Assessment of Capecitabine and Bevacizumab With or Without Atezolizumab for the Treatment of Refractory Metastatic Colorectal Cancer: A Randomized Clinical Trial.

Importance: Cotargeting vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 may produce anticancer activity in refractory metastatic colorectal cancer (mCRC). The clinical benefit of atezolizumab combined with chemotherapy and bevacizumab remains unclear for the treatment of mCRC. Objectives: To assess whether the addition of atezolizumab to capecitabine and bevacizumab therapy improves progression-free survival (PFS) among patients with refractory mCRC and to perform exploratory analyses among patients with microsatellite-stable (MSS) disease and liver metastasis. Design, Setting, and Participants: This double-blind phase 2 randomized clinical trial enrolled 133 patients between September 25, 2017, and June 28, 2018 (median duration of follow-up for PFS, 20.9 months), with data cutoff on May 4, 2020. The study was conducted at multiple centers through the Academic and Community Cancer Research United network. Adult patients with mCRC who experienced disease progression while receiving fluoropyrimidine, oxaliplatin, irinotecan, bevacizumab, and anti-epidermal growth factor receptor antibody therapy (if the patient had a RAS wild-type tumor) were included. Interventions: Patients were randomized (2:1) to receive capecitabine (850 or 1000 mg/m2) twice daily on days 1 to 14 and bevacizumab (7.5 mg/kg) on day 1 plus either atezolizumab (1200 mg; investigational group) or placebo (placebo group) on day 1 of each 21-day cycle. Main Outcomes and Measures: The primary end point was PFS; 110 events were required to detect a hazard ratio (HR) of 0.65 with 80% power (1-sided α = .10). Secondary end points were objective response rate, overall survival (OS), and toxic effects. Results: Of 133 randomized patients, 128 individuals (median age, 58.0 years [IQR, 51.0-65.0 years]; 77 men [60.2%]) were assessed for efficacy (82 in the investigational group and 46 in the placebo group). Overall, 15 patients (11.7%) self-identified as African American or Black, 8 (6.3%) as Asian, 1 (0.8%) as Pacific Islander, 101 (78.9%) as White, 1 (0.8%) as multiple races (Asian, Native Hawaiian/Pacific Islander, and White), and 2 (1.6%) as unknown race or unsure of race. Microsatellite-stable disease was present in 110 patients (69 in the investigational group and 41 in the placebo group). Median PFS was 4.4 months (95% CI, 4.1-6.4 months) in the investigational group and 3.6 months (95% CI, 2.2-6.2 months) in the placebo group (1-sided log-rank P = .07, a statistically significant result; HR, 0.75; 95% CI, 0.52-1.09). Among patients with MSS and proficient mismatch repair, the HR for PFS was 0.66 (95% CI, 0.44-0.99). The most common grade 3 or higher treatment-related adverse events in the investigational vs placebo groups were hypertension (6 patients [7.0%] vs 2 patients [4.3%]), diarrhea (6 patients [7.0%] vs 2 patients [4.3%]), and hand-foot syndrome (6 patients [7.0%] vs 2 patients [4.3%]). One treatment-related death occurred in the investigational group. In the investigational group, the response rate was higher among patients without liver metastasis (3 of 13 individuals [23.1%]) vs with liver metastasis (4 of 69 individuals [5.8%]). The benefit of atezolizumab for PFS and OS was greater among patients without vs with liver metastasis (primary analysis of PFS: HR, 0.63 [95% CI, 0.27-1.47] vs 0.77 [95% CI, 0.51-1.17]; OS: HR, 0.33 [95% CI, 0.11-1.02] vs 1.14 [95% CI, 0.72-1.81]). Conclusions and Relevance: In this randomized clinical trial, the addition of atezolizumab to capecitabine and bevacizumab therapy provided limited (ie, not clinically meaningful) clinical benefit. Patients with MSS and proficient mismatch repair tumors and those without liver metastasis benefited more from dual inhibition of the vascular endothelial growth factor and programmed cell death 1 or programmed cell death ligand 1 pathways. Trial Registration: ClinicalTrials.gov Identifier: NCT02873195.

Giant aneurysm following coil occlusion of patent ductus arteriosus.

A case is described in which a giant aneurysm developed following successful PDA coil occlusion in an infant with Marfan syndrome. This rare and severe complication brings into question the need for careful evaluation of these children before and after transcatheter occlusion.

Complicated pericardial cyst: atypical anatomy and clinical course.

Pericardial cysts are usually detected by chance are are clinically silent in most cases. Nevertheless, symptoms and serious complications may occur. We describe a case of pericardial cyst diagnosed in an 8-year-old boy who was admitted with chest pain. Echocardiography revealed a mild to moderate pericardial effusion and a 7.5 x 5.5 cm intrapericardial echo-free lesion consistent with a pericardial cyst. Surgery was carried out 3 days afterward because of the patient's worsening condition, the progressive increase of pericardial effusion, and the onset of initial signs of cardiac tamponade. The cyst showed a long and easily movable vascular pedicle and inflammatory areas involving the pericardial surface. Like the pericardial effusion, the contents of the mass appeared as serosanguineous fluid on aspiration. Histologic examination confirmed the diagnosis of pericardial cyst and showed findings according to ischemia-related lesions of the cyst. The coexistence of pericardial cyst and cardiac tamponade is very unusual. The atypical anatomy and clinical course suggest a distinct and so far undescribed pathogenetic mechanism for this association: the torsion of a vascular pedicle and the subsequent development of ischemia-related lesions of the cyst.

[The treatment of choanal atresia]. / Trattamento dell'atresia coanale.

Choanal atresia occurs in approximately 1 out of every 8000 live births. In about 60% of these cases it is unilateral and is often associated with other major craniofacial anomalies or visceral malformations such as the so-called CHARGE syndrome (i.e. Choloboma, Heart defects, choanal Atresia, Retarded growth and development, Genital anomaly, and Ear defect with deafness) first described by Pagon in 1981. In newborns the clinical manifestations of choanal atresia consist of respiratory distress strictly related to the entity of nasal obstruction. Total bilateral congenial choanal atresia must, therefore, be considered a surgical emergency since nasal obstruction impedes the suction mechanism and hence normal feeding in the newborn. For this reason, prompt surgery is mandatory. The surgical approach employed in choanal atresia consists of both the trans-nasal and trans-palatal approaches. Between 1985 and 1997 31 patients with choanal atresia were treated in our department (16 males, 15 females; age range 2 days-5.5 years; mean 11.4 months). In 25 cases (80.6%) the malformation was bilateral. Associated anomalies were seen in 8 patients (25.8% of cases). All of these patients were treated using the trans-nasal approach, under general anesthesia, and endoscopic control. In 27 cases a trocar was employed to perforate the bony atresia and a stent was then positioned. Three patients underwent contact-laser resection of the stenosis without requiring any further stent and without any complications. None of these patients developed total recurrences, although after varying amounts of time, in 8 of the 27 patients operated using the trocar (29.6% of cases) a partial reduction of the airway occurred, the substenosis requiring dilatation with progressive Hegar dilators. In the remaining cases contact-laser therapy was associated with dilation. Three of the patients were treated by laser-therapy alone and none developed a recurrence. One patient dropped out of the follow-up for other serious malformations.

Intracoronary angiotensin II potentiates coronary sympathetic vasoconstriction in humans.

BACKGROUND: In humans with coronary artery disease, ACE inhibition attenuates coronary sympathetic vasoconstriction. Whether this is due to removal of angiotensin (Ang) II production or to a reduced bradykinin breakdown, however, is unknown. METHODS AND RESULTS: In eight normotensive patients with angiographic evidence of mild left coronary artery lesions (< or = 50%), mean arterial pressure (MAP, intra-arterial catheter), heart rate (HR, ECG lead), coronary sinus blood flow (CBF, thermodilution method), and coronary vascular resistance (CVR, ratio between MAP and CBF) were measured before and during a 15-minute left intracoronary infusion of Ang II at a dose that had no direct coronary or systemic vasomotor effects. The same measurements were made before and during a 15-minute infusion of saline. A 2-minute cold pressor test (CPT) and a 45-second diving were performed at the end of either infusion period. These maneuvers were used because their coronary vasomotor effects are abolished by phentolamine and thus depend on sympathetic activation. During saline infusion, both CPT and diving caused a marked increase in MAP. HR increased with CPT and fell with diving. CBF increased in parallel to the MAP increase, with little change in CVR. The MAP and HR responses were similar during Ang II infusion, which, however, caused either no change or a reduction in CBF with a consequent marked increase in CVR with both CPT and diving. In four additional patients, the diameter of the stenotic vessels remained unchanged during the CPT performed under saline and Ang II infusion. CONCLUSIONS: Ang II markedly enhances sympathetic influences on coronary circulation in humans, presumably by acting at the arteriolar level. This may explain the blunting effect of ACE inhibition on sympathetic coronary vasoconstriction in patients with coronary artery disease.

Lysis of a right atrial thrombus of more than a week's duration by high dose urokinase in a one-year-old child.

The case of a one-year-old child in whom a large catheter-related right atrial thrombus of more than a week's duration was dissolved by urokinase is presented. After one week of unsuccessful heparin treatment, urokinase, via a central venous catheter, was added at a dose of 1500 IU/kg/h. Urokinase was subsequently increased by 1000 U/kg/h every day up to a maximum of 4500 IU/kg/h on the basis of thrombus size reduction as assessed by daily cross-sectional echocardiography. One week later the thrombus was almost completely dissolved. No major bleeding occurred. Warfarin was given for the next three months and the international normalized ratio (INR) was maintanied between 2 and 3. At the end of warfarin treatment echocardiography was negative for right atrial thrombosis. This case suggests that local high dose urokinase therapy can be safely and successfully used to dissolve large right atrial thromboses of more than a week's duration.

[Primary carcinoma of the thyroglossal duct. 2 case reports]. / Il carcinoma primitivo del dotto tireoglosso. Due casi clinici.

AA. present two cases of carcinoma arising on thyroglossal duct's cystic. Those carcinomas are a rare event and will be suspected in the patients that present an irregular tumefaction of medial neck's district. Etiology is unknown; is possible that a preceding irradiation on the neck will represent a factor risk. AA. retained that in case of medial neck's district tumefactions is necessary executed a total examination of neck's and head's district, an echography, a thyroid scintigraphy, a thoracic radiography, a panendoscopy and a FNAB. When we found a squamous carcinoma on residual thyroglossal duct the therapy is chirurgical in function of dimension of T and N with following radiotherapy in function of stage (possible lymph node metastasis). When we found a different adenoma is necessary chirurgical removal of tumefactions with hyoid bone's a body resection (Sistrunk's operation) with total thyroidectomy and following Pochin's test for seeking eventual residual with radiometabolic and suppressive therapy.

Effects of amlodipine on coronary hemodynamics and vascular responses to sympathetic stimulation in patients with coronary heart disease.

Dihydropyridines (DHPs) exert a powerful coronary vasodilator action, but whether they actually affect the coronary vasomotor effects elicited by an increase in cardiac sympathetic drive is controversial. We assessed the effects of the DHP calcium antagonist amlodipine on coronary hemodynamics and vascular response to sympathetic activation in patients with coronary heart disease. In the control condition, mean arterial pressure (MAP, aortic catheter), heart rate (HR, ECG), rate-pressure product (RPP), coronary sinus blood flow (CBF, thermodilution) and coronary vascular resistance (CVR) (ratio between MAP and CBF) were measured in all our case series (13 patients with angiographically documented severe coronary artery disease) before and during a 2-min cold pressor test (CPT) and a 30-s diving (D) and, in the 8 patients of this case series who were smokers, also before and during smoking a cigarette (S, nicotine content 1.0 mg for 10 min). The same protocol used in control condition was repeated 30 min after intravenous (i.v.) bolus administration of 11 mg amlodipine. CPT, diving, and smoking increased MAP and RPP and caused a marked and significant increase in CVR (+12.1 +/- 4.8, +30.4 +/- 6.8, and +16.8 +/- 7.2%, respectively). Amlodipine reduced MAP, increased CBF, and caused a marked decrease in CBF. The drug did not modify responses to CPT and diving or pressure and HR responses to smoking, whereas the smoking-induced increase in coronary vascular resistance was attenuated after amlodipine administration (+3.2 +/- 2.7%, p < 0.05 vs. control condition). Thus, amlodipine does not attenuate the sympathetic coronary vasoconstrictor effects of CPT and diving.(ABSTRACT TRUNCATED AT 250 WORDS)

Impairment of the arterial baroreflex during symptomatic and silent myocardial ischemia in humans.

OBJECTIVES: The aim of this study was to assess whether transient episodes of symptomatic or silent myocardial ischemia after baroreceptor modulation of heart rate. BACKGROUND: Animal and human studies have shown that myocardial infarction is accompanied by an impairment of the baroreceptor influences on the sinus node. However, whether this also occurs during transient myocardial ischemia has never been documented. METHODS: In 12 patients undergoing coronary angiography, systolic blood pressure (intraarterial catheter) was reduced by an intravenous bolus of nitroglycerin during a spontaneous episode of transient chest pain and myocardial ischemia (ST segment depression on the electrocardiogram) and 30 min after recovery. The slope of the linear regression between the decrease in systolic blood pressure and the RR interval shortening was taken as the measure of baroreflex sensitivity. RESULTS: During ischemia, baroreflex sensitivity was 1.3 +/- 0.3 ms/mm Hg (mean +/- SEM), whereas after recovery it was markedly and significantly greater (2.6 +/- 0.5 ms/mm Hg, p < 0.01). Similar results were obtained in eight other patients who experienced a silent ischemic episode either spontaneously or during coronary angioplasty. The reduction in baroreflex sensitivity was similarly pronounced during inferior (10 patients) and anterior (10 patients) ischemia, and its magnitude showed little or no relation to the ischemia-dependent changes in blood pressure and heart rate. CONCLUSIONS: Transient myocardial ischemia is associated with marked baroreflex impairment. The impairment occurs even during symptomless ischemic episodes and is therefore not related to pain or to other nonspecific influences on the baroreflex.

[Mycosis of the paranasal sinuses: a report of 4 cases]. / Micosi dei seni paranasali: report su 4 casi.

With recent advances in medicine, fungal diseases are not only being better under stood, but are also becoming increasingly important in the management of patients with paranasal sinus disease. Fungal sinus diseases range from allergic fungal sinusitis to invasive and fulminant fungal sinusitis. Although patients often have some predisposing factor, such as local tissue hypoxia or massive fungal ++exposure, most patients are not immuno-compromised. Invasive fungal sinusitis may be treated with the traditional Caldwell-Luc surgical technique or with newer endoscopic procedures. Fulminant fungal sinusitis generally occurs in immuno-suppressed patients and requires aggressive surgical excision and debridement as well as systemic chemotherapy, usually amphotericin B. In this article we review fungal diseases of the paranasal sinuses and present four cases of paranasal fungal sinusitis.

Coronary response to diving in subjects with mild and severe left coronary artery disease.

The cold pressor test (CPT) is commonly used to determine the vasospastic origin of angina and to investigate the factors modulating coronary vasomotor tone. However, coronary vasoconstriction associated with this manoeuvre is often limited, particularly in patients with mild coronary atherosclerosis. To identify stimuli that can more powerfully constrict the coronary arteries we compared the effects on coronary blood flow (thermodilution) and vascular resistance (mean aortic pressure divided by coronary blood flow) of CPT (2 min) and diving (D, 45 s) in subjects with angiographically documented mild (n = 11) or severe (n = 11) left anterior descending coronary artery stenosis. In subjects with severe coronary artery stenosis the rate-pressure product increased to a similar extent with CPT and D. The latter stimulus, however, caused a more marked fall in coronary blood flow and a much more pronounced increase in coronary resistance as compared to CPT (+44 +/- 3.1% vs +19 +/- 1.6%, P less than 0.01). In the face of a similar increase in rate-pressure product, D caused a significant increase in coronary vascular resistance also in patients with mild coronary artery stenosis (less than or equal to 50%) in which CPT failed to induce any coronary vasoconstriction (+16 +/- 1.8% vs +0.3 +/- 1.3%, P less than 0.01). Thus, diving is a much more powerful coronary vasoconstrictor stimulus than CPT. It can thus replace CPT when an increase in coronary resistance is needed for diagnostic purposes or for investigating abnormalities in coronary vascular regulation.