Incidence, mechanism and prognostic value of activated AKT in pancreas cancer.

When activated, the serine/threonine kinase AKT mediates an antiapoptotic signal implicated in chemoresistance of various cancers. The mechanism(s) of AKT activation are unknown, though overexpression of HER-2/neu has been implicated in breast cancer. Therefore, we determined the incidence of activated AKT in human pancreatic cancer, whether HER-2/neu is involved in AKT activation, and if AKT activation is associated with biologic behaviour. HER-2/neu expression and AKT activation were examined in seven pancreatic cancer cell lines by Western blotting. The in vitro effect of HER-2/neu inhibition on AKT activation was similarly determined. Finally, 78 pancreatic cancer specimens were examined for AKT activation and HER-2/neu overexpression, and correlated with the clinical prognostic variable of histologic grade. HER-2/neu was overexpressed in two of seven cell lines; these two cell lines demonstrated the highest level of AKT activation. Inhibition of HER-2/neu reduced AKT activation in vitro. AKT was activated in 46 out of 78 (59%) of the pancreatic cancers; HER-2/neu overexpression correlated with AKT activation (P=0.015). Furthermore, AKT activation was correlated with higher histologic tumour grade (P=0.047). Thus, it is concluded that AKT is frequently activated in pancreatic cancer; this antiapoptotic signal may be mediated by HER-2/neu overexpression. AKT activation is associated with tumour grade, an important prognostic factor.

AKT inhibition is associated with chemosensitisation in the pancreatic cancer cell line MIA-PaCa-2.

Activation of the serine/threonine kinase AKT is common in pancreatic cancer; inhibition of which sensitises cells to the apoptotic effect of chemotherapy. Of the various downstream targets of AKT, we examined activation of the NF-kappaB transcription factor and subsequent transcriptional regulation of BCL-2 gene family in pancreatic cancer cells. Inhibition of either phosphatidylinositol-3 kinase or AKT led to a decreased protein level of the antiapoptotic gene BCL-2 and an increased protein level of the proapoptotic gene BAX. Furthermore, inhibition of AKT decreased the function of NF-kappaB, which is capable of transcriptional regulation of the BCL-2 gene. Inhibiting this pathway had little effect on the basal level of apoptosis in pancreatic cancer cells, but increased the apoptotic effect of chemotherapy. The antiapoptotic effect of AKT activation in pancreatic cancer cells may involve transcriptional induction of a profile of BCL-2 proteins that confer resistance to apoptosis; alteration of this balance allows sensitisation to the apoptotic effect of chemotherapy.

Cost-benefit analysis of biopsy methods for suspicious mammographic lesions; discussion 994-5.

HYPOTHESIS: Stereotactic core biopsy (SCB) is more cost-effective than needle-localized biopsy (NLB) for evaluation and treatment of mammographic lesions. DESIGN: A computer-generated mathematical model was developed based on clinical outcome modeling to estimate costs accrued during evaluation and treatment of suspicious mammographic lesions. Total costs were determined for evaluation and subsequent treatment of cancer when either SCB or NLB was used as the initial biopsy method. Cost was estimated by the cumulative work relative value units accrued. The risk of malignancy based on the Breast Imaging Reporting Data System (BIRADS) score and mammographic suspicion of ductal carcinoma in situ were varied to simulate common clinical scenarios. MAIN OUTCOME MEASURES: Total cost accumulated during evaluation and subsequent surgical therapy (if required). RESULTS: Evaluation of BIRADS 5 lesions (highly suggestive, risk of malignancy = 90%) resulted in equivalent relative value units for both techniques (SCB, 15.54; NLB, 15.47). Evaluation of lesions highly suspicious for ductal carcinoma in situ yielded similar total treatment relative value units (SCB, 11.49; NLB, 10.17). Only for evaluation of BIRADS 4 lesions (suspicious abnormality, risk of malignancy = 34%) was SCB more cost-effective than NLB (SCB, 7.65 vs. NLB, 15.66). CONCLUSIONS: No difference in cost-benefit was found when lesions highly suggestive of malignancy (BIRADS 5) or those suspicious for ductal carcinoma in situ were evaluated initially with SCB vs. NLB, thereby disproving the hypothesis. Only for intermediate-risk lesions (BIRADS 4) did initial evaluation with SCB yield a greater cost savings than with NLB.

Sentinel lymph node biopsy for breast cancer.

Sentinel lymph node biopsy (SLNB) is an emerging surgical technique to improve lymph node staging for breast cancer. Despite the rapid development of this technique, there remain aspects of SLNB that need to be further defined to provide a standardized approach. Variables, including patient selection, technical details for the performance of SLNB, extent of pathologic evaluation of the sentinel lymph node, and the impact of micrometastases, are areas of controversy. This paper reviews the controversies and discusses available data as well as personal experience and opinion.

Intraoperative use of automated external defibrillator.

We report on the anesthetic management of a patient with peripartum cardiomyopathy and frequent episodes of ventricular tachycardia, who underwent surgery for tracheal stenosis. Prior to this surgery, the patient had been implanted with an automatic implantable cardioverter-defibrillator (AICD), placed abdominally. In the operating room, the AICD was deactivated, and an automated external defibrillator (AED) was placed. Intraoperatively, the AED identified and treated the patient's ventricular tachycardia. Advantages of the AED in this hospital setting included rapid response to the cardiomyopathy, safe, hands-free operation, and minimal disruption of the surgical procedure. Safety concerns when using the AED are also detailed.

Transesophageal echocardiographic detection of gas embolism and cardiac valvular dysfunction during laparoscopic nephrectomy.

UNLABELLED: We used transesophageal echocardiography (TEE) to monitor venous gas embolism, cardiac performance, and the hemodynamic effects of positioning and pneumoperitoneum in 16 healthy kidney donors undergoing laparoscopic nephrectomy. A four-chamber view was used continuously, except at predetermined intervals, when a complete TEE examination for cardiac function was performed. Other clinical variables recorded include systolic, diastolic, and mean arterial blood pressure; heart rate (HR), pulse oximetric saturations; and end-tidal CO2. Baseline valvular incompetence was seen in 13 of the 16 patients when supine and asleep. After positioning for surgery and induction of pneumoperitoneum, TEE revealed valvular incompetence with regurgitation more pronounced from baseline in 15 of the 16 patients. In one patient, during renal vein dissection, gas entered the right atrium from the inferior vena cava, worsening tricuspid regurgitation. Hemodynamic variables and ejection fraction were tested by using repeated-measures analysis of variance for significance (P < 0.05). Pneumoperitoneum increased (P < 0.05) systolic blood pressure (from 102.8 +/- 3.89 to 120.8 +/- 3.88 mm Hg) and HR (from 68.9 +/- 3.19 to 75.6 +/- 2.62). Ejection fraction was unchanged. The high incidence of valvular incompetence indicates that further studies are needed to assess these effects during laparoscopic nephrectomy with cardiac disease. IMPLICATIONS: Laparoscopic surgery has gained popularity as a procedure for the removal of donated kidneys. Although the insufflation of gas necessary for this relatively simple approach poses a low risk of venous air embolism, it may increase the risk of changes in valvular competency.

Cytochrome c release from brain mitochondria is independent of the mitochondrial permeability transition.

Ca2+ uptake by brain mitochondria induces the release of up to 40% of total cytochrome c in a cyclosporin A-insensitive manner. In the presence of ATP and Mg2+, this process is not accompanied by mitochondrial swelling. There is a moderate decrease in membrane potential under these conditions, but it is completely reversible upon removal of accumulated Ca2+ by addition of EGTA+A23187 but not by EGTA alone. These observations provide evidence that cytochrome c release from brain mitochondria does not require the membrane permeability transition. However, brain mitochondria can undergo the permeability transition in the absence of ATP and Mg2+, which results in cyclosporin A-sensitive large amplitude swelling, loss of Ca2+ uptake capacity and release of matrix solutes.

Effects of split torso positioning and laparoscopic surgery for donor nephrectomy on respiratory mechanics.

STUDY OBJECTIVE: To test whether split torso positioning, abdominal insufflation, and other procedures performed during laparoscopic nephrectomy would affect mechanical impedances to inflation [i.e., elastance (E) and resistance (R) of the total respiratory system (Ers, and Rrs), lungs (EL and RL), and chest wall (Ecw and Rcw)] differently from previously studied laparoscopic procedures. DESIGN: Unblinded study, each patient serving as own control. SETTING: University hospital. PATIENTS: 12 ASA physical status I and II patients scheduled for laparoscopic donor nephrectomy, all without cardiopulmonary disease. INTERVENTIONS: Patients were anesthetized and paralyzed, tracheally intubated and mechanically ventilated at 10, 20, and 30 breaths/minute and at tidal volumes of 250, 500, and 800 ml. Measurements were made in the following positions: supine, split torso, abdominal insufflation (Pab = 15 mmHg), and supine after deflation. MEASUREMENTS AND MAIN RESULTS: Airway flow and pressure and esophageal pressure were measured. Discrete Fourier transformation was used to calculate E and R. These were analyzed with repeated measures, linear multiple regression with accepted level of significance at p < 0.05. Ers, Ecw, and Rcw increased (p < 0.05) while EL decreased (p < 0.05) when patients changed from supine to split torso. During Pab = 15 mmHg, Ers, Ecw, and Rcw increased further and Rrs and RL increased (p < 0.05). Following abdominal deflation, Ecw and Ers remained elevated (p < 0.05). The changes in Ecw caused by laparoscopy and surgery were greater than we have previously measured in other laparoscopic procedures, while the changes in EL were less. CONCLUSIONS: Laparoscopic nephrectomy affects lung and chest wall mechanical properties differently from other laparoscopic procedures. This finding could be due to the split torso positioning, and the effects of abdominal swelling on the chest wall caused by administration of more perioperative fluids with laparoscopic nephrectomy.

Epidemiology and molecular genetics of colorectal cancer.

Colorectal cancer is among the most common cancers affecting the western world. By the age of 70 yr, at least 50% of the Western population will develop some form of colorectal tumor, spanning the spectrum from an early benign polyp to an invasive adenocarcinoma. It is estimated that approximately 10% of the benign polypoid lesions will progress to invasive carcinoma. The concept that serial genetic changes are responsible for the transition from benign to neoplastic disease is not new. The description of hereditary cancers and the demonstration of carcinogenic substances inducing DNA damage have provided the foundation for the field of molecular oncology. During the past three decades, our understanding of how genetic alterations culminate in cancer has progressed rapidly, though the complete process has not been fully defined. The research to date has spanned many oncologic diseases, but has been especially well defined in colorectal cancer. The knowledge of the genetic alterations that result in colorectal cancer has important ramifications for future prevention, detection, and treatment of this disease.

Effects of PEEP on respiratory mechanics are tidal volume and frequency dependent.

How the effects of frequency, tidal volume (VT) and PEEP interact to determine the mechanical properties of the respiratory system is unclear. Airway flow and airway and esophageal pressures were measured in ten intubated, anesthetized/paralyzed patients during mechanical ventilation at 10-30 breaths/min and VT of 250-800 ml. From these measurements, Fourier transformation was used to calculate elastance (E) and resistance (R) of the total respiratory system (subscript rs), lungs (subscript L) and chest wall (subscript cw) at 5, 10 and 0 cm PEEP. As PEEP increased from 0-5 cmH2O, all elastances and resistances decreased (P < 0.05). Increasing PEEP to 10 cmH2O decreased EL, Rrs, and RL further (P < 0.05). The changes in Ers, EL, Rrs and RL caused by PEEP were less (P < 0.05) as VT increased, while changes in Rrs, RL and Ers were less (P < 0.05) as frequency increased. VT dependences in Ers and Rrs were enhanced (P < 0.05) at 0 cmH2O PEEP. The ratio of EL to chest wall elastance was not affected by PEEP (P > 0.05), but increased (P < 0.05) with increasing VT at 5 and 10 cmH2O PEEP. We conclude that it is critical to standardize ventilatory parameters when comparing groups of patients or testing clinical intervention efficacy and that the differential effects on the lungs and chest wall must be considered in optimizing the application of PEEP.

Retained fragment of a lumbar subarachnoid drain.

We present two patients who each had a retained subarachnoid drain catheter broken during postoperative removal. Management of these fragments should be individualized. The fragment remained in one patient, but was removed in the other because of further procedures required for hydrocephalus. We discuss possible causes of this complication as well as suggestions for prevention.

Outcomes of advance directive education of pulmonary rehabilitation patients.

We performed a two-site prospective, controlled interventional study of patients enrolled in pulmonary rehabilitation to assess effects of advance directive education on completion of (1) living wills, (2) durable powers of attorney for health care (DPAHC), (3) patient-physician discussions about advance directives, and (4) discussions about life support, in addition to (5) patient impressions that their physicians understood their end-of-life preferences. The educational group had an increase (p < 0.05) in all five study outcomes compared with baseline values; the control group had an increase in three of five outcomes. The effect strength was greater in the educational compared with the control group for completion of DPAHC (odds ratio [OR] = 3.6, 95% confidence interval [CI] 1.1 to 12.9), advance directive discussions (OR = 2.9, 95% CI 1.1 to 8.3), initiation of life-support discussions (OR = 2.7, 95% CI 1.0 to 7.7), and development of patient assurance that their physicians understand their preferences (OR = 3.7, 95% CI 1.3 to 13.4). The educational intervention was an independent explanatory factor by multivariate analysis. We conclude that patients enrolled in pulmonary rehabilitation are receptive to advance care planning, which is promoted by education on end-of-life issues.

Attitudes regarding advance directives among patients in pulmonary rehabilitation.

We performed a cross-sectional, descriptive questionnaire study in two pulmonary rehabilitation programs to assess: (1) attitudes of 105 subjects with chronic lung conditions about end-of-life decision-making; (2) the determinants of these attitudes; and (3) patient acceptance of rehabilitation programs as foci for education about advance directives (ADs). We found that 99 of the 105 subjects (94.3%) had health worries, the most common of which was fear of increasing dyspnea (33.3%). Although 93.8% had opinions about intubation, less than 42% had completed an AD. Most subjects wanted information about ADs (88.6%) and life-support (68.6%); pulmonary rehabilitation programs, lawyers, and physicians were preferred sources for AD information. Although 98.9% of the patients wanted patient-physician AD discussions, only 19.0% had such discussions, only 15.2% had discussed life-support, and only 14.3% thought that their physicians understood their end-of-life wishes. Subject willingness to undergo intubation varied with baseline health, likelihood of survival, and anticipated health following extubation. We conclude that patients in pulmonary rehabilitation programs desire more information about end-of-life issues than is currently provided by physicians. They regard pulmonary rehabilitation educators as valuable sources of AD education.

Effects of Trendelenburg and reverse Trendelenburg postures on lung and chest wall mechanics.

STUDY OBJECTIVE: To test whether the Trendelenburg ("head-down") or reverse Trendelenburg ("head-up") postures change lung and chest wall mechanical properties in a clinical condition. DESIGN: Unblinded study, each patient serving as own control. SETTING: University of Maryland at Baltimore Hospital, Baltimore, Maryland. PATIENTS: 15 patients scheduled for laparoscopic surgery. INTERVENTIONS: Patients were anesthetized and paralyzed, tracheally intubated and mechanically ventilated at 10 to 30 per minute and at a tidal volume of 250 to 800 ml. Measurements were made before surgery in supine, head-up (10 degrees from horizontal) and head-down (15 degrees from horizontal) postures. MEASUREMENTS AND MAIN RESULTS: Airway flow and airway and esophageal pressures were measured. From these measurements, discrete Fourier transformation was used to calculate elastances and resistances of the total respiratory system, lungs, and chest wall. Total respiratory elastance and resistance increased in the head-down posture compared with supine due to increases in lung elastance and resistance (p < 0.05); but chest wall elastance and resistance did not change (p > 0.05). Lung elastance also exhibited a negative dependence on tidal volume while head-down that was not observed in the supine posture. The change in lung elastance compared with supine was positively correlated to body mass index (weight/height2) and negatively correlated to tidal volume. Lung and chest wall elastance and resistance were not affected by shifting from supine to head-up (p > 0.05). CONCLUSIONS: The Trendelenburg posture increases the mechanical impedance of the lung to inflation, probably due to decreases in lung volume. This effect may become clinically relevant in patients predisposed with lung disease and in obese patients.

Pseudoobstruction of the colon: early recognition and therapy.

A case of pseudoobstruction of the colon in a patient receiving oral nimodipine therapy is presented. Early recognition of this entity, diagnostic aids, and therapy are discussed. Successful colonoscopic decompression and close observation allowed completion of nimodipine course of therapy.

Changes in lung and chest wall properties with abdominal insufflation of carbon dioxide are immediately reversible.

Previously we have reported that large increases in lung and chest wall elastances as well as lung resistance occur with abdominal insufflation of carbon dioxide during laparoscopic surgery. To examine whether these effects were reversible with abdominal deflation, we calculated lung and chest wall elastances and resistances from measurement of airway flow and pressure and esophageal pressure in 17 anesthetized/paralyzed patients undergoing laparoscopic surgery. Measurements were made immediately prior to abdominal insufflation and after deflation. Lung and chest wall elastances and resistances were not changed from baseline (P > 0.05), although total respiratory elastance remained slightly increased compared to baseline (P < 0.05). The change in total respiratory elastance did not correlate with abdominal insufflation time, surgical site, smoking history, or physical characteristics of the patients. There were no differences in frequency and tidal volume dependences of the elastances and resistances before and after abdominal insufflation (P > 0.5). We conclude that residual changes in respiratory mechanics caused by carbon dioxide insufflation during laparoscopic surgery are minor, and that the reported compromise of respiratory function indicated by pulmonary function tests after laparoscopy does not appear to be due to changes in passive mechanical properties of the lungs or chest wall.

Advance directive education during pulmonary rehabilitation.

We conducted a questionnaire survey of 346 pulmonary rehabilitation programs to determine the present utilization and potential value of these sites for promoting advance directive education for patients with chronic lung diseases. Responses were analyzed for all responding programs and for programs categorized by size. Eighty-two percent of the 218 responding programs discussed with patients prognostic information. Only 33% of programs asked patients if they had advance directives and 17% kept these documents on file. Thirty-three percent of programs provided some form of advance directive education, and 42% distributed directive educational material, usually through informal and unstructured methods. Seventy-seven percent of responders considered pulmonary rehabilitation an appropriate site for directive education, and 86% indicated willingness to incorporate directive education into their programs. Larger programs were more likely to present information about patient prognosis (p = 0.0003) and advance directives (p = 0.021). We conclude that most of the responding pulmonary rehabilitation programs do not educate patients about advance directives but are willing to do so if supplied with appropriate teaching materials. Rehabilitation programs may be valuable sites for educating patients with chronic disorders about advance directives and promoting an improved patient-physician dialogue about these issues.

Anesthesia with antiphospholipid antibodies: anesthetic management of a parturient with lupus anticoagulant and anticardiolipin antibody.

The anesthetic management of a parturient with a circulating lupus anticoagulant and an anticardiolipin antibody presenting to the obstetric suite taking heparin and aspirin is discussed. Issues concerning placement of a regional anesthetic with recent aspirin ingestion and heparin therapy are discussed. Documentation of heparin dissipation via a whole blood heparin concentration assay before induction of regional anesthesia, including several laboratory tests that could be used in monitoring coagulation status in this patient population, is discussed in detail.