Prognostic impact of positive microscopic margins (R1 resection) in patients with GIST (gastrointestinal stromal tumours): Results of a multicenter European study.

BACKGROUND: Although several prognostic factors in GIST have been well studied such as tumour size, mitotic rate, or localization, the influence of microscopic margins or R1 resection remains controversial. The aim of this study was to evaluate the influence of R1 resection on the prognosis of GIST in a large multicentre retrospective series of patients. METHODS: From 2001 to 2013, 1413 patients who underwent surgery for any site of GIST were identified from 61 European centers. 1098 patients were included, excluding synchronous metastases, concurrent malignancies, R2 resection or GIST recurrence. Tumour rupture (TR) was reclassified according to the Oslo sarcoma classification. Cox proportional hazards ratio and Kaplan-Meier survival estimates were used to analyse 5-year recurrence-free survival (RFS). RESULTS: Of 1098 patients, 38 (3%) underwent R1 resection with a risk of TR of 11%. The 5-year RFS was 89.6% with a median follow-up of 81 months [range: 31.2-152 months]. On univariate analysis, lower RFS was significantly associated with R1 resection [HR = 2.13; p = 0.04], high risk score according to the modified NIH classification, administration of adjuvant therapy [HR = 2.24; p < 0.001] and intraoperative complications [HR = 2.82; p < 0.001]. Only intraoperative complications [HR = 1.79; p = 0.02] and high risk according to the modified NIH classification including the updated definition of TR [HR = 3.43; p = 0.04] remained significant on multivariate analysis. CONCLUSION: This study shows that positive microscopic margins are not an independent predictive factor for RFS in GIST when taking into account the up-dated classification of TR. R1 resection may be considered a reasonable alternative to avoid major functional sequelae and should not lead to reoperation.

Phase II study of cabazitaxel as second-third line treatment in patients with metastatic adrenocortical carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a poor prognosis. No efficacious treatment options are currently available for patients with advanced metastatic disease with disease progression to standard etoposide, doxorubicin, cisplatin and mitotane (EDP-M) therapy. We assessed the activity and tolerability of cabazitaxel as a second/third-line approach in metastatic ACC. PATIENTS AND METHODS: Patients included in this single-center, phase II study (ClinicalTrials.gov identifier NCT03257891) had disease progression to a cisplatin-containing regimen (such as EDP) plus mitotane, plus/minus a further chemotherapy line. Cabazitaxel was administered intravenously at 25 mg/m2 on day 1 of a 21-day cycle, for a maximum of six cycles. The primary endpoint was a disease control rate after 4 months. RESULTS: From March 2018 to September 2019, 25 eligible patients were enrolled. A disease control rate after 4 months was obtained in six patients (24%). No patients attained a disease response according to RECIST 1.1, 9 patients (36%) had stable disease and 16 patients (64%) progressive disease. Median progression-free survival and overall survival were 1.5 months (range 0.3-7 months) and 6 months (range 1-22.2 months), respectively. Cabazitaxel therapy was well tolerated and only three (12%) patients developed grade 3 toxicity which were nausea in one patient (4%) and anemia in two patients (8%). CONCLUSIONS: Cabazitaxel has a manageable toxicity profile but is poorly active as second/third-line treatment in advanced ACC patients. These results do not support further evaluation of cabazitaxel in this setting.

Factors influencing survival after hepatectomy for metastases from gastric cancer.

PURPOSE: To investigate clinical factors influencing the prognosis of patients submitted to hepatectomy for metastases from gastric cancer and their clinical role. METHODS: Retrospective multi-center chart review. We evaluated how survival from surgery was influenced by patient-related, gastric cancer-related, metastasis-related and treatment-related candidate prognostic factors. RESULTS: One hundred and five patients submitted to hepatectomy for metastases from gastric cancer, in the synchronous and metachronous setting of the disease. In 89 cases a R0 resection was achieved, while in 16 a R+ hepatic resection was performed. Adjuvant chemotherapy was administered to 29 patients. Surgical mortality was 1% and morbidity 13.3%. Median disease-free survival was 10 months, median overall survival was 14.6 months. Overall 1, 3, and 5-year survival rates were 58.2%, 20.3%, and 13.1%, respectively. Survival was influenced independently by the factor T of the gastric primary (p < 0.001), by the curativity of surgical procedure (p = 0.001), by the timing of hepatic involvement (p < 0.001) and by adjuvant chemotherapy (p < 0.001). T4 gastric cancer, R+ resection, synchronous metastases, and abstention from adjuvant chemotherapy were associated with a worse prognosis; T4 gastric cancer and R+ resections displayed a cumulative effect (p < 0.001). CONCLUSIONS: Our data show that R0 resection must be pursued whenever possible. Furthermore, in the synchronous setting, the coexistence of T4 gastric primaries and R+ resections suggests prudence and probably abstention from hepatectomy. Finally, a multimodal treatment associating surgery and chemotherapy offers the best survival results.

Lymphatic endothelial cells derived from metastatic and non-metastatic lymph nodes of human colorectal cancer reveal phenotypic differences in culture.

Colorectal cancer is one of the most frequent causes of death in Western countries. Most patients develop metastasis traveling through the lymphatic system, and regional lymph node metastasis is considered a marker for dissemination, increased stage, and worse prognosis. Despite rapid advances in tumor biology, the processes that underpin lymphatic invasion and lymph node metastasis remain poorly understood. The aim of this study was to establish an easy protocol for isolation of pure tumor lymphatic endothelial cells derived from lymph nodes to study differences compared with normal endothelial cells of uninvolved tissue from the same patients. Cells were isolated with very high purity via magnetic cell sorting and express the specific lymphatic markers Prox-1 and Lyve-1. They show differences in expression of adhesion molecules, chemokines, and growth factor secretion, and capability to form capillaries when seeded on basal membrane, thereby, revealing important differences between the two cell type. These cultures may provide a promising platform for the comparative analysis of both cell types at the molecular and biological level and to optimize treatment strategies.

Metachronous hepatic metastases from gastric carcinoma: a multicentric survey.

BACKGROUND: The treatment of hepatic metastases from gastric cancer is controversial, due to biologic aggressiveness of the disease. OBJECTIVE: To survey the clinical approach to the subset of patients presenting with metachronous hepatic metastases as sole site of recurrence after curative resection of gastric cancer, focusing on the results achieved by different therapies and to investigate the prognostic factors of major clinical relevance. METHODS: Retrospective multi-center chart review evaluating 73 patients, previously submitted to D >or= 2 gastrectomy for gastric cancer, who developed exclusive hepatic recurrence. Prognostic factors related to the patient, to the gastric malignancy and its treatment, and to the metastatic disease and its therapy were evaluated. RESULTS: Forty-five patients received supportive care, 17 were submitted to chemotherapy, and 11 to hepatic resection. Survival was independently influenced by the variables T (p=0.019), N (p=0.05) and G (p=0.018) of the gastric primary and by the therapeutic approach to the metastases (p<0.005). In particular, T4 gastric cancer, presence of lymph-node metastases and G3 tumor displayed a negative prognostic value. Therapeutic approach to the metastases was the principal prognostic variable: 1, 2, and 3 years survival rates were 22.2%, 4.4% and 2.2%, respectively, for patients without specific treatment; 44.9%, 12.8% and 6.4% after chemotherapy (p=0.08) and 80.8%, 30.3% and 20.2% after surgical resection (p<0.001). CONCLUSIONS: Our data suggest some clinical criteria that may facilitate selection of therapy for patients with hepatic recurrence after primary gastric cancer resection. The best survival rates are associated with surgical treatment, which should be chosen whenever possible.

Traumatic lesions of the diaphragm. Our experience in 33 cases and review of the literature.

We reviewed 33 consecutive patients with diaphragmatic injuries. Twenty-nine were admitted in emergency conditions after blunt (22 patients) or penetrating injury, presenting shock, dyspnoea, coma or acute abdomen in 21 cases; major associated lesions were found in 23 patients. Four patients presented acute complications of visceral herniation 2, 4, 84 and 216 months after the trauma. The diagnosis was preoperative in 23 cases, intraoperative in 9; in one case it was missed at laparotomy, becoming evident the day after. The sensibility of preoperative chest x-ray and CT was 86% and 100% in presence of visceral herniation, 14% and 0% in absence of visceral hernia. The diaphragmatic repair was always obtained by direct suture, following 20 haemostatic procedures (liver, spleen, mesenterium) and two bowel resections. The mortality rate was 24.4%; the morbidity rate was 48%. Traumatic lesions of the diaphragm are generally expression of particularly severe trauma whose outcome is mainly influenced by the associated lesions. They are also correlated to specific morbidity and mortality, so the surgical exploration is mandatory whenever this injury is suspected, considering that the preoperative diagnosis relies on visceral dislocation. Associated lesions influence the surgical strategy but a direct suture is usually effective in preventing specific complications.

[Results of elective open surgery for juxtarenal aortic aneurysms]. / I risultati del trattamento elettivo in open surgery degli aneurismi juxtarenali dell'aorta.

Review of the most significant surveys (data base: Pub Med on September 2003) of elective open surgery for Juxtarenal aneurysms and personal results of 106 cases (9.3% of AAA consecutively operated in the last 11 yrs.) are reported. Mortality and morbidity are discussed related to: technique of aortic cross-clamping; protective measures on splanchnic and renal perfusion; risks from previous CAD and chronic renal failure. Over all, the main predictive factor is the accuracy of the selected technique, without any difference among different approaches, and the same results of infrarenal aneurysms can be obtained.

Retrospective histologic comparison of Helicobacter pylori infection in gastric carcinoma, ulcerous disease and non-ulcerous dyspepsia.

Although a number of epidemiological, biological and clinical studies have been published, the effective role of Helicobacter pylori infection in gastric carcinogenesis remains unclear. In the present work we retrospectively compared Helicobacter infection rate, by means of histologic examination of gastric bioptic samples, in 70 patients affected by gastric carcinoma, 70 with ulcerous disease and 70 with non-ulcerous dyspepsia. The analysis was carried out by a single pathologist. The differences between the 3 groups were not statistically significant. From our present and previously reported data, the Helicobacter infection cannot be considered per se a significant risk factor for malignant gastric disease and further studies are needed to evaluate the role of Helicobacter infection in the development of some preneoplastic conditions such as chronic atrophic gastritis and intestinal metaplasia.

Combined surgical approach for carotid and coronary stenosis. Sixty-four patients and review of literature.

BACKGROUND: The proper role of combined carotid endarterectomy (CEA) and coronary bypass (CABG) is still controversial. We contribute to the discussion through the critical evaluation of 64 consecutive patients, whose data have been collected in a prospective way. METHODS: Between 1990 and 1999, 64 patients presenting a critical coronary disease (unemendable by PTA) associated with severe carotid stenosis (= or >70% if symptomatic, = or >80% if asymptomatic), underwent combined CEA-CABG. Cardiological symptoms were evident in 90.6% of cases. Thirty-five patients (54.7%) had a three-vessel coronaropathy, 18 (28.1%) a two-vessel disease and 11 (17.2%) severe stenosis of the common trunk; furthermore 7 patients (10.9%) had a low ejection fraction (<50%). A positive neurologic history was present in 22 (44%) patients. Thirty-four patients (55%) had a carotid stenosis >90%; a significant disease of the contralateral carotid axis was observed in 53% of cases: stenosis >50% in 30 patients and thrombosis in 4. CEA was performed with somato-sensorial evoked potential monitoring. RESULTS: The hospital mortality rate was 6.2% (4 patients). The cause of death was cardiac in 2 cases (1 early bypass thrombosis and 1 irreversible coronary spasm) and related to a multiorgan failure in 2. The neurologic morbidity rate was 0%. CONCLUSIONS: Our data highlight that in these high-risk patients the combined approach dramatically reduces the stroke risk although the mortality rate is still higher than that observed after CEA or CABG.

Is there an association between Helicobacter pylori cytotoxin Cag A seropositivity and risk for gastric cancer?

BACKGROUND: Since discovered in 1990, Cag A, a protein expressed by specific strains of Helicobacter pylori, was thought able to explain why only a few Helicobacter infected patients develop peptic diseases and gastric cancer. However, clinical trials provide discordant results. MATERIALS AND METHODS: In this study we evaluate Helicobacter pylori and Cag A seropositivity in 35 cancer affected patients, in 36 gastritis affected patients and in 40 healthy blood donors by means of two commercially available fluorescence enzyme-immunoessay (ELISA). RESULTS: Odds ratios determination strongly suggests that Cag A bearer Helicobacter strains play a pathogenetic role in gastric diseases (OR 4.23, 95% CI 3.22-5.24 for cancer versus healthy volunteers, OR 3.2, 95% CI 2.19-4.21 for gastritis versus asymptomatic patients), but is unable to demonstrate a direct carcinogenic activity (cancer-gastritis difference is not significant: OR 1.32, 95% CI 0.39-1.25). CONCLUSIONS: Cag A seropositivity can be considered a risk factor for peptic disease, and only indirectly for gastric carcinoma. The paper also discuss some sampling, laboratory and statistical bias that can explain a wide eterogenity of the results reported in the literature.

Endothelial dysfunction in small resistance arteries of patients with non-insulin-dependent diabetes mellitus.

OBJECTIVE: Arterial hypertension is frequently associated with the presence of endothelial dysfunction in human subcutaneous small resistance arteries, as evaluated by responses to acetylcholine or bradykinin; however it is not known whether patients with diabetes mellitus show similar alterations. Therefore, we have investigated endothelial function in subcutaneous arteries of normotensive subjects (NT), of patients with essential hypertension (EH), of patients with non-insulin-dependent diabetes mellitus (NIDDM), as well as of patients with both essential hypertension and non-insulin-dependent diabetes mellitus (NIDDM+EH). PATIENTS AND METHODS: All subjects were submitted to a biopsy of the subcutaneous fat Small arteries were dissected and mounted on a micromyograph. The media to lumen ratio (M/L) was calculated. A concentration-response curve to acetylcholine, to bradykinin as well as to the endothelium-independent vasodilator sodium nitroprusside were performed. We also evaluated the contractile response to endothelin-1. Intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) plasma levels were also measured. RESULTS: The vasodilatation to acetylcholine and bradykinin (but not to sodium nitroprusside) was significantly and similarly reduced in EH, in NIDDM, and in NIDDM+EH compared with NT. The contractile response to endothelin-1 was similarly reduced in EH, in NIDDM and in NIDDM+EH. Plasma ICAM-1 and VCAM-1 concentrations were higher in EH, NIDDM and NIDDM+EH than in NT. CONCLUSIONS: An evident endothelial dysfunction was detected in patients with NIDDM, and the simultaneous presence of EH did not seem to exert an additive effect. The contractile responses to endothelin-1 were reduced possibly as a consequence of ET(A) receptor down-regulation.

Right subclavian artery aneurysms of fibrodysplastic origin: two case reports and review of literature.

Right subclavian aneurysms involving the intrathoracic portion of the artery are rare and those of fibrodysplastic origin are mentioned in literature only as sporadic cases. In this article, we present two cases of this uncommon pathologic condition and discuss problems concerning diagnostic tools and technical choices. The two patients underwent a successful vascular graft substitution; an echo-Doppler scan revealed that they had no disease 1 and 2 years after the operation.

Suprarenal aortic cross-clamping in elective abdominal aortic aneurysm surgery.

INTRODUCTION: this retrospective study was undertaken to evaluate whether suprarenal aortic cross-clamping increased the perioperative mortality and morbidity as compared to infrarenal clamping, in order to create the rationale for a more extensive application of this apparently more traumatic manoeuvre. MATERIALS AND METHODS: in a series of 734 elective aortic substitutions for abdominal aneurysm (AA), performed consecutively from January 1992 to June 1999, aortic cross-clamping was performed at a suprarenal level in 56 juxtarenal aneurysms, i.e. aneurysms extending to the lower edge of the renal arteries (8%, Group 1), and at an infrarenal level in 634 subrenal aneurysms (92%, Group 2). When analysing preoperative data, the diameter of aneurysms was larger in Group 1 than in Group 2 (p<0. 005). No significant differences were found between the two groups as regards age, sex, postinfarction cardiomyopathy, chronic obstructive pulmonary disease, chronic renal insufficiency and ASA classification of operative risks. RESULTS: the average time of renal exclusion in the juxtarenal aneurysms was 20 min (range 12-35 min). There is no difference between the two groups as regards the time of aortic clamping (mean 50 vs. 60 min) or the need for homologous blood transfusion (7% vs. 11% of patients). Perioperative (30 days) mortality did not differ: 3.6% vs. 1.9% (n.s.); nor did the incidence of acute myocardial infarction (3.6% vs. 2.3%). Renal function deteriorated in 8 (14%) vs. 0 (0%) (p<0.001) and 1 patient (2%) required permanent dialysis, as compared to 0% in Group 2. The incidence of ischaemic colitis was also significantly higher in Group 1 (7%) than in Group 2 (2%, p<0.01). CONCLUSION: this data shows that suprarenal clamping, which is necessary for the radical treatment of juxtarenal aortic aneurysms, can be performed with a low risk.

[Video laparoscopic cholecystectomy in a female patient with cholelithiasis in Steinert's myotonic dystrophy]. / Colecistectomia videolaparoscopica in paziente affetta da colelitiasi in distrofia miotonica di Steinert.

Steinert's disease (SD) is a rare (3-5/100000) myotonic myopathy responsible for chronic restrictive respiratory insufficiency and dilatative myocardiopathy. The authors report the case of a 52-years-old female patient with SD who underwent laparoscopic cholecystectomy for cholelithiasis. Postoperative course was uneventful and the patient was discharged after 4 days. Laparoscopic surgery was effective and safe in the treatment of this pathology.

Complete in vitro prosthesis endothelialization induced by artificial extracellular matrix.

This report presents our research on the conditions necessary to substain optimal in vitro prosthetic endothelialization using human endothelium cultures. Human vein endothelial cells were seeded at a concentration of 3 x 10(5)/cm2 in a gelatinized Dacron patch graft coated with a commercial collagen film, using a solution of fibrin glue. Endothelium adhesion, proliferation, and survival were measured by [3H]thymidine incorporation, after 7 days of incubation. Finally, the morphology of prosthetic endothelialization was analyzed by scanning electron microscopy. We observed that the Dacron patch grafts coated with collagen film were able to promote endothelialization better than the prostheses coated with highly concentrated collagen solution or gelatin. We therefore concluded that the collagen film that supports endothelial cell adhesion and proliferation uniformly covers the entire synthetic endoluminal surface of the Dacron graft, thus preventing endothelial cell alterations induced by direct contact with the synthetic prosthetic surface.

Early and long-term prognostic factors after liver resection for HCC.

The Authors discuss the principal early and long term predictive factors after liver resection in patients with hepatocellular carcinoma (HCC). The Authors report (131 cases) early mortality as 7.6%, entirely confined in the group, numerically prevalent and affected by cirrhosis. None of the 50 patients with chronic hepatitis (29 cases) or normal liver (21 cases) died after hepatic resection. Mortality is higher in Child B patients (20.7%) and in cases in which a massive haemotransfusion was given (p < 0.05), apart from the width of resection and from the number of hepatic resections. None of 41 cirrhotic Child A patients undergoing a limited hepatic resection (< or = 1 segment) died during the perioperative period. In the group of patients which survived to the resection, global survival at 5 years was 45%. The most important prognostic factor is local recurrence while cirrhosis and the degree of liver failure are not statistically significant. No feature can identify a subgroup of patients with a higher risk of recurrence, which is observed in 52% of patients with a follow up observation after more than 1 year. Among the 29 patients alive after more than 4 years from liver resection, only 11 didn't have local recurrence. The others were treated with iterative hepatic resections or with radiological techniques. In conclusion, the present experience suggests that, in selected cases, hepatic resection could be a low risk therapy (in cirrhotic patients as well). The long term results could improve with an aggressive attitude towards recurrence.

D2 lymphectomy in the treatment of gastric cancer: a retrospective view on our experience (1990-1997).

From 1990 to 1997 we observed, in our department, 267 patients affected by gastric cancer. In the first four years of our experience (1990-93) we resected 87 patients out of 136 gastric cancers observed (63.9%): 56 pts. (64.4%) were classified as ASA I-II, 21 (24.1%) as ASA III, 10 (11.5%) as ASA IV. In 2 cases (2.3%), operated in emergency, a DO-1 lymphectomy was performed, with a mean of 4 nodes resected; 67 pts. (77.0%) had a D2, with a mean of 36.5 nodes resected; in 18 pts. (20.7%) we performed a D3, with a mean of 64.3 nodes resected. Post-operative technical complications were 13 (14.9%). We observed 5 post-operatory deaths (5.7%), 3 due to technical complications. Absolutely and relatively curative resections have been 62 (71.3%). In the second period (1994-97) we resected 89/131 patients (67.9%): in this group 50 pts. (56.2%) were classified as ASA I-II, 24 (26.9%) as ASA III, 15 (16.9%) as ASA IV. With the exception of 3 patients (3.4%) who were operated in emergency (D0-1 procedures, with a mean number of 2.3 nodes resected) we adopted D2 lymphadenectomy plus hepatic peduncle as the procedure of choice, performed in 86 pts. (96.6%), with a mean of 34.1 nodes resected. Post-operative technical complications were 5 (5.6%). We observed 5 post-operatory deaths (5.6%), 1 due to technical problems. Absolutely and relatively curative resections have been 76 (85.4%). Morbidity and mortality due to technical complications in the second period are lower than observed in the first period, without any difference in the curability rate. D2 lymphectomy seems to be an effective procedure, safe even in high anesthesiological risk patients. Increasing experience and standardization of the technique reduced risk of surgical complications and mortality.

[Splanchnic aneurysms: 10 treated cases and review of the literature]. / Gli aneurismi splancnici: 10 casi trattati e revisione della letteratura.

The splanchnic aneurysms, which are complicated by rupture in 25% of cases with a mortality of 25-70%, are usually a surprise during diagnostic tests for other abdominal pathologies or emergency laparotomies. 10 cases treated (8 in elective and 2 in emergency surgery) are presented here: the aneurysm was in celiac trunk (1 patient), common hepatic artery (1 pt.), hepatic artery (2 pts.), gastroduodenal artery (1 pt.), superior mesenteric artery (1 pt.), inferior pancreaticoduodenal artery (1 pt.), right colic artery (1 pt.) and inferior mesenteric artery (1 pt.). There were 1 case of Marfan syndrome and 9 cases of atherosclerosis, 4 of which arteries presenting hyperdynamic flow consequent to occlusions of the superior mesenteric artery and/or the celiac trunk. The 2 cases operated on for hemoperitoneum underwent aneurysmectomy and ligation of the inflow vessels (1 death from pulmonary embolism on 5th postoperative day), whereas the 8 cases electively treated (with no deaths and I case of transient diarrhoeal syndrome) underwent 4 aneurysmal resections with end-to-end arterial reconstruction, 3 PTFE-graft substitutions and 1 autologous saphenous vein substitution. At follow-up (12-74 months; mean 30.6) all the reconstructions resulted successful. These data confirm the consistent indications of the recent Literature suggesting the indication to the surgical treatment of the incidental aneurysms in the splanchnic area.

[Carotid endarterectomy in patients with neurological non-side related (NSRS) symptoms]. / La endoarterectomia della carotide in pazienti con sintomi neurologici non lateralizzati (NSRS).

Out of 970 carotid endarterectomies (CE) performed for high-grade (> 80%) stenosis of the internal carotid artery (ICA) until 1995, 147 patients with neurological non side-related symptoms (NSRS) and without any cardiac, ocular or vestibular significant pathology have been evaluated, analyzing the medium and long-term functional results (mean follow-up 37.6 months) related to the morphological status of the ICA contralateral and the vertebral arteries. NSRS disappeared in 126 pts (85.71%): contralateral ICA was non-stenotic in 32 cases (25.39%), stenotic < 75% in 68 cases (53.96%), stenotic > 75% in 7 cases (5.55%) and occluded in 19 cases (15.09%); vertebral arteries were pathological in only 6 cases (4.75%), among which 4 were on the same side and 2 on the opposite side of CE. NSRS persisted in 20 pts (13.6%): contralateral ICA was non-stenotic in 5 cases (25%), with a stenosis < 75% in 11 cases (55%) and with stenosis > 75% in 4 cases (20%); vertebral obliterative lesions were 3 (15.78%), among which 1 on the same and 2 on the opposite side of CE. No one statistical comparison among the groups of cases obtained on the ground of the status of ICA and vertebral arteries were significant (p always > 0.05 at chi-square analysis). Authors' data confirmed that high grade stenoses of ICA can cause NSRS and that CE--always performed at the aim to prevent major neurological attacks--can relieve also these functional disorders in the most of cases, independently from the status of the contralateral ICA and the vertebral arteries.