Tumor Manipulation Research Articles

Alterations in plasma neuropeptide Y immunoreactivity and catecholamine levels during surgical removal of pheochromocytoma.

Neuropeptide Y, an abundant neurohormone present with catecholamines in the adrenal medulla, is a potent non-adrenergic vasoconstrictor and a vascular growth factor. To determine the mechanism of the release from, and possible role of neuropeptide Y in, pheochromocytomas, compared with those of catecholamines. Plasma and tumour levels of neuropeptide Y-immunoreactivity (by, radioimmunoassay) and of noradrenaline and adrenaline (by a radioenzymatic method) in 29 patients (19 women and 10 men, aged 22-68 years) were measured during surgical removal of the tumour, during alpha-adrenergic and beta-adrenergic blockade. Arterial systemic blood samples were withdrawn before the ligation of the vessels supplying the tumour, during its surgical manipulations and after its removal, while haemodynamics was monitored. Plasma neuropeptide Y levels in 17 patients (58.6%, group I) significantly increased during manipulations of the pheochromocytoma and returned completely to normal after its removal. This response was independent of the plasma neuropeptide Y immunoreactivity manipulation and was correlated to increases in plasma noradrenaline (r = 0.638, P < 0.02) but not adrenaline levels. Manipulation-induced increases in plasma neuropeptide Y-immunoreactivity were associated with greater neuropeptide Y content in tumours (r = 0.508, P < 0.05) but neither plasma nor tumour levels of neuropeptide Y immunoreactivity were correlated to tumour mass. Plasma levels of neuropeptide Y immunoreactivity in the remaining 12 patients (41.4%, group II) remained unchanged throughout the experimental period, while levels of circulating catecholamine rose. In all, in spite of our attempt at complete adrenergic blockade, tumour manipulation elevated arterial blood pressure and these changes were significantly correlated to increases in levels of catecholamines in patients in both groups but also to plasma neuropeptide Y immunoreactivity in patients in group I. Pheochromocytomas exhibit different patterns of secretion. For about half of the patients either the secretion of neuropeptide Y is uncoupled from that of catecholamines or its secretion could be obscured by an increase in degradation of neuropeptide Y to inactive fragments undetectable by radioimmunoassay.

Port Site Recurrences after Laparoscopic Surgery

Port site metastasis has been a surprising event after laparoscopic procedures in cancer patients. No clear data exist about this phenomenon. The aim of this study is to summarize current epidemiologic knowledge about the risk of this complication. A review of all case reports about port site recurrences was undertaken. To date, 164 cases of port site metastases after videoscopic procedures have been reported in 90 papers. We found 108 cases of implantation after laparoscopy for digestive tumors, 23 after thoracoscopy, 29 after gynecological and 4 after urological laparoscopy. Analysis of the current literature confirms that laparoscopy is associated with abdominal cell mobilization to the trocars and instruments. Also low-staged and highly differentiated tumors have been reported to cause post-laparoscopy tumor seeding. The temporary data of the CAE registry ‘port site metastases’ (Workgroup for Surgical Endoscopy of the German Society of Surgery) are also reported. The analysis of 80 histologically confirmed cases of port site recurrence shows a particular frequency after laparoscopic cholecystectomy for unsuspected gallbladder cancer (n = 59). Postoperative specimen examination revealed a T1 carcinoma in 9 cases (15%), T2 carcinoma in 33 (21%), T3 in 3 (5%) and T4 in 1 case (1.7%). The mean time to clinical tumor relapse was 6 months. Similar patterns were found in a lower number of port site metastases after laparoscopy for colon cancer (n = 2) and for other cancers (n = 9).Clinical evidence that laparoscopy with CO₂ pneumoperitoneum can enhance tumor dissemination is given. Port site metastases seem to be secondary to multiple factors including the gas used, local trauma, tumor manipulation, biologic properties of the tumor, and individual surgical skills.

Anesthetic Implications for Surgical Patients with Endocrine Tumors

The preoperative evaluation and safe anesthetic treatment of patients with endocrine gland tumors mandate an understanding of the physiologic dysfunctions attributable to these tumors. Some patients will exhibit various signs and symptoms characteristic of the MEN syndromes. In the patient with acromegaly, a fiberoptic-guided intubation of the trachea to secure the airway before induction of general anesthesia must be anticipated. Anesthetic treatment of the patient with hyperadrenocorticism requires knowledge of the physiologic effect of excess cortisol. In the patient with severe hyperparathyroidism, we attempt to correct the markedly elevated plasma calcium levels and maintain adequate hydration and urine output perioperatively. Following thyroidectomy for MCT, 2 potential problems of concern are upper airway obstruction and aspiration resulting from injury (unilateral or bilateral) to the recurrent laryngeal nerve and the superior laryngeal nerve, respectively. The major focus during excision of an insulinoma is prevention of wide swings in blood glucose concentrations. In the gastrinoma patient, the anesthesiologist not only must correct any intravascular fluid volume deficit or electrolyte imbalance but must also consider the patient to have a full stomach at the time of anesthetic induction. Correction of hypokalemia and control of hypertension may be required in the preoperative preparation of the patient with an adrenal cortex tumor. Preoperative alpha-adrenergic blockade must be initiated in the patient with a pheochromocytoma to prevent dangerous elevations in blood pressure during anesthesia and surgery for the tumor's removal. Vasodilators with rapid onset and short duration are used to treat intraoperative hypertension. After ligation of the tumor's blood supply, falls in blood pressure may require treatment with fluids and vasopressors. Carcinoid syndrome patients should be treated with somatostatin to prevent stimuli such as anxiety, abdominal scrubbing, or tumor manipulation from precipitating severe hypotension, hypertension, bronchospasm, or tachycardia. In both pheochromocytoma and carcinoid patients, a smooth anesthetic induction and tracheal intubation plus avoidance of drugs that release histamine or activate the sympathetic nervous system may also prevent intraoperative crises.

LeFort I Orbitotomy

Numerous approaches to the orbit have been elegantly described in the literature. One area of the orbit that remains difficult to approach with standard techniques is the inferonasal apex. We describe a new surgical procedure we have termed the LeFort I orbitotomy. The technique involves creation of a LeFort I osteotomy to separate the maxilla from the zygoma and nose bilaterally. The posterior inferomedial orbital bone is then removed and the periorbita opened. This approach allows a more direct, less tangential view to this area of the orbit than does a Caldwell-Luc approach. Wider access for tumor manipulation is gained than would be possible with a transnasal endoscopic approach. An illustrative case report is presented.

Anesthesia for patients with carcinoid syndrome.

Carcinoid syndrome, although rare, can create serious problems to the anesthetist, both by the nature and variability of clinical manifestations and by the complications that can occur peroperatively. Recent research has led to a better understanding of the pathophysiology of the disease process. However, modern medicine is far from unraveling the precise nature and physiological effects of all the peptide mediators produced by these tumors. The severity of symptoms does not predict the severity of perioperative complications, so that patients with minor preoperative symptoms may have significant intraoperative complications. While urinary 5-HIAA levels provide a good indicator of disease progression, they cannot predict the degree or type of physiological response to intraoperative tumor manipulation. Indeed, urinary 5-HIAA may be normal both in the presence of a clinical diagnosis of carcinoid syndrome and in the face of a peroperative carcinoid crisis. The keys to successful anesthetic management of patients with carcinoid syndrome are good communication between endocrinologist, anesthetist, and surgeon and preoperative optimization of the patient. This includes appropriate investigation and treatment of the effects of carcinoid peptides and the prevention of their release from tumors. If possible, advice should be sought from centers with experience at managing this group of patients. Octreotide has largely replaced the use of other drugs both for symptomatic control and acute treatment of the symptoms associated with carcinoid syndrome. However, other drugs, such as aprotinin, still have a significant place in the symptomatic control and treatment of peroperative complications, as serotonin is only one of a large variety of peptides responsible for the clinical effects of this disease. Anesthetic technique should be aimed at minimizing carcinoid mediator release, in response to stress it induction of anesthesia and tracheal intubation and during tumor manipulation. It is equally important to prepare for carcinoid crisis by, for example, ordering drugs, which are otherwise uncommonly used in the theater setting, ahead of time. Cardiovascular instability, particularly hypotension, is common, so that full monitoring and vigilance is vital to predict its onset. The current surgical view of management is that, while curative resection of carcinoid tumors less than 2 cm in diameter with no evidence of invasion or metastatic spread is appropriate, patients with disseminated disease should be medically managed unless symptom control is poor. The exceptions to this are those patients with early and correctable carcinoid cardiac disease and those who require palliative procedures such as defunctioning obstructed bowel. Survival rates in patients following excision of gastric and appendical carcinoid tumors approach those of the general population as a whole and the chance of metastasis is extremely low. Only two series have been published in the anesthetic literature on anesthesia for patients with carcinoid syndrome, although there are many single-case reports. Despite the rarity of this syndrome, further formal studies into the anesthetic management of this condition should be encouraged.

Gasless laparoscopy may reduce the risk of port-site metastases following laparascopic tumor surgery.

To compare the incidence of port-site metastases in an experimental tumor model following tumor manipulation during laparoscopy aided by conventional insufflation with laparoscopy using a gasless technique. An experimental model applied in a research laboratory. Malignant tumors were implanted in the abdominal wall of 24 rats. Twelve rats underwent tumor laceration at laparoscopy with carbon dioxide insufflation, and 12 rats underwent the same procedure during gasless laparoscopy achieved by abdominal wall suspension. Rats were killed 1 week later and were examined for evidence of tumor metastases. The surgical wounds were examined microscopically by a histopathologist who was unaware of the operative technique used and the site of origin of the specimens. Histologically confirmed tumor metastasis to laparoscopic port wounds. Growth of the primary tumor was equal in both groups. Wound metastases were less likely in the gasless laparoscopy group (3 of 12 vs 10 of 12; P = .01, Fisher exact test). The use of laparoscopy without gas insufflation may reduce the risk of wound metastasis following laparoscopic surgery for cancer.

Molecular detection of circulating solid carcinoma cells in the peripheral blood: the concept of early systemic disease.

Detection of the mRNA of selected genes by reverse transcriptase-polymerase chain reaction (RT-PCR) is a sensitive and powerful tool for detecting cancer cells in bone-marrow or peripheral-blood samples. In this study, we determined whether carcinoembryonic antigen (CEA) mRNA is detectable in the peripheral blood of patients with gastrointestinal or breast cancer. In addition, we studied selected patients undergoing surgical procedures to assess whether tumor manipulation during operation enhances cancer-cell dissemination. Peripheral blood from 55 patients with gastrointestinal or breast cancer and from 22 control cases was analysed for CEA mRNA using RT-PCR. For 15 selected cases undergoing curative surgery for cancer, samples were also obtained during and after surgery. The lower limit of detection was 1 to 10 CEA-positive cells diluted among 1 x 10(7) blood mononuclear cells. The test was positive for 20 of the 55 patients with cancer (36%). None of the 22 control samples were positive. An increase in positivity was observed with increasing stage of disease; however, even some patients with early-stage cancer showed positive results. In addition, CEA mRNA could be detected in the peripheral blood during operation in 3 of 13 patients whose pre-operative CEA mRNA in the peripheral blood had been negative. These findings suggest that, (1) RT-PCR amplification of CEA mRNA is an efficient means of detecting circulating solid cancer cells in the peripheral blood, although long-term clinical studies should be done to evaluate its usefulness; (2) not only breast cancer but also gastrointestinal cancer might be better regarded as a systemic disease even in early stages of carcinoma; and (3) surgical manipulation can provoke cancer-cell dissemination.

Factors Influencing Organ Placement Efforts in Donors with Brain Tumors

A 3-year retrospective review of brain tumor cases was performed to determine factors that influence organ procurement in light of the increase in references in transplant literature to the hazards of transplanting organs from donors with brain tumors. A 3-year review of cases in which organ procurement efforts occurred were evaluated. Of 314 cases resulting from this review, organ procurement efforts yielded 10 patients with a diagnosis of brain tumor. Of those 10 cases, seven progressed to organ donation, with at least one organ per patient recovered. Manipulation of brain tumors or manipulation along with tissue diagnosis does not seem to hinder procurement of organs. Without tissue diagnosis, the ability of the organ procurement organization to place organs decreases significantly.

Factors influencing organ placement efforts in donors with brain tumors.

A 3-year retrospective review of brain tumor cases was performed to determine factors that influence organ procurement in light of the increase in references in transplant literature to the hazards of transplanting organs from donors with brain tumors. A 3-year review of cases in which organ procurement efforts occurred were evaluated. Of 314 cases resulting from this review, organ procurement efforts yielded 10 patients with a diagnosis of brain tumor. Of those 10 cases, seven progressed to organ donation, with at least one organ per patient recovered. Manipulation of brain tumors or manipulation along with tissue diagnosis does not seem to hinder procurement of organs. Without tissue diagnosis, the ability of the organ procurement organization to place organs decreases significantly.

Port-Site Recurrence of Cancer Associated With Laparoscopic Diagnosis and Resection: The European Experience

Port-site recurrences of cancer have drawn attention to the potential risks of laparoscopy for the diagnosis and treatment of digestive cancers. The first observations concerned unsuspected gallbladder cancers shown by laparoscopic cholecystectomy for lithiasis. Seventeen cases in patients with advanced or early colon cancer followed. It eventually became clear that all cancers could be the origin of such recurrences, which present as apparently isolated nodules embedded in the wall. These parietal recurrences were well known in open surgery, having been reported for most cancers, but they drew little attention because they usually occur in the context of carcinosis. It must be remembered that digestive cancers in general have a high potential for dissemination and that nearly 30% of patients have micrometastases in the bloodstream, the lymph nodes, the peritoneum, or even the bone marrow. The mechanism of tumor implantation is analogous to development of an inflammatory reaction. Under these conditions, laparoscopic surgery is susceptible to cause neoplastic dissemination for a number of mechanical reasons: CO2 insufflation, tumor manipulation, failure to isolate the tumor, forceful extraction of the surgical specimen, and exsufflation. Multiinstitutional trials of well-defined laparoscopic protocols based on the same oncologic principles as in open surgery should reduce the frequency of tumor cell dissemination and the incidence of port-site recurrences.

Port-Site Recurrence of Cancer Associated With Laparoscopic Diagnosis and Resection: The European Experience.

Port-site recurrences of cancer have drawn attention to the potential risks of laparoscopy for the diagnosis and treatment of digestive cancers. The first observations concerned unsuspected gallbladder cancers shown by laparoscopic cholecystectomy for lithiasis. Seventeen cases in patients with advanced or early colon cancer followed. It eventually became clear that all cancers could be the origin of such recurrences, which present as apparently isolated nodules embedded in the wall. These parietal recurrences were well known in open surgery, having been reported for most cancers, but they drew little attention because they usually occur in the context of carcinosis. It must be remembered that digestive cancers in general have a high potential for dissemination and that nearly 30% of patients have micrometastases in the bloodstream, the lymph nodes, the peritoneum, or even the bone marrow. The mechanism of tumor implantation is analogous to development of an inflammatory reaction. Under these conditions, laparoscopic surgery is susceptible to cause neoplastic dissemination for a number of mechanical reasons: CO2 insufflation, tumor manipulation, failure to isolate the tumor, forceful extraction of the surgical specimen, and exsufflation. Multiinstitutional trials of well-defined laparoscopic protocols based on the same oncologic principles as in open surgery should reduce the frequency of tumor cell dissemination and the incidence of port-site recurrences.

Adenosine for per‐operative blood pressure control in an infant with neuroblastoma

We describe a child with a localised pelvic neuroblastoma and a hypertensive crisis during the first weeks of life due to elevated systemic norepinephrine of tumoural origin. In spite of treatment with high doses of alpha-blockers, blood pressure did not respond fully and the boy had a very unstable circulation. Surgery was performed at one month of age. Adenosine, a potent short-acting vasodilator, was used for peroperative blood pressure control to protect the patient from an uncontrolled hypertensive crisis. During tumour manipulation the child became hypertensive with systolic pressure exceeding 130 mm Hg and adenosine infusion (100 micrograms.kg-1.min-1) was started with a prompt normalisation of the blood pressure. Adenosine infusion could be discontinued after tumour removal. Norepinephrine, dopamine, homovanillic acid and vanillylmandelic acid in urine were elevated preoperatively and normalised at follow up. Plasma concentrations of norepinephrine and dopamine were elevated preoperatively. Norepinephrine increased during hypertension due to tumour manipulation. Plasma neuropeptide Y increased during tumour manipulation but still within the normal range for infants. It is concluded that adenosine can be used peroperatively in children with severe hypertension and in this case no adverse effects of adenosine were noted. Furthermore, tumour synthesis and systemic release of norepinephrine, but not neuropeptide Y, contributed to hypertension in this child with neuroblastoma.

Should We Schedule Breast Surgery Based on a Woman's Menstrual Cycle?

: The timing of surgery of breast cancer patients has been reported to impact recurrence and survival. It is well known that surgical manipulation of tumor induces micrometastasis. During the menstrual cycle, profound hormonal changes occur affecting the local environment of the breast and breast cancer. A significant amount of scientific research now suggests that estrogen may establish an environment more likely to produce micrometastasis, and an immune system less likely to manage micrometastasis. Progesterone may protect against the effects of estrogen, leading to improved disease-free and overall survival during the luteal phase. The studies examining this association are conflicting, but claim a 30% advantage for those patients undergoing surgery during progesterone predominance. A solid prospective study examining this possible benefit has yet to be performed. Until then, no harm can come from scheduling patients for surgery during the early luteal phase, and these patients may actually have a significant improved survival over those whose tumors are excised during the follicular phase.

Anesthesia for Aortic and Mitral Valve Replacement in a Patient with Carcinoid Heart Disease

Anesthesia for Aortic and Mitral Valve Replacement in a Patient with Carcinoid Heart Disease

Invited Commentary

The authors discuss a topic rarely covered in the current surgical literature: quantitation of shed tumor cells during the course of oncologic operations. The subject is reminiscent of past discussions of the "no-touch" technique or of suture line implantation during resection of colorectal cancers. The findings are relevant today as scientists seek to understand the intricate mechanisms of tumor metastasis and tumor-host interactions. Tumor cells were isolated from blood in the operative field by density gradient centrifugation in most (57 of 61) of the diverse group of patients undergoing oncologic operations in this study; this finding may be explained by tumor manipulation and the existence of malignant cells in adjacent cut vessels and lymphatics. The methods used are sophisticated, eg, the ability to detect two to four of 10 tumor cells (by their content of cytokeratin and nucleolar organizer regions) in 500 mL of blood. The authors also injected cell

Detection of intraoperative tumor cell dissemination in patients with breast cancer by use of reverse transcription and polymerase chain reaction

Animal studies have shown that malignant cells are shed into the blood stream during surgical resection of a primary tumor and that this may enhance the development of metastases. The evidence for tumor cell dissemination during surgical manipulation of human cancer is unclear. We have applied the technique of reverse transcription and polymerase chain reaction to detect circulating tumor cells in peripheral venous blood of patients with breast cancer perioperatively. To target breast-specific gene transcription complementary DNA was prepared by reverse transcription of blood messenger RNA with oligonucleotide primers unique to CK18 and DF3 antigens. Preliminary assessment of specificity showed that the DF3 antigen was more suitable than CK18 for the purpose of this study. Assessment of sensitivity showed that as few as 10 tumor cells per 5 ml blood could be identified by this method. Peripheral blood samples were obtained by venepuncture from patients before, during, and 24 hours after breast surgery (nine malignant and three benign). In the group of patients with malignant disease, tumor cells were detected in one patient before operation and four patients during operation. No tumor cells were detected in the postoperative samples nor in any of the samples of patients with benign disease. These findings suggest that tumor manipulation during operation encourages tumor cell dissemination.

Somatostatin and vasoactive intestinal peptide (VIP) in neuroblastoma and ganglioneuroma: chromatographic characterisation and release during surgery.

Neuroblastomas and ganglioneuromas frequently produce somatostatin (SOM) and vasoactive intestinal peptide (VIP), and elevated concentrations in tumour tissue are associated with favourable outcome. Both somatostatin and VIP have been shown to have an autocrine effect on tumour growth and differentiation in vitro, and VIP may cause clinical symptoms when released systemically. Using gel-permeation chromatography and specific radioimmunoassays, we further characterised somatostatin-like immunoreactivity (SOM-LI) and VIP-like immunoreactivity (VIP-LI) in neuroblastoma and ganglioneuroma tumour tissue. The major part of SOM-LI and VIP-LI in both neuroblastoma and ganglioneuroma represents the biologically active forms SOM-28, SOM-14 and VIP-2, respectively. 21 children with neuroblastoma and ganglioneuroma were monitored with serial plasma samples during surgery. In 8 children with measurable concentrations of SOM-LI, all showed increased concentrations during tumour manipulation (P = 0.004) that subsequently decreased below preoperative levels in all but one case (P = 0.06). The only child presenting with diarrhoea showed the highest preoperative plasma VIP-LI in the study (54 pmol/l). 2 children with increased concentrations of VIP-LI preoperatively showed a rapid decrease after surgical tumour removal. These findings indicate a systemic release from the tumours. It is concluded that plasma and tumour tissue from children with neuroblastoma and ganglioneuroma contain biologically active molecular forms of somatostatin and vasoactive intestinal peptide. These peptides may bear significance both for specific symptoms in certain patients as well as influencing tumour growth and differentiation in vivo.

Pancreastatin immunoreactivity in favourable childhood neuroblastoma and ganglioneuroma

Neuroblastoma and its benign counterpart, ganglioneuroma, are tumours of the sympathetic nervous system, and known to produce and release various regulatory peptides. In this study, pancreastatin, a 52 amino acid regulatory peptide derived from chromogranin A, was analysed in plasma and tumour tissue from 15 children with neuroblastoma and one with ganglioneuroma. Detectable pancreastatin immunoreactivity (> 1.9 pmol/l) was found in plasma in 13 of 15 children with highest concentrations in samples from children with favourable outcome (P < 0.05). In tumour tissue, non-metastatic tumours showed higher concentrations of pancreastatin immunoreactivity (P < 0.05). However, the highest concentrations were detected in tumours from children with favourable prognosis, regardless of clinical stage at presentation (P < 0.01). Serial plasma samples from one child with neuroblastoma and one with ganglioneuroma were investigated and showed significant systemic release of pancreastatin immunoreactivity during surgical manipulation of tumours with high pancreastatin concentrations. It is concluded that pancreastatin immunoreactivity may be detected in plasma samples and tumour extracts from children with neuroblastoma and ganglioneuroma. Systemic release during surgery implied tumour origin of elevated plasma pancreastatin. Furthermore, higher pancreastatin concentrations correlate with tumour differentiation, localised clinical stage and a favourable outcome for children with these tumours. It is suggested that pancreastatin in plasma and tumour tissue may be utilised as a marker indicating favourable tumour behaviour.

Leiomyosarcoma of the Inferior Vena Cava

A case of a thirty-nine-year-old woman with leiomyosarcoma of the inferior vena cava (IVC) is described. The tumor arose from the middle segment of the IVC, and liver metastasis of the tumor was found. The tissue of the tumor obtained at laparotomy was positive for estrogen receptor and progesterone receptor. The patient has been treated with combined multimodal therapy including resection of the main tumor, intrahepato-arterial chemotherapy, and hormonal manipulation. To the authors' knowledge, this is the first case of leiomyosarcoma of the IVC in which the presence of steroid receptors was determined.

Anesthetic management of children with neuroblastoma

Study Objective: To review the 11-year anesthetic experience with neuroblastoma at Children's Hospital Medical Center, Boston, MA. Design: Retrospective study. Setting: Children's Hospital, Boston, MA. Patients: 59 consecutive children with neuroblastomas who underwent surgical procedures between 1977 and 1989. Interventions: Symptoms, physical findings, laboratory data, and results of echocardiographic examination were recorded. Type of chemotherapy and urine catecholamine levels were noted. Intraoperative information was extracted about the surgical procedure, anesthetic technique, blood loss, and intraoperative vital sign changes. Postoperative data were reviewed for complications. Measurements and Main Results: 18 patients presented with a posterior mediastinal tumor. Five children presented with stridor, wheezing, pneumonia, and pleural effusion. Two children presented with hypertension. Left ventricular ejection fraction was within normal limits preoperatively in all patients evaluated by echocardiography. intraoperative hypertension and tachycardia occurred in 3.5% of the children during tumor manipulation. No hypotension was noted following tumor removal. Of the 18 patients presenting with a posterior mediastinal mass, 3 had tracheal deviation caused by the tumor. The intraoperative course and extubation were uneventful in 2 of the patients, and the other patient remained intubated postoperatively. No adverse effect was identified for any particular anesthetic drug or technique used. Conclusions: Although neuroblastomas may be associated with hypertension upon presentation, intraoperative hypertension is rare. Tracheal compression and deviation were noted in 5.2% of patients with posterior mediastinal masses; however, airway complications did not occur. No specific optimal anesthetic regimen can be recommended.