Comparison of HER2 status in primary and paired metastatic sites of gastric carcinoma.

BACKGROUND: Trastuzumab has recently shown efficacy in the treatment of HER2-positive advanced gastric adenocarcinoma. Although antibody-based therapies target the metastatic disease, HER2 status is usually evaluated in the primary tumour because metastatic sites are rarely biopsied. The aim of this study was to compare HER2 status in primary and paired metastatic sites of gastric adenocarcinoma. METHODS: The HER2 status was assessed by fluorescence in situ hybridisation (FISH) and immunohistochemistry (IHC) in 72 secondary lesions of gastric adenocarcinoma and in the corresponding primary tumours. RESULTS: Concordance of FISH results, evaluable in 68 primary and matched metastatic sites, was 98.5%. Concordance of IHC results, available in 39 of the 72 paired cases, was 94.9%. Only one case showed discordance between primary tumour and metastasis, being negative by both IHC and FISH in the primary and showing HER2 overexpression and amplification in the corresponding pancreatic lymph node metastasis. CONCLUSION: The high concordance observed between HER2 results obtained by both IHC and FISH on primary tumours and corresponding metastases suggests that in gastric cancer HER2 status is maintained in most cases unchanged during the metastatic process.

Impact of 2013 ASCO/CAP guidelines on HER2 determination of invasive breast cancer: A single institution experience using frontline dual-color FISH.

PURPOSE: The new ASCO/CAP guidelines published in 2013 (AC2013) significantly modified the scoring criteria for HER2-FISH, introducing the most controversial change to the HER2-equivocal category. We retrospectively evaluated the impact of AC2013 in a cohort of consecutive invasive breast cancers (IBCs) analyzed with frontline dual-color FISH. METHODS: 2788 consecutive IBCs were reclassified based on the AC2013 guidelines. Clinico-pathological features of equivocal IBCs were compared with HER2-negative and HER2-positive IBCs. FISH HER2-equivocal cases underwent reflex tests: HER2-IHC, RARA-FISH, and SMS-FISH. Overall and disease-free survivals were evaluated in AC2007 HER2-positive patients treated with trastuzumab and in patients that became eligible for target-therapy according to AC2013. RESULTS: Two-hundred HER2-negative cases (7.2%) were classified differently, following AC2013: 0.3% (8/2788) became HER2-positive and 6.9% (192/2788) HER2-equivocal. AC2013, compared with AC2007, significantly increased initial HER2-equivocal cases (6.9%vs1.6%, p < 0.001). AC2013 equivocal-IBCs affected older patients and showed pathological features between HER2-negative and HER2-positive IBCs. After reflex tests, 102 of the 190 equivocal cases (53.7%) were reclassified as HER2-positive, 51 (26.8%) as negative and 37 (19.5%) as equivocal. IHC tested negative in 44.7% of cases, whereas SMS-FISH showed the highest percentage of positive results (45.8%). Clinical outcomes showed no statistically significant differences. CONCLUSION: Overall, 80.5% of FISH-equivocal cases were solved with at least one reflex test and 3.6% of patients became AC2013 HER2-positive, therefore eligible for target-therapy, but showed clinical outcomes similar to HER2-positive patients treated with trastuzumab. Our data belittle the clinical impact of AC2013 HER2-equivocal reclassification; further prospective randomized clinical studies are necessary to support these findings.

Determinants of myocardial ischemia during percutaneous transluminal coronary angioplasty in patients with significant narrowing of a single coronary artery and stable or unstable angina pectoris.

Previous studies have assessed the determinants of collateral vessel recruitment during coronary occlusion in patients undergoing percutaneous transluminal coronary angioplasty (PTCA). However, the determinants of severity of myocardial ischemia after sudden coronary occlusion do not necessarily coincide with those responsible for collateral vessel recruitment. The aim of this study was to assess the determinants of severity of myocardial ischemia during balloon inflation by recording surface and intra-coronary electrocardiograms (ECGs). In 62 consecutive patients with 1-vessel disease and without previous myocardial infarction undergoing successful PTCA for stable (n = 33) or unstable (n = 29) angina pectoris, the summation of the absolute values of ST-segment shifts from baseline on the intracoronary and surface ECG at the end of the first 2-minute inflation was obtained as an index of the severity of myocardial ischemia. Stenosis severity before PTCA was measured using computerized coronary angiography, while the grade of collateral filling was scored according to Rentrop's classification. The mean (+/- 1 SD) ST-segment shift at the end of balloon inflation was less in patients with than without collateral vessels (12 +/- 10 vs 23 +/- 15 mm, p < 0.05). Despite a similar prevalence of collateral vessels (34% vs 24%, p = NS), the mean ST-segment shift was also less in patients with unstable than stable angina (15 +/- 9 vs 24 +/- 17 mm, p < 0.05). However, the mean ST-segment shift was not associated with the severity of coronary stenosis before PTCA (r = 0.0004, p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Doppler echocardiography evaluation of the CarboMedics valve in patients with small aortic anulus and valve prosthesis-body surface area mismatch.

A Doppler echocardiographic study was performed to evaluate the hemodynamic performances of small diameter CarboMedics aortic valves (CarboMedics, Inc., Austin, Tex.) in patients with a mismatch between the prosthetic valve and body surface area. Fourteen patients receiving either a 19 mm (n = 7) or a 21 mm valve (n = 7) prosthesis were studied. Only patients with a body surface area greater than 1.65 m2 were included in the study. Pulsed and continuous wave Doppler echocardiography was performed at rest and 2 minutes after treadmill exercise with the Bruce protocol. Peak and mean gradients across the valve prosthesis were estimated; effective orifice area, performance index, and discharge coefficient of the valve prosthesis were calculated. All patients achieved a significant increase in heart rate, systolic blood pressure, and cardiac output with exercise. Mean gradients +/- standard deviation of the mean at rest and 2 minutes after exercise were 20.1 +/- 7.1 mm Hg and 21.8 +/- 9 mm Hg for the 19 mm prosthesis and 12.3 +/- 3.4 mm Hg and 15.9 +/- 3.9 mm Hg for the 21 mm prosthesis. The 19 mm valve prosthesis significantly increased the effective orifice area with exercise (1.02 +/- 0.2 versus 1.20 +/- 0.3; p < 0.05), whereas it was almost unmodified for the 21 mm valve (1.38 +/- 0.2 versus 1.39 +/- 0.3; p = not significant). Therefore, despite a similar increase in cardiac output with exercise, only the 21 mm valve prosthesis showed a significant increase in peak (25.4 +/- 5.2 versus 34.9 +/- 8.1 mm Hg) and mean gradient (p < 0.01). We conclude that small diameter CarboMedics valves have satisfactory hemodynamic performances even after strenuous exercise in patients with large body surface areas. The hemodynamic performances of the 19 mm valve prosthesis seem to be optimized with exercise.

Regression of left ventricular hypertrophy after aortic valve replacement for aortic stenosis with different valve substitutes.

OBJECTIVE: Stentless biologic aortic valves are less obstructive than stented biologic or mechanical valves. Their superior hemodynamic performances are expected to reflect in better regression of left ventricular hypertrophy. We compared the regression of left ventricular hypertrophy in 3 groups of patients undergoing aortic valve replacement for severe aortic stenosis. Group I (10 patients) received stentless biologic aortic valves, group II (10 patients) received stented biologic aortic valves, and group III (10 patients) received bileaflet mechanical aortic valves. METHODS: Echocardiographic evaluations were performed before the operation and after 1 year, and the results were compared with those of a control group. Left ventricular diameters and function, left ventricular wall thickness, and left ventricular mass were assessed by echocardiography. RESULTS: Group I patients had a significantly lower maximum and mean transprosthetic gradient than the other valve groups (P = .001). One year after operation there was a significant reduction in left ventricular mass for all patient groups (P < .01), but mass did not reach normal values (P = .05). Although the rate of regression in the interventricular septum and posterior wall thickness differed slightly among groups, their values at follow-up were comparable and still higher than control values (P = .002). The ratio between interventricular septum and posterior wall and the ratio between wall thickness and chamber radius did not change significantly at follow-up. CONCLUSIONS: Because the number of patients was relatively small, we could not use left ventricular mass regression after I year to distinguish among patients undergoing aortic valve replacement for aortic stenosis by means of valve prostheses with different hemodynamic performances.

Correction of pectus excavatum with a self-retaining seagull wing prosthesis. Long-term follow-up.

Between June 1958 and December 1991, 315 patients (217 male and 98 female, mean age = 17.8 +/- 5.5 years) affected by pectus excavatum (PE) were surgically treated. Most of the patients required operation for aesthetic reasons only (299 patients; 95 percent). The grade of PE (Chin classification) was I in 72 patients, II in 152, and III in the remaining 91. The surgical technique consisted of a double transversal sternotomy at the level of the lowest and highest part of the depression associated with a longitudinal sternotomy. A wedge resection of the ribs was then performed and the sternum was fixed using a stainless steel strut molded into a seagull wing prosthesis. The strut was removed 12 months postoperatively. There were no operative mortalities. Four patients had sternal wound infection that was successfully treated. The mean follow-up was 15.8 years per patient and was 60 percent complete. From the aesthetic point of view, the postoperative results were excellent in 246 patients (78 percent), good in 57 (18 percent), and poor in 12 (4 percent). All subjective symptoms, when present, disappeared after surgery. The seagull wing prosthesis appears to be safe, easy to implant and to remove, and comfortable for the patient. This technique has shown good long-term results independently of type of deformity and patient age.

Extent and pattern of regression of left ventricular hypertrophy in patients with small size CarboMedics aortic valves.

OBJECTIVE: To assess the extent and pattern of regression of left ventricular hypertrophy after valve replacement for aortic stenosis, we studied 26 patients receiving either 19 or 21 mm CarboMedics valves (group I, 13 patients) or either 23 or 25 mm CarboMedics valves (group II, 13 patients). The studies were done before the operation and after 3 years, and results were compared with those of 10 control patients. METHODS: Left ventricular end-diastolic and end-systolic diameters and volumes, ejection fraction and fractional shortening, and interventricular septum and posterior wall thickness were measured. The ratio between interventricular septum and posterior wall thickness, the ratio between left ventricular wall thickness and left ventricular chamber radius, and the left ventricular mass were then calculated. RESULTS: At follow-up there was a significant reduction in the left ventricular mass, interventricular septum, and posterior wall thickness for both patient groups (p < 0.01). However, only the posterior wall thickness reached normal values; the interventricular septum and the left ventricular mass indices were still significantly greater than in the control group (p < 0.01). Because of the incomplete regression of interventricular septal hypertrophy, the ratio between interventricular septum and posterior wall thickness was similar between both patient groups but it was significantly higher than in control subjects (p < 0.01). The ratio between wall thickness and chamber radius did not decrease significantly in group II patients, in whom it remained above the control values. CONCLUSION: Having a bileaflet aortic prosthesis of one size larger did not seem to significantly influence the pattern and the extent of regression of left ventricular hypertrophy after an intermediate period of follow-up.

Replacement of a prosthetic valve after the Bentall procedure.

Patients undergoing a composite graft replacement of the aortic root with reimplantation of the coronary ostia (Bentall procedure) are at risk for late prosthetic heart valve dysfunction: approximately 10% of the patients are expected to experience this complication at 10 years. Therefore, replacement of the prosthetic valve is indicated. This procedure involves technical problems related to the manipulation and the reconstruction of the composite graft without distortion of the coronary arteries. We describe a simple surgical approach to treat these particular patients.

Residual aortic valve regurgitation after aortic root remodeling without a direct annuloplasty.

BACKGROUND: Aortic insufficiency secondary to degenerative aneurysms of the ascending aorta can be surgically treated with replacement of the valve or with remodeling of the aortic root. METHODS: In 15 patients who underwent aortic root remodeling from January 1994 to December 1996, we evaluated the postoperative aortic regurgitation and correlated it with several anatomic and functional variables. Operative success was defined as a residual aortic regurgitation less than or equal to 1 on a scale of 0 to 4. RESULTS: Root dimensions and aortic incompetence decreased significantly after the operation (p < 0.0001). The difference between preoperative and postoperative root diameters (p = 0.0006) and the presence of Marfan's syndrome (p < 0.0001) were independently predictive of persisting significant aortic insufficiency. Operative success was obtained in patients with a difference between preoperative and postoperative root diameters smaller than 30 mm. CONCLUSIONS: Aortic root remodeling is effective in reducing aortic regurgitation. Severe aortic root dilatation may result in excessive geometric alteration, leading to suboptimal results. The choice of a larger graft contributes to avoiding excessive geometric constraint of a profoundly diseased aortic root. Indication to undergo root remodeling should be evaluated cautiously in patients with Marfan's syndrome.

Levels of troponin I and cardiac enzymes after reinfusion of shed blood in coronary operations.

BACKGROUND: Reinfusion of shed blood after coronary artery bypass grafting might increase the levels of cardiac enzymes with consequent difficulties in the diagnosis of perioperative myocardial infarction. METHODS: Thirty consecutive patients undergoing coronary artery bypass grafting who bled at least 400 mL within the first 4 hours after operation underwent reinfusion of shed blood. Thirty consecutive patients who were not autotransfused served as control. All patients underwent enzyme determination (total creatine kinase, MB fraction, lactate dehydrogenase, and troponin I) in the shed blood and in circulating blood preoperatively, at arrival in the intensive care unit, and 6, 24, and 48 hours after operation. RESULTS: The shed blood contained significantly higher concentration of cardiac enzymes than the circulating blood at all time intervals (p = 0.0001). The levels of creatine kinase, its MB fraction, and lactate dehydrogenase in circulating blood were significantly elevated in patients receiving autotransfusion up to 24 hours after autotransfusion. The blood levels of troponin I were not significantly different between the two group of patients at all time points. The percent fraction of MB did not increase after autotransfusion. CONCLUSIONS: The measurement of cardiac troponin I is a useful marker for the diagnosis of perioperative myocardial infarction in patients undergoing transfusion of shed blood after coronary operation.

Hemodynamic performances of small diameter carbomedics and St. Jude valves.

BACKGROUND AND AIMS OF THE STUDY: Optimal hemodynamic performances are of paramount importance when implanting a mechanical valve in patients with a small aortic annulus. A Doppler echocardiographic study was performed to compare the hemodynamic performances of small CarboMedics and St. Jude valves. MATERIALS AND METHODS: Twenty-nine patients receiving either a 19 mm (n = 10) or a 21 mm (n = 10) CarboMedics valve or a 19 mm (n = 9) St. Jude Med HP valve were evaluated. A Doppler echocardiographic study was performed at rest and two minutes after treadmill exercise with the Bruce protocol. Peak and mean gradients across the valve were estimated; effective orifice area, performance index and discharge coefficient were calculated. Heart rate, blood pressure and cardiac output were all significantly increased with exercise. RESULTS: Peak and mean gradients at rest were significantly higher (p < 0.05) in the 19 mm CarboMedics valve (40.2 +/- 15 mmHg and 22.6 +/- 9 mmHg, respectively) when compared either with 21 mm CarboMedics valve (27.6 +/- 6.8 mmHg and 14.2 +/- 3.4 mmHg, respectively) or with the 19 mm St. Jude HP valve (23.6 +/- 10.4 mmHg and 13.6 +/- 5 mmHg, respectively). Peak and mean gradients were not modified with exercise for the 19 mm CarboMedics valve and significantly increased for the 21 mm CarboMedics and the 19 mm St. Jude HP valves. Although these values were still higher in the 19 mm CarboMedics valve, they did not reach the level of statistical significance when compared with the other two valve groups. CONCLUSIONS: The 19 mm St. Jude HP valve shows hemodynamic performances at rest that are similar to those of the 21 mm CarboMedics valve and superior to those of the 19 mm CarboMedics valve. With exercise both sizes of the CarboMedics valve show an in vivo discharge coefficient close to one, testifying to a full utilization of the internal orifice area.

Early coronary artery bypass graft thrombosis in a patient with protein S deficiency.

A 59-year-old white man underwent multiple coronary artery bypass grafts (CABGs) on an emergency basis for severe stenosis of the left main, and occlusion of the right coronary, artery. One month after operation recurrence of angina prompted a new diagnostic evaluation. Occlusion of the grafts was detected at angiography. Accurate hematological screening before reoperation showed decreased levels of protein S. One year after his second operation, the patient is asymptomatic on oral anticoagulant therapy. Tallium-201 scintigraphy shows normal myocardial perfusion.

Mid-term follow-up of aortic root remodelling compared to Bentall operation.

OBJECTIVES: Aortic valve sparing with root remodelling has proven useful in cases of aortic regurgitation secondary to ascending aorta disease. An excessive rate of re-operation for recurrent aortic regurgitation after this conservative approach might compensate the prosthesis-related risk of the Bentall operation. METHODS: From January 1995 to September 2000, 69 consecutive patients with aortic expansive aneurysm and concomitant aortic valve disease, were submitted to the Bentall operation (group A, n=37) in the presence of an abnormal valve, or to root remodelling (group B, n=32) in cases of secondary aortic incompetence. One patient in group A and four in group B had Marfan syndrome. The follow-up was 1021 patient-months (range, 1-68 months) in group A and 926 in group B (1-64 months). The event-free survival was calculated using the Kaplan-Meier method, and the difference between curves was evaluated using the Mantel-Cox log-rank test. RESULTS: The operative mortality was 5% in group A and 0% in group B. One patient died at follow-up in group A and none in group B. Four patients (three Marfan) in group B were re-operated on because of recurrent aortic regurgitation. The 5-year event-free survival was 88+/-7% in group A and 82+/-8% in group B (P=0.58). Early residual aortic regurgitation remained stable over time only in patients with good early results. CONCLUSIONS: Mid-term follow-up failed to reveal statistically significant differences in the clinical outcome between remodelling and the Bentall operation. Our results support the widespread use of root remodelling, provided that an indication to this conservative approach is achieved after careful, case-by-case evaluation. A good early operative result is likely to remain stable over time.

[Esthetic suture of the lower limbs after a saphenous vein graft in cardiac surgery. Polydioxanone vs Vicryl]. / Sutura estetica degli arti inferiori dopo prelievo della vena safena in cardiochirurgia. Polidiossanone vs Vicryl.

The vena saphena magna is widely used as a passage during myocardial revascularisation surgery (CABG). The preparation of the vein involves a long incision on the thigh and leg which is routinely closed using a continuous suture thread in Vicryl of the subcutis and continuous intradermal suture of the cutis. The authors retrospectively evaluated the functional and esthetic results of intradermal suture performed using two different types of reabsorbable thread: PDS II and Vicryl. A total of 178 patients underwent CABG surgery at the Heart Surgery Division of Tor Vergata University of Rome during the period January-September 1992. Mean age was 63 year +/- 7 (SD), 140 were males and 38 females. PDS II 3/0 was used for intradermal suture in 88 patients, whereas Vicryl 3/0 was used in 90. There were no significant differences between the two groups with regard to age, sex, number of grafts, associated pathologies or wound length. After 1-9 months (mean 5.6 months) the surgical wound on the saphenectomized limb was evaluated. It was found that compared to Vicryl the use of PDS II presented a higher incidence of keloids (p > 0.05). This was probably due to the greater reaction provoked in the dermis by the monofilament compared to twisted thread. The authors conclude that the use of a reabsorbable twisted thread, such as Vicryl or Vicryl Rapid, is preferable owing to the higher rate of compliance and lower incidence of complications.

[Bentall-DeBono intervention: 8 years of clinical experience]. / Intervento di Bentall-DeBono: otto anni di esperienza clinica.

BACKGROUND: Annulo-aortic ectasia is a dilation of the aortic root with the involvement of the Valsalva sinuses. In 1968 Bentall and DeBono proposed to replace the aortic valve, the Valsalva sinuses and the ascending aorta with a composite tube graft containing aortic valve prosthesis. Consequently coronary ostia had to be reimplanted on the prosthetic tube. Recently the use of new materials has resulted in a more acceptable operative risk, and postoperative bleeding and late mortality have been reduced. METHODS: From January 1991 to December 1998, 44 out of 241 patients were operated on with the Bentall-DeBono procedure, affected by dissecting or expansive aneurysm of the ascending aorta. Of the 44 patients (35 males, 9 females, mean age 53.7 years), 3 presented with acute aortic dissection, 5 were asymptomatic, 10 were in NYHA functional class II, 14 in class III, 9 in class IV, and 2 in CCS class 4; 1 patient had dysphonia; 37 patients presented with isolated aortic regurgitation, and 7 associated aortic valvular stenosis. The diagnosis of acute dissection was made by transesophageal echocardiography and that of expansive aneurysm by thorax helical computed tomographic scanning and/or magnetic resonance imaging and cardiac catheterization. Follow-up was obtained in 100% of the patients for an average of 23 +/- 20.9 months (range 4-79 months). RESULTS: Four patients (9%) died; in 4 patients (9%) postoperative bleeding needed reoperation, in 5 (11.4%) a permanent pacemaker for atrioventricular block was implanted, and 1 patient (2.3%) had transient hemiparesis. At univariate analysis predictive factors for operative risk were NYHA functional class IV (p < 0.005) and atherosclerotic etiology (p < 0.05). At follow-up 7 late deaths occurred for an actuarial survival at 24 months of 75 +/- 9%. Causes were sudden death in 3 patients, cardiac failure in 3 and stroke in 1 patient; 31 surviving patients (94%) were in NYHA functional class I and 2 patients in class II (6%). CONCLUSIONS: The Bentall-DeBono procedure involves moderate risk with good results; clinical presentation and associated valvular pathology influence early and mid-term results.

Synergistic antitumor activity of lapatinib and retinoids on a novel subtype of breast cancer with coamplification of ERBB2 and RARA.

All-trans retinoic acid (ATRA), the only clinically available cyto-differentiating agent, has potential for the therapy/chemoprevention of breast carcinoma. Given the heterogeneous nature of this tumor, a rational use of ATRA and derivatives (retinoids) in the clinic requires the identification of patients that would benefit from retinoid-based protocols. Here, we demonstrate that 23-32% of the human ERBB2(+) breast cancers show coamplification of retinoic acid receptor alpha (RARA), encoding the retinoic acid receptor, RARα. This represents a novel subtype of breast cancer characterized by remarkable sensitivity to ATRA and RARα agonists, regardless of positivity to the estrogen receptor, a known modulator of retinoid sensitivity. In estrogen-receptor-negative cellular models showing coamplification of ERBB2 and RARA, simultaneous targeting of the corresponding gene products with combinations of lapatinib and ATRA causes synergistic growth inhibition, cyto-differentiation and apoptosis. This provides proof-of-principle that coamplification of ERBB2 and RARA can be exploited for the stratified and targeted therapy of a novel subtype of breast cancer patients, with an approach characterized by tumor cell selectivity and low predicted toxicity. The available cellular models were exploited to define the molecular mechanisms underlying the antitumor activity of combinations between lapatinib and ATRA. Global gene expression and functional approaches provide evidence for three components of the antiproliferative/apoptotic responses triggered by lapatinib+ATRA. Induction of the retinoid-dependent RARRES3 protein by ATRA stabilizes the effect of lapatinib inhibiting ERBB2 phosphorylation. Upregulation and activation of the transcription factor FOXO3A integrates ATRA-dependent transcriptional and lapatinib-dependent posttranscriptional signals, controlling the levels of effector proteins like the antiapoptotic factor, BIRC5. Stimulation of the TGFß pathway by ATRA mediates other components of the apoptotic process set in motion by simultaneous targeting of ERBB2 and RARα.