By D. Benito. Shimer College.
Aside from the ability to identify rare variants and the obvious substantial cost reduction (∼20-fold) cheap 12.5 mg hyzaar free shipping, this approach has the advantage of focusing on nonsynonymous variants in coding genes for which there are well-established methods of functional validation and interpretation of biologic effects purchase cheap hyzaar on line, thus enabling their implication as causal variants buy discount hyzaar line. Early results suggest that whole-exome sequencing is an effective approach to identify causal mutations for monogenic disorders but also to distinguish signal (causal rare variants) from noise (background rate of rare mutations) for complex traits. These studies have demanded the development of novel statistical methods to associate rare variants with the phenotype. The first integrated analysis of a complete human genome in a clinical context, in a patient with a family history of vascular disease and early sudden death has been reported in the Lancet in 2010. Furthermore, the patient had variants associated with clopidogrel resistance, a positive response to lipid-lowering therapies, and a low initial dosing requirement for warfarin, suggesting that routine whole-genome sequencing can yield clinically relevant information for individual patients. Equally important for medical progress is the sequencing of genomes of the billions of microorganisms that dwell within us as part of the Human Microbiome Project. Other known limitations of genetic association studies include potential false positive findings resulting from population stratification (i. Replication of findings across different populations or86 related phenotypes remains the most reliable method of validating a true relationship between genetic polymorphisms and disease, but poor reproducibility in subsequent studies has been one of the main criticisms of the candidate gene association approach. Therefore, it is particularly87 important to follow initial association analysis results with functional analyses using in silico, in vitro, and in vivo experiments aimed at identifying the causal genetic variants, causal epigenetics, and affected biologic pathways. Translation of genomic findings to the clinic ultimately revolves around either new disease mechanisms (better disease definition or disease stratification) or new therapeutic strategies (new targets, drug repurposing, or drug response stratification). A particular focus of recent efforts to translate genome sequence information into clinical-decision making revolves around the “actionability” of specific genetic variants, and the level of evidence required to establish whether a variant is actionable. In the context of incidental findings or in an asymptomatic individual, clinical actionability represents the degree to which an intervention exists that can mitigate harm before a clinical diagnosis is made. Related terms are clinical validity, the accuracy and reliability of a variant in identifying or predicting an event with biologic or medical significance in an asymptomatic individual, and clinical utility, the usefulness of information in clinical-decision making and improving health outcomes. The National Institutes of Health has created the Clinical88 Genome Resource (ClinGen) to serve as an authoritative public portal defining the clinical relevance of genomic variants for use in precision medicine (www. Several applications to perioperative89 medicine are presented in the following sections. Genomics and Perioperative Risk Profiling More than 40 million patients undergo surgery annually in the United States at a cost of $450 billion. Each year approximately 1 million patients sustain medical complications after surgery, resulting in costs of $25 billion annually. Although many preoperative predictors have been identified and are constantly being refined, risk stratification based on clinical, procedural, and biologic markers explains only a small part of the variability in the incidence of perioperative complications. As mentioned earlier, it is becoming increasingly recognized that perioperative morbidity arises as a direct result of the environmental stress of 416 surgery occurring on a landscape of susceptibility that is determined by an individual’s clinical and genetic characteristics, and may even occur in otherwise healthy individuals. Such adverse outcomes will develop only in patients whose combined burden of genetic and environmental risk factors exceeds a certain threshold, which may vary with age. Identification of such genetic contributions not only to disease causation and susceptibility but also to the response to disease and drug therapy, and incorporation of genetic risk information in clinical decision-making, may lead to improved health outcomes and reduced costs. For instance, understanding the role of genetic variation in proinflammatory and prothrombotic pathways, the main pathophysiologic mechanisms responsible for perioperative complications, may contribute to the development of target-specific therapies, thereby limiting the incidence of adverse events in high-risk patients. To increase clinical relevance for the practicing perioperative physician, we summarize next existing evidence by specific outcome while highlighting candidate genes in relevant mechanistic pathways (Tables 6-3 through 6-5). Table 6-3 Representative Genetic Polymorphisms Associated with Altered Susceptibility to Adverse Perioperative Cardiovascular Events 417 418 Predictive Biomarkers for Perioperative Adverse Cardiac Events Perioperative Myocardial Infarction and Ventricular Dysfunction Patients with underlying cardiovascular disease can be at increased risk for perioperative cardiac complications. Over the last few decades several multifactorial risk indices have been developed and validated for both noncardiac (e. Table 6-4 Representative Genetic Polymorphisms Associated with Altered Susceptibility to Adverse Perioperative Neurologic Events 420 Table 6-5 Representative Genetic Polymorphisms Associated with Other Adverse Perioperative Outcomes Inflammation biomarkers and perioperative adverse cardiac events. The balance between normal hemostasis, bleeding, and thrombosis is markedly influenced by the rate of thrombin formation and platelet activation, with genetic variability known to modulate each of these mechanistic pathways, suggesting significant heritability of the prothrombotic state (see Table 6-5 for an overview of genetic variants associated with postoperative bleeding). Functional genetic variants regulating platelet activation have also been associated with adverse postoperative outcomes. Advanced heart failure patients requiring ventricular mechanical support represent a unique population that might benefit from a thorough preoperative risk profiling, given that implantation of ventricular assist devices can unmask previously undiagnosed thrombophilia. Finally, a point mutation in coagulation factor V (1691G>A) resulting in resistance to activated protein C (factor V Leiden), was also associated with various postoperative thrombotic complications following noncardiac surgery. Conversely, in patients 423 undergoing cardiac surgery, factor V Leiden was associated with significant reductions in postoperative blood loss and overall risk of transfusion. For noncardiac surgery, these have been summarized in two meta-analyses that overall indicate an approximately 20-fold increase in risk of adverse perioperative cardiovascular outcomes. Although these observations are intriguing, future follow-up studies will be needed to translate these initial findings into biologic insights that could lead to predictive and therapeutic advances in perioperative care. The mechanism of action of this genetic locus is unknown, but it lies close to several genes involved in the development of pulmonary myocardium, or the sleeve of cardiomyocytes extending from the left atrium into the initial portion of the pulmonary veins. Variability in the reported incidence of both early and late neurologic deficits remains poorly explained by procedural risk factors, suggesting that environmental (operative) and genetic factors may interact to determine disease onset, 429 progression, and recovery. The pathophysiology of perioperative neurologic injury is thought to involve complex interactions between primary pathways associated with atherosclerosis and thrombosis, and secondary response pathways like inflammation, vascular reactivity, and direct cellular injury. Many functional genetic variants have been reported in each of these mechanistic pathways involved in modulating the magnitude and the response to neurologic injury, which may have implications in chronic as well as acute perioperative neurocognitive outcomes. Consistent with the observed role of platelet activation in the pathophysiology of adverse neurologic sequelae, genetic variants in surface platelet membrane glycoproteins, important mediators of platelet adhesion and platelet–platelet interactions, increase the susceptibility to prothrombotic events. The implications for perioperative medicine include identifying populations at risk who might benefit not only from an improved informed consent, stratification, and resource allocation, but also from targeted anti- inflammatory strategies. Further identification of genotypes predictive of76 adverse perioperative renal outcomes may facilitate individually tailored 431 therapy, risk stratify the patients for interventional trials targeting the gene product itself, and aid in medical-decision making (e. Genetic Variants and Risk for Postoperative Lung Injury Prolonged mechanical ventilation (inability to extubate patient by 24 hours postoperatively) is a significant complication following cardiac surgery, occurring in 5. The use of such outcome predictive models incorporating genetic information may help stratify mortality and morbidity in surgical patients, improve prognostication, direct medical decision-making both intraoperatively and during postoperative follow-up, and even suggest novel targets for therapeutic intervention in the perioperative period. Pharmacogenomics and Anesthesia Interindividual variability in response to drug therapy, both in terms of efficacy and safety, is a rule by which anesthesiologists live. In fact, much of 432 the art of anesthesiology is the astute clinician being prepared to deal with outliers. The term pharmacogenomics is used to describe how inherited variations in genes modulating drug actions are related to interindividual variability in drug response.
The researcher should carefully choose and report the adjustment/individualization of experimental treatments buy hyzaar 12.5mg on line. Control Groups Even if a researcher is studying just one experimental group purchase generic hyzaar, the results of the experiment are usually not interpreted solely in terms of that one group but are also contrasted and compared with other experimental groups purchase cheap hyzaar online. Examining 466 the effects of a new drug on blood pressure during anesthetic induction is important, but what is more important is comparing those results with the effects of one or more standard drugs commonly used in the same situation. There are several possibilities: (1) each patient could receive the standard drug under identical experimental circumstances at another time, (2) another group of patients receiving the standard drug could be studied simultaneously, (3) a group of patients could have been studied previously with the standard drug under similar circumstances, and (4) literature reports of the effects of the drug under related but not necessarily identical circumstances could be used. Under the first two possibilities, the control group is contemporaneous—either a self- control (crossover) or parallel control group. Because historical controls already exist, they are convenient and seemingly cheap to use. Unfortunately, the history of medicine is littered with the “debris” of therapies enthusiastically accepted on the basis of comparison with past experience. A classic example is operative ligation of the internal mammary artery for the treatment of angina pectoris—a procedure now known to be of no value. Proposed as a method to improve coronary artery blood flow, the lack of benefit was demonstrated in a trial where some patients had the procedure and some had a sham procedure; both groups showed benefit. There is now firm empirical evidence that studies using1 historical controls usually show a favorable outcome for a new therapy, whereas studies with concurrent controls, that is, parallel control group or self-control, less often reveal a benefit. Nothing seems to increase the2 enthusiasm for a new treatment as much as the omission of a concurrent control group. If the outcome with an old treatment is not studied simultaneously with the outcome of a new treatment, one cannot know if any differences in results are a consequence of the two treatments, or of unsuspected and unknowable differences between the patients, or of other changes over time in the general medical environment. One possible exception would be in studying a disease that is uniformly fatal (100% mortality) over a very short time. Random Allocation of Treatment Groups Having accepted the necessity of an experiment with a control group, the question arises as to the method by which each subject should be assigned to the predetermined experimental groups. Should it depend on the whim of the investigator, the day of the week, the preference of a referring physician, the wish of the patient, the assignment of the previous subject, the availability of a study drug, a hospital chart number, or some other arbitrary criterion? All 467 such methods have been used and are still used, but all can ruin the purity and usefulness of the experiment. It is important to remember the purpose of sampling: By exposing a small number of subjects from the target population to the various experimental conditions, one hopes to make conclusions about the entire population. Thus, the experimental groups should be as similar as possible to each other in reflecting the target population; if the groups are different, selection bias is introduced into the experiment. Although randomly allocating subjects of a sample to one or another of the experimental groups requires additional work, this principle prevents selection bias by the researcher, minimizes (but cannot always prevent) the possibility that important differences exist among the experimental groups, and disarms the critics’ complaints about research methods. Random allocation is most commonly accomplished by the use of computer-generated random numbers. Even with a random allocation process, selection bias can occur if research personnel are allowed knowledge of the group assignment of the next patient to be recruited for a study. Failure to conceal random allocation leads to biases in the results of clinical studies. In clinical trials, the necessity for blinding starts even before a patient is enrolled in the research study; this is called the concealment of random allocation. There is good evidence that, if the process of random allocation is accessible to view, the referring physicians, the research team members, or both are tempted to manipulate the entrance of specific patients into the study to influence their assignment to a specific treatment group ; they do so5 having formed a personal opinion about the relative merits of the treatment groups and desiring to get the “best” for someone they favor. Each subject should remain, if possible, ignorant of the assigned treatment group after entrance into the research protocol. The patient’s expectation of improvement, a placebo effect, is a real and useful part of clinical care. But when studying a new treatment, one must ensure that the fame or infamy of the treatments does not induce a bias in outcome by changing patient expectations. A researcher’s knowledge of the treatment assignment can bias his or her ability to administer the research protocol and to observe and record data faithfully; this is true for clinical, animal, and in vitro research. If the treatment group is known, those who observe data cannot trust themselves to record the data impartially and dispassionately. The appellations single-blind and double-blind to describe blinding are commonly 468 used in research reports, but often applied inconsistently; the researcher should carefully plan and report exactly who is blinded. Experimental Medicine: Statistical Analysis Hypothesis Formulation The researcher starts work with some intuitive feel for the phenomenon to be studied. Whether stated explicitly or not, this is the biologic hypothesis; it is a statement of experimental expectations to be accomplished by the use of experimental tools, instruments, or methods accessible to the research team. The biologic hypothesis of the researcher becomes a statistical hypothesis during research planning. In a statistical hypothesis, statements are made about the relationship among parameters of one or more populations. The most frequently used method of setting up the algebraic formulation of the statistical hypothesis is to create two mutually exclusive statements about some parameters of the study population (Table 7-3); estimates for the values for these parameters are acquired by sampling data. The alternative hypothesis is usually nondirectional, that is, either φ1 is less than φ2 or φ1 is more than φ2; this is known as a two-tail alternative hypothesis. This is a more conservative alternative hypothesis than assuming that the inequality can only be either less than or greater than. Table 7-3 Algebraic Statement of Statistical Hypotheses 469 Logic of Proof One particular decision strategy is used most commonly to choose between the null and alternative hypothesis. The approach is to assume that the null hypothesis is true even though the goal of the experiment is to show that there is a difference. One examines the consequences of this assumption by examining the actual sample values obtained for the variable(s) of interest. This is done by calculating what is called a sample test statistic; sample test statistics are calculated from the sample numbers. One also chooses the level of significance; the level of significance is the probability level considered too low to warrant support of the null hypothesis being tested. Because the statistics deal with probabilities, not certainties, there is a chance that the decision concerning the null hypothesis is erroneous. These errors are best displayed in table form (Table 7-4); condition 1 and condition 2 could be different drugs, two doses of the same drug, or different patient groups. The error of wrongly rejecting the null hypothesis (false-positive) is called the type I or α-error. The experimenter should choose a probability value for α before collecting data; the experimenter decides how cautious to be against falsely claiming a difference.
Therefore cheap hyzaar 12.5mg line, laboratories would greatly beneﬁt by the availability of commer- cial kits based on the array technology for fungal identiﬁcation in the near future buy discount hyzaar 50mg line. Chang aspergillosis in France: a six-year multicentric survey in the Greater Paris area buy hyzaar in united states online. Enache-Angoulvant A, Hennequin C (2005) Invasive Saccharomyces infection: a comprehen- sive review. Fanci R, Pecile P (2005) Central venous catheter-related infection due to Candida membranae- faciens, a new opportunistic azole-resistant yeast in a cancer patient: a case report and a review of literature. Mele G, Musci M, Musto C, D’Amato L, Traﬁcante A, Di Renzo N (2005) Pneumonia caused by Trichosporon pullulans in an autologous peripheral blood stem cell transplant recipient: possible misidentiﬁcation. Panagopoulou P, Evdoridou J, Bibashi E et al (2002) Trichosporon asahii: an unusual cause of invasive infection in neonates. Appl Environ Microbiol 69:5389–5397 39 Application of Microarrays for Laboratory Detection and Identiﬁcation... Volokhov D, Rasooly A, Chumakov K, Chizhikov V (2002) Identiﬁcation of Listeria species by microarray-based assay. Seifarth W, Krause U, Hohenadl C, Baust C, Hehlmann R, Leib-Mösch C (2000) Rapid identiﬁcation of all known retroviral reverse transcriptase sequences with a novel versatile detection assay. J Antimicrob Chemother 55:312–316 39 Application of Microarrays for Laboratory Detection and Identiﬁcation... Rodero L, Cuenca-Estrella M, Cordoba S et al (2002) Transient fungemia caused by an amphotericin B-resistant isolate of Candida haemulonii. J Clin Microbiol 44:693–699 Chapter 40 Laboratory Technical Advances in the Diagnosis of Clostridium dif ﬁ cile Karen C. The organism can also be found in a variety of environmental sources including soil, river water, domestic animals, and home and healthcare environments. During logarithmic growth, when vegetative cells predominate, the organism is very aerointolerant. In 1978, prior knowledge of the organism and the observation that antibiotic associated diarrhea was associated with a cytotoxin in the hamster model, converged in the work by Bartlett et al. Later it was established that the organism produces two toxins, toxin A, a 308 kDa enterotoxin and toxin B, a 270 kDa cytotoxin. Glycosylation of these small proteins disrupts signaling pathways causing irreversible changes in cellular morphology and consequent inhibition of cell divi- sion and membrane trafﬁcking, leading to cell death [2, 6]. The genes that encode toxins A and B, tcdA and tcdB, are found along with three other genes (tcdC, tcdE , tcdR) on the pathogenicity locus (PaLoc), a conserved 19. Carroll (*) Division of Medical Microbiology , The Johns Hopkins University School of Medicine, The Johns Hopkins Medical Institutions, Meyer B1-193, 600 N. Carroll tcdC is found downstream of tcdA and this gene has been shown to be a negative regulator of toxin production that prevents transcription of the PaLoc [6–10]. Mutations in many of these various genes have a signiﬁcant impact on expression of one or both toxins and have been shown to be responsible for the emergence of hypervirulent toxin variant strains (see Epidemiology section). Binary toxin may contribute to virulence by enhancing cytotoxicity and also by increasing adherence of C. Failure to remove spores from contaminated hospital environments contributes to nosocomial spread in healthcare facilities. Prior to 2001, this particular strain accounted for less than 1 % of all infections. More impor- tantly, the “wild type” strain was quinolone susceptible, but the outbreak strain was found to be ﬂuoroquinolone resistant . Subsequently the 18 bp deletion was shown not to be important with respect to organism virulence [9, 10]. There is a correlation between truncation of TcdC, due to the single base-pair deletion at position 117, which results in the formation of a stop codon, and increased toxin production 40 Laboratory Technical Advances in the Diagnosis of Clostridium dif ﬁ cile 771 due to derepression of the Pathogenicity Locus [9, 18–20]. Depending upon the geographic location, other strains have been implicated in outbreaks and severe disease. Ribotype 017, prevalent in Asia, is a toxin A negative, toxin B positive strain that is quinolone and macrolide resistant and has been associ- ated with hospital outbreaks and increase rates of pseudomembranous colitis [23, 24]. The emerging epi- demiology and potential risk factors including age, quinolone antibiotics, and potentially, proton pump inhibitors, for acquisition of C. Against this backdrop of evolving strains and emerging epidemiology has been the impetus to implement better and faster diagnostic methods for the detection of C. Practice guidelines from professional societies have been published to guide the clinical and laboratory approaches to diagnosis [26, 27] and a variety of molecular assays have been approved for diagnosis. This chapter focuses on the rationale for the diagnostic guidelines and the performance of new methods and algorithms for C. Both documents agree that toxigenic culture is the most sensitive method for detection of C. Finally, culture is useful for surveillance of drug resistance and is sometimes helpful in patient management. Toxigenic anaerobic culture requires inoculation of the stool to anaerobic media, incubating the media anaerobically for 2–5 days, and once recovered, determining whether the C. There is no agreed upon standard method, but a well done culture has been shown to signiﬁcantly increase the yield of C. Factors to consider when developing a culture method include (1) the need for and type of spore enrichment, (2) the type of media, and (3) the best method for conﬁrming toxin production in the recovered isolate. Nonselective anaerobic media have the advantages of being less expen- sive and more readily available in clinical labs than selective agars or broths, but do not allow for easy presumptive identiﬁcation of C. Over the years incorporation of substances to enhance germination of spores such as horse blood in place of the egg yolk, taurocholate, and lysozyme have been shown to improve recovery [2, 31]. Whatever medium is chosen, it is important to use prereduced media as the failure to do so can impact the sensitivity of the culture method [33 ]. Other studies have examined the utility of broth enrichment compared to direct plating on solid media as well as spore enrichment techniques. In the former situa- tion, fecal specimens are inoculated to an enrichment broth that contains tauro- cholate, antibiotics, increased carbohydrates and/or lysozyme to reduce normal fecal ﬂora and enhance recovery of small concentrations of C. Several stud- ies have shown enhanced recovery of enrichment broth compared to direct plating on solid media [35–37]. Spore enrichment involves treating the fecal specimen with either heat or ethanol to reduce competing normal ﬂora.
Neurochirurgia (Stuttg) 1959;1:133–150 To make matters more imprecise order 50mg hyzaar free shipping, the world is smaller to- 11 purchase generic hyzaar online. Curr Probl Surg day than it ever was thanks to the Internet buy line hyzaar, globalization, 1981;18:609–679 wireless communication, and the unfettered access to infor- 12. Transsphenoidal and transcranial surgery for pitu- mation and disinformation, so that it is just as easy to spread itary adenomas. Trans-sphenoidal surgery of pituitary fossa practitioners partially educated or vulnerable to self-claims tumors with televised radiofuoroscopic control. J Neurosurg of evangelists not vetted by scientifc tribunals or other more 1965;23:612–619 trusted discourse. In spite of this, surgical innova- Can 1967;96:702–712 tion, has survived and will continue to survive, bypassing 15. Acta Neurochir (Wien) 1978;41:163–175 We must foster and breed bold shifts and advances in 16. Endoscopic endonasal transsphenoidal surgery: our surgical portfolio, and change must occur for the feld to experience with 50 patients. Endoscopic repair of cerebro- shed our willingness and readiness to query, assess, and re- spinal fuid fstulae and encephaloceles. Laryngoscope 1996;106 port the gains or cost of such advances so that those who (9 Pt 1):1119–1125 23 Microscopic and Endoscopic Transsphenoidal Pituitary Surgery: A Reasoned and Balanced Dialectic 247 19. Transsphenoidal scope 2001;111:2131–2134 microsurgery of pituitary macroadenomas with long-term follow- 20. J R Soc Med 1986;79:262–269 transsphenoidal microsurgical approach to the sella turcica. J Neurosurg 1978;49:138–142 plications of transsphenoidal operation for pituitary adenomas. The “classic” transsphenoidal approach Neurosurgery 1987;20:920–924 for resection of pituitary tumors. Neurosurgery 1997;40:225–236; discus- sellar region: anatomic comparison of the microscope versus endo- sion 236–227 scope. Endoscopic endonasal patients who underwent transsphenoidal surgery for Cushing’s dis- transsphenoidal surgery. J Neurosurg 2009;111:545–554 pituitary tumors in the United States, 1996–2000: mortality, mor- 28. Combined micro-endoscopic trans-sphenoid excisions of bidity, and the efects of hospital and surgeon volume. Surgical complica- Surg 2000;126:1487–1490 tions after endoscopic transsphenoidal pituitary surgery. Endoscopic transsphenoidal approach rosci 2009;16:786–789 through a widened nasal cavity for pituitary lesions. Flexible endoscope-assisted 1529–1530 endonasal transsphenoidal surgery for pituitary tumors. The use of the rigid endoscope [Endoscope-assisted microsurgery for invasive endo- and suprasellar in trans-sphenoidal pituitary surgery. J Laryngol Otol 1994;108: pituitary macroadenomas: a consecutive retrospective study with 19–22 13 patients]. J Neurooncol croscopic approach for pituitary adenomas and other parasellar tu- 2001;54:187–195 mors: a 10-year experience. Endoscopic endonasal 256, discussion 256 transsphenoidal approach: outcome analysis of 100 consecutive pro- 52. Minim Invasive Neurosurg 2002;45:193–200 surgery: principles of endonasal oncological surgery. Comparison of endonasal endoscopic surgery and 2008;97:658–664 sublabial microsurgery for prolactinomas. Brief history 375, discussion 375–376 of endoscopic transsphenoidal surgery—from Philipp Bozzini to the 36. Laryngoscope 1992;102: 1999;109:1838–1840 198–202 Extended Endonasal, Endoscopic 24 Transsphenoidal Approach versus Craniotomy for Giant Pituitary Macroadenomas Christoph P. Schwartz With the exception of medically treatable prolactinomas, sur classifed tumors as follows: type A, tumor that is bulging gery is the frst-line treatment for symptomatic giant pituitary into the chiasmatic cisterns; type B, tumor that reaches the adenomas. The surgical treatment for giant pituitary mac foor of the third ventricle; type C, large suprasellar tumor roadenomas has evolved considerably over the past 100 years growth into the third ventricle up to the foramen of Monro; including the development of the transsphenoidal approach, and type D, tumors that extend into the anterior or middle extended transsphenoidal approach, endoscopic endonasal cranial fossa. The suprasellar extensions techniques can be employed for the treatment of giant pitu of macroadenomas were graded, and the giant tumors were itary macroadenomas; sometimes both approaches have been considered to be grades C and D. Maximiz with >3 cm suprasellar extension above the foramen of ing the extent of resection in the setting of a low morbidity Monro or a grade C tumor with asymmetrical or multiple and mortality rate is also a goal of surgery. Not all giant pi cal experience with transcranial surgery for pituitary tumors tuitary adenomas extend into the third ventricle, and other in general led to development of extracranial approaches to studies have limited them to tumors over 3 or 4 cm in diam the sella. He then used a sub The use of the microsurgical technique in combination frontal and middle fossa approach with a mortality rate of with traditional transfrontal or transtemporal approaches 20% in 10 patients between 1904 and 1906. At the same to giant pituitary adenomas led to a substantial reduction time Krause27,28 removed a pituitary tumor using a mostly in operative mortality. McArthur29 incor with giant pituitary adenomas measuring >4 cm in diam porated removal of the supraorbital ridge and orbital roof eter, there was only one postoperative mortality second to expose a pituitary tumor in 1908. These techniques were later modifed had evidence of hypopituitarism before surgery. Postop by Cushing,32 Dandy,3 and Heuer,33 and a large experience eratively, seven patients had improvement in their endocri with transcranial surgery for pituitary tumors was devel nologic and ophthalmologic symptoms, and the rest were oped. However, a radical excision was not achieved to open the sylvian fssure and refnement of the pterional in any of the 21 patients52 (Table 24. In contrast, in a se approach with sphenoid wing removal, Yasargil et al37 ries of 319 patients with pituitary adenomas, there were described an unobstructed direct view to the parasellar 21 patients with giant adenomas (the authors defne giant structures. The shift from macrosurgical approaches to micro adenomas vaguely as adenomas with massive suprasellar surgical approaches in the 1970s dramatically reduced the extension) who underwent transcranial tumor resection morbidity and mortality of transcranial surgery for giant with a subfrontal pterional approach. Postoperative worsening of visual function occurred in ventricle, and to minimize brain retraction (orbitozygo two (9. Following transcranial surgery there was one peri The operative mortality after transcranial surgery for operative mortality secondary to a pulmonary embolism 2 giant pituitary adenomas was unacceptably high in the months after surgery.