectively: Stroke volume (Teichholtz) 69.50 +/- 12.16 cc; 84.92 +/- 24.14 cc (P less than 0.005); 67.64 +/- 16.48 cc (P less than 0.005). Cardiac output 5.27 +/- 1.18 lt/min; 12.46 +/- 3.83 (P less than 0.001); 6.25 +/- 1.00 (P less than 0.005). Ejection fraction 68.33 +/- 4.68%, 78.58 +/- 8.80 (P less than 0.001); 68.82 +/- 8.16 (P less than 0.005). Mean normalized velocity of circumferential fibre shortening 1.33 +/- 0.25 circ/sec; 2.37 +/- 0.33 (P less than 0.001); 1.55 +/- 0.031 (P less than 0.001). These results indicate that in untrained healthy subjects, variations of cardiac output during exercise and recovery depend mainly on heart rate and left ventricular fibre shortening rate. Severe exertion produces an increase of left ventricular dimension due to a Frank-Starling effect. Sitting bicycle exercise Echocardiography appears to be a suitable method to assess Left ventricular performance with a chest position relevant to normal human conditions.

[Left ventricular behaviour before and after left anterior descending coronary artery bypass graft. M-mode echocardiographic study in 30 patients (author's transl)]. / L'ecocardiogramma del ventricolo sinistro prima e dopo by pass aorto-coronarico. Studio M-mode in 30 pazienti.

30 coronary artery disease (CAD) patients (pts) were studied by echocardiography before and after left anterior descending (LAD) coronary bypass graft in order to evaluate left ventricular (LV) behaviour. Echocardiograms were recorded early pre- (48 hours) and post-operatively (mean 12 days) and at a mean distance of 12 months (6 to 15) after operation. The following parameters were considered: left ventricular end diastolic dimension (LVDD), right ventricular diastolic dimension (LVDD), right ventricular diastolic dimension (RVDD), diastolic thickness, systolic thickening and motion of the interventricular septum (IVS) and of the LV posterior wall (LVPW). 21 pts (70%) showed reduced systolic thickening (RST less than or equal to 30%) and 17 (57%) reduced systolic motion (RSM less than or equal to 3 mm) of the septum. Before surgery no patient showed IVS paradoxical movement, left bundle branch block, valvular regurgitation, shunt, LV aneurysm. A previous myocardial infarction was present in the story of 7 pts: anterior location in 4 pts, inferior in 3 pts. Soon after operation (mean 12 days) 4 pts showed normal IVS motion; in 7 pts it was reduced (less than or equal to 3 mm) and in 19 IVS was paradoxical. In 15 pts of this last group LVPW motion resulted remarkably increased after the bypass graft. The other echo parameters didn't show significant variation. Averaging 12 months after operation, IVS systolic thickening resulted normal in 21 of the 30 pts. (70%); in 14 of the last group of 21 there was a RST preoperatively. IVS motion resulted normal in 21 of the 30 pts (70%), reduced in 5 (17%), paradoxical in 4 (13%). LVPW motion returned to the preoperative value in all but 3 pts, in whom it remained elevated. The other echo parameters didn't show any significant variation. We conclude that: 1) IVS paradoxical motion is frequently recorded by echo shortly after coronary bypass graft surgery. 2) In most pts it is accompanied by an increased excursion of LVPW, probably compensatory in origin. Both tend to normalize within few months in most of the subjects.

[Echocardiography in Ebstein's anomaly (author's transl)]. / L'ecocardiografia nella malattia di Ebstein.

Results about an echocardiographic study of 20 patients with Ebstein's anomaly diagnosed by cardiac catheterization and angiography, are referred. In 8 patients an echocardiogram and phonocardiogram were recorded and in five patients an echocontrast examination was performed. The echocardiographic features constantly recorded in Ebstein's anomaly are represented by anterior chamber dilatation, interventricular septum paradoxical movement, anterior tricuspid leaflet wide excursion, decreased diastolic closure rate and delayed closure of tricuspid valve compared to mitral valve. The reduced left ventricular dimension and frequent incidence of "hammock-like" shape of mitral valve during systole and reduced diastolic closure rate of anterior mitral leaflet are pointed out. Possible causes of anterior chamber dilatation, of interventricular septum paradoxical motion and delayed tricuspid closure are discussed. According to the previous study no echocardiographic pattern is surely diagnostic of the disease by itself; a delayed tricuspidal closure (more than 70 msec) when associated to an anterior tricuspid leaflet wide excursion and decreased E-F slope, is of particular value for diagnosis.

[Value of echocardiography in the diagnosis of dissecting aneurysm of the aorta]. / Validita' dell'ecocardiografia nella diagnosi di aneurisma dissecante dell'aorta.

A revision of 1300 echocardiograms of adults showed 14 patients whose echocardiographic diagnosis of aortic root dissecting aneurism (D.A.). Of these, 8 didn't have any anamnestic, clinical or instrumental evidence of D.A. In the other 6, admitted to our department with a suspected D.A., echocardiography proved to be useful in confirming such diagnosis in 4, in excluding it in 1, but gave a false positive diagnosis of D.A. in the sixth, affected by a diffuse carcinomatosis with pleuropericardial blood effusion. From the examination of the present experience, the Authors deem echocardiography is a useful diagnostic tool in the screening of D.A. when the following conditions are fulfilled: 1) presence of all the major criteria of Nanda and Gramiak, especially the aortic root anterior wall dilatation beyond 16 mm; 2) an almost suggestive story and clinical evidence of D.A. The usefulness of an echocardiographic pattern recently described as diagnostic of D.A. (loss of continuity between the borders of the anterior aortic wall with interventricular septum, and/or posterior aortic wall with mitral anulus) was confirmed: it was detected in 3 of the 4 D.A. patients but in none of the others. The presence of a false positive and the possibility of technical artifacts nevertheless induce caution in the interpretation of the echocardiographic pattern alone.