PXR, CAR and HNF4alpha genotypes and their association with pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin in Asian patients.

Previously studied candidate genes have failed to account for inter-individual variability of docetaxel and doxorubicin disposition and effects. We genotyped the transcriptional regulators of CYP3A and ABCB1 in 101 breast cancer patients from 3 Asian ethnic groups, that is, Chinese, Malays and Indians, in correlation with the pharmacokinetics and pharmacodynamics of docetaxel and doxorubicin. While there was no ethnic difference in docetaxel and doxorubicin pharmacokinetics, ethnic difference in docetaxel- (ANOVA, P=0.001) and doxorubicin-induced (ANOVA, P=0.003) leukocyte suppression was observed, with Chinese and Indians experiencing greater degree of docetaxel-induced myelosuppression than Malays (Bonferroni, P=0.002, P=0.042), and Chinese experiencing greater degree of doxorubicin-induced myelosuppression than Malays and Indians (post hoc Bonferroni, P=0.024 and 0.025). Genotyping revealed both PXR and CAR to be well conserved; only a PXR 5'-untranslated region polymorphism (-24381A>C) and a silent CAR variant (Pro180Pro) were found at allele frequencies of 26 and 53%, respectively. Two non-synonymous variants were identified in HNF4alpha (Met49Val and Thr130Ile) at allele frequencies of 55 and 1%, respectively, with the Met49Val variant associated with slower neutrophil recovery in docetaxel-treated patients (ANOVA, P=0.046). Interactions were observed between HNF4alpha Met49Val and CAR Pro180Pro, with patients who were wild type for both variants experiencing least docetaxel-induced neutropenia (ANOVA, P=0.030). No other significant genotypic associations with pharmacokinetics or pharmacodynamics of either drug were found. The PXR-24381A>C variants were significantly more common in Indians compared to Chinese or Malays (32/18/21%, P=0.035) Inter-individual and inter-ethnic variations of docetaxel and doxorubicin pharmacokinetics or pharmacodynamics exist, but genotypic variability of the transcriptional regulators PAR, CAR and HNF4alpha cannot account for this variability.

Failure patterns of cryopreserved vein grafts in liver transplantation.

Reports of early success with cryopreserved saphenous veins (CSV) as arterial conduits led us to develop cryopreserved iliac veins (CIV) as interposition grafts for portal vein reconstruction in living-related liver transplantation (LRLT). Despite encouraging short-term results, retrospective analysis of long-term cryopreserved vein graft performance in LRLT at our institution has revealed a high rate of late graft failures. Between July 1992 and JUly 1994, interposition grafts (CIV for portal vein interposition n=4, CSV for portal vein interposition n=3, and CSV for hepatic artery interposition n=2) were utilized in 7 LRLT. (Two transplanted organs had both CIV and CSV grafts.) Recipients included 5 children and two small adults (median: 3.5 years, range: 0.5--59 years). Posttransplant follow-up in excess of 36 months revealed portal vein (PV) and hepatic artery (HA) complications of cryopreserved grafts in each patient. PV complications included aneurysm (n=4) diagnosed at 28, 24, 18, and 1.5 mo, stricture (n=1) diagnosed at 11 mo, and thrombosis (n=1) diagnosed at 18 mo posttransplantation. All portal vein complications have been managed without retransplantation, but one (PV thrombosis) necessitated surgical shunt therapy. Each CSV hepatic artery interposition graft has been complicated by thrombosis (diagnosed at 11 days and 24 mo posttransplant) necessitating retransplantation. Based on these observations, we have adopted alternative strategies for HA and PV reconstruction. At present, 11 LRLT have been performed without cryopreserved vein conduits over 17 mo with no vascular complications. While this study does not permit statistical analysis, these results discourage the use cryopreserved iliac veins for portal interposition and cryopreserved saphenous veins for arterial interposition in liver transplantation.

Generation of tissue factor by patient monocytes: correlation to thromboembolic complications.

Thromboembolic complications are often a common pathological consequence of severe soft tissue trauma. Recent demonstration that monocytes (M0) produce tissue factor (TF) has led to the suggestion that these TF producing M0 might play a role in coagulopathy. We have previously demonstrated that trauma patients with splenectomy develop aberrant monocyte function and this patient group is also known to be at high risk of hypercoagulability episodes. This paper is an initial report on the use of M0 TF as an indicator of and/or correlated to clotting episodes. Monocytes isolated form the Ficoll-Hypaque purified mononuclear cells of 46 normal individuals, 17 trauma patients and 6 surgical controls were assayed at 3 day post-injury intervals for their levels of TF activity. Changes in monocyte TF activity were correlated to increases in the fractional catabolic rate (FCR) of 125 I-fibrinogen. Trauma patients were retrospectively divided into those whose FcR was elevated to a level indicative of coagulopathy and those whose FCR levels were not associated with coagulation abnormalities. All trauma patients who exhibited significantly increased FCR experienced thromboembolic episodes and had monocytes whose TF activity was increased an average of 300% (mean = 47 units vs mean = 12 units) over surgical controls. These increase in monocyte TF activity occurred at 6-13 days post injury and preceded clinical manifestation of coagulopathy by 4-6 days. The increased monocyte TF activity demonstrated in this study was significantly correlated to detection of pathologically increased FCR (R = 0.850) and compared to other indices of hypercoagulability.

Late sequelae of penetrating cardiac wounds.

Physiological and psychological parameters of 20 survivors of penetrating wounds of the heart were examined 7 to 52 months after recovery. All survivors had cardiac complaints. The psychological parameters for hypochondriasis, compulsiveness, and internalization were much greater in the patients than in control subjects but were similar to those in victims of violent major abdominal trauma. Physiological abnormalities were present in 19, although no particular pattern or abnormality could be related with certainty to the type of wound, operative procedure, or postoperative course. One recovered and re-employed victim required late surgical repair of a traumatic ventricular septal defect and ventricular diverticulum. Although functional work capacity measured by stress testing was normal in 90 percent, only eight survivors resumed employment. Complete rehabilitation was impaired by a residual traumatic neurosis. Management goals for patients with penetrating cardiac wounds should be broadened to include prevention of psychological disabilities.

Is splenic salvage safe in the traumatized patient?

Thirty-three patients with splenic injuries were treated with splenic salvage techniques. These patients were seriously injured trauma victims, often with multiple organ system damage. Hemostasis of the spleen was achieved with topical agents in 26 patients. Six patients required suture repair, with one hemisplenectomy. The postoperative complication rate was 37%; however, none of the complications could be attributed to the splenic repair. No patient required reoperation for control of bleeding. There were no subphrenic abscesses, and delayed rupture of the spleen could not be established. Splenic salvage can be done safely in selected patients. Young patients, those with isolated splenic injuries, and those in whom the repair will not unduly complicate the operation should be considered for this procedure.

Hepatocellular carcinoma. Changing concepts in diagnosis and management.

We studied 86 cases of hepatocellular carcinoma treated between 1968 and 1982. All other liver tumors were excluded. There were 73 male and 13 female patients (average age, 59 years). The most frequent symptoms were pain (73%), weight loss (56%), and increased abdominal girth (23%). The alpha 1-fetoprotein level was elevated in 23 of 32 patients, and the hepatitis B surface antigen was positive in 15 of 36. Significant differences in the hematocrit reading and total bilirubin and total protein levels were found between those patients with resectable and unresectable tumors. Forty-six patients underwent laparotomy, with a resection rate of 48%. There were six right hepatic lobectomies, four left hepatic lobectomies, and 12 trisegmentectomies . The long-term survival in patients who underwent laparotomy and biopsy only was 4.2 months, while those who underwent resection had an average longevity of 18.7 months (the longest was 11.5 years). Using new imaging techniques, the extent of tumor involvement and operability can be determined with greater accuracy. Criteria for resectability include (1) the absence of vena caval occlusion, (2) the lack of spread between lobes, (3) the absence of portal vein obstruction, and (4) the lack of extrahepatic metastasis.

Determinants of survival after vena caval injury. Analysis of a 14-year experience.

The records of 70 patients with vena caval injuries who were treated from 1970 through 1983 were reviewed to define factors determining patient survival. Fifty-two percent of patients survived, with the highest mortality in patients with blunt or shotgun injuries. The primary determinants of survival were the mechanism and type of injury, the initial BP, the hemodynamic response to fluid resuscitation, the location of the vena caval injury, the presence of multiple other vascular and solid organ injuries.

Calciphylaxis in secondary hyperparathyroidism. Diagnosis and parathyroidectomy.

Calciphylaxis is a rare, severe complication of secondary hyperparathyroidism. Patients present with painful, violaceous, mottled skin lesions of the upper and lower extremities, which become necrotic and produce nonhealing ulcers. Gangrene of fingers and toes frequently requires amputation, produces nonhealing wounds, and can lead to sepsis and death. We reviewed the clinical course of five patients with calciphylaxis treated in our institution. The three men and two women (aged 47 to 72 years) had secondary hyperparathyroidism from chronic renal failure. All patients had severe pruritus, painful ulcers, and severe hyperphosphatemia with elevated serum calcium-phosphate product (greater than 12 mmol2/L2), but the serum parathyroid hormone levels were only moderately elevated. Most patients had medical calcification of medium and small blood vessels, and some had soft-tissue calcification visible on roentgenography. Treatment consisted of local wound care, antibiotics, phosphate-binding agents, and parathyroidectomy. Two patients died of uncontrollable sepsis. The three survivors had dramatic improvement of pain and ulcers after parathyroidectomy. Calciphylaxis is a limb- and life-threatening complication of secondary hyperparathyroidism. Diagnosis can be made by recognizing the characteristic painful skin lesions, ulcers, and gangrene of the digits, and patients should be treated with subtotal parathyroidectomy.

Postoperative treatment of patients after liver resection for trauma: a follow-up study.

In the last ten years, 89 hepatic resections were performed for trauma. Thirty-three patients survived and were followed up for one month to seven years: 15 patients had right lobectomy, nine left lobectomy, and nine left lateral segmentectomy. Complications were primarily pulmonary. All patients had transient derangement of liver function tests, but only three patients had liver dysfunction. Long-term follow-up showed no ill effects from the liver resection. Important postoperative treatment includes (1) adequate dependent drainage, (2) maintenance of blood volume, (3) intravenous albumin and glucose, (4) adequate nutritional support, and (5) selective use of intravenous glucagon.

Systems of trauma care. A study of two counties.

Cases of motor vehicle trauma victims who died after arrival at a hospital were evaluated in both Orange County (90 cases) and in San Francisco County (92 cases), Calif. All victims in San Francisco County were brought to a single trauma center, while in Orange County they were transported to the closest receiving hospital. Approximately two thirds of the non-CNS-related deaths and one third of the CNS-related deaths in Orange County were judged by the authors as potentially preventable; only one death in San Francisco County was so judged. Trauma victims in Orange County were younger on the average, and the magnitude of their injuries was less than for victims in the San Francisco County. We suggest that survival rates for major trauma can be improved by an organized system of trauma care that includes the resources of a trauma center.

Transmetatarsal amputation.

We have reviewed the records of 25 patients who underwent a transmetatarsal amputation at San Francisco General Hospital. The average patient age was 63 years old. Twelve of the patients were diabetic, while transmetatarsal amputations were performed in eleven with simple arteriosclerosis. Two patients underwent amputations for either trauma or nonhealing ulcer. Thirteen of the patients healed their amputation, and twelve of these became ambulatory. Eleven required higher amputation, because of nonhealing due to infection in seven and progressive ischemia in four. One patient died on the first postoperative day of pneumonia. The failure group was younger, contained more diabetics, and had a higher incidence of infection. The operative procedure of transmetatarsal amputation is described. We believe that patients with distal gangrene without spreading infection should be considered for transmetatarsal amputation, reserving initial below-knee amputation for those with greater involvement of the foot.

Morbidity and mortality following major penetrating liver injuries.

OBJECTIVE: To establish the mortality and morbidity associated with major penetrating liver injuries and to describe the nature and treatment of complications related to these injuries. We postulated that there had been a trend toward less radical initial surgery, as well as an increased utilization of modern imaging techniques in both diagnosing and treating postoperative complications following penetrating liver trauma. DESIGN: A retrospective survey of medical records and radiology files. SETTING: A university trauma center in an urban setting. PATIENTS: Of the 188 patients admitted to our trauma center with penetrating liver trauma between April 1988 and December 1991, 36 had major liver trauma (grades 3 through 5) and are described in this report. MAIN OUTCOME MEASURES: The mortality rate, type of operative treatment, and the nature and treatment of complications for each grade of major liver injury. RESULTS: The mortality rate from major liver injuries was 17%. Surgical techniques employed primarily consisted of the use of hemostatic agents and cautery, simple suturing, direct vessel ligation, and packing. Fifty-two percent of the survivors had major complications related to the liver injury itself, but only two required operative therapy. The remaining patients were successfully treated with interventional radiologic techniques. CONCLUSIONS: The morbidity and mortality following major penetrating liver injuries remain significant. The majority of hepatobiliary complications can be successfully managed without further surgery but require the combined efforts of the surgeon and interventional radiologist.

Efficacy of a fibrin hemostatic bandage in controlling hemorrhage from experimental arterial injuries.

OBJECTIVE: To determine if a pressure dressing containing fibrinogen and thrombin could provide more effective control of arterial hemorrhage than a pressure dressing alone in an animal model of arterial injury. DESIGN: Randomized acute (nonsurvival) experiment in swine. SETTING: Federal biomedical research institute. ANIMALS: Six anesthetized Yorkshire swine. INTERVENTIONS: Uncontrolled arterial hemorrhage was induced in anesthetized swine by creating femoral artery lacerations. Hemorrhage was controlled by a gauze bandage containing fibrinogen and thrombin, applied with 1 minute of 3.5-kg pressure. The dressings were left in place for 1 hour after the pressure was removed. The contralateral limbs received identical treatment with plain gauze dressings. MAIN OUTCOME MEASURES: Total blood loss, mean arterial pressure, and mortality were measured after 1 hour. RESULTS: After 1 hour, blood loss in the fibrin bandage group was 123 +/- 48 mL, compared with 734 +/- 134 mL in the control group (P = .0022). In the group treated with the fibrin bandages, there was no significant decrease in the mean arterial pressure after arterial laceration. In contrast, there was a decrease of 30 mm Hg in the group treated with gauze dressings alone. There was no animal mortality during the study period. CONCLUSIONS: Bandages containing fibrinogen and thrombin significantly reduced the amount of blood loss and allowed mean arterial pressures to be maintained in animals with uncontrolled hemorrhage from femoral artery lacerations. A hemostatic bandage may be an important adjuvant for controlling severe extremity hemorrhage in the prehospital setting.

Total vascular exclusion for major hepatectomy in patients with abnormal liver parenchyma.

BACKGROUND: Total vascular exclusion (TVE) of the liver has been used to increase the safety of hepatectomy and the feasibility of difficult resections. Until recently, however, concern about the detrimental effect of warm ischemia has limited the use of this technique to patients with normal liver parenchyma. OBJECTIVE: To compare surgical outcomes of 12 patients with abnormal livers (group 1) with outcomes of 48 patients with normal parenchyma (group 2), based on the hypothesis that uncontrolled bleeding may be more detrimental than planned hepatic ischemia. DESIGN AND SETTING: Retrospective analysis of 60 consecutive patients undergoing liver resection under TVE in a university medical center. PATIENTS: All 10 patients with cirrhosis had albumin levels of 30 g/L or higher and normal prothrombin times preoperatively; none had ascites. Two patients with cholestasis (one with cholangiocarcinoma and one with hepatocellular carcinoma) are included in group 1. INTERVENTION: All 12 group 1 patients and 44 of 48 group 2 patients underwent total or extended lobectomy, with TVE induced by clamping the hilum and the vena cava above and below the liver during parenchyma division. MAIN OUTCOME MEASURES: Hospital survival and selected surgical and laboratory parameters. RESULTS: Operative times, ischemic times, and blood loss (1975 +/- 1601 vs 1255 +/- 1291 mL) (P = .10) were comparable in both groups. Sixty-day operative mortality was zero in both groups. There was an increased rate of complications in group 1 (44% vs 17% [P = 0.06]). Transient abnormal liver function was observed in both groups. However, significant delay in restoration of normal function was observed in group 1 with respect to bilirubin levels and prothrombin time. CONCLUSIONS: Patients with cirrhosis can undergo successful resection using TVE. This conclusion must be limited to cirrhotic patients with good liver function. The trend toward increased blood loss may reflect greater difficulties in establishing hemostasis after reperfusion in group 1. While this group appears to have a higher risk for hepatic insufficiency, successful outcomes were achieved in all cases. Prospective study will be required to define the parameters for use of TVE in cirrhosis.

Laparoscopic vs open adrenalectomy for the treatment of primary hyperaldosteronism.

HYPOTHESIS: That the clinical presentations, biochemical profiles, and surgical outcomes of patients treated with laparoscopic vs open adrenalectomy for primary hyperaldosteronism are different. DESIGN, SETTINGS, PATIENTS, AND INTERVENTIONS: The medical records of 80 patients with primary hyperaldosteronism who underwent open adrenalectomy between 1975 and 1986 or laparoscopic adrenalectomy between 1993 and 1998 at the University of California-San Francisco were reviewed by a single unblinded researcher (W.T.S.). MAIN OUTCOME MEASURES: Severity of hypertension and hypokalemia at diagnosis, their improvement after adrenalectomy, and operative complications. RESULTS: Thirty-eight patients underwent open adrenalectomy and 42 patients underwent laparoscopic adrenalectomy. The patients who underwent open adrenalectomy had documented hypertension for a median of 5 years before surgery; all had diastolic blood pressures greater than 100 mm Hg. Laparoscopically treated patients had documented hypertension for a median of 2.5 years preoperatively, and 20 (48%) had diastolic blood pressures greater than 100 mm Hg. The median preoperative serum potassium levels for the open and laparoscopic groups were 2.6 mmol/L and 3.3 mmol/L, respectively; the mean serum aldosterone levels were 1.47 nmol/L and 1.30 nmol/L. Thirty-two (84%) of the 38 patients who underwent open surgery and 41 (98%) of the 42 patients treated laparoscopically had adrenal adenomas. The sensitivity of preoperative computed tomographic scanning for adenomas was 83% for the patients treated with open adrenalectomy and 93% for those treated laparoscopically. There were 4 postoperative complications in the open surgery group and none in the laparoscopic group. Postoperatively, 30(81%) of 37 patients (excluding 1 patient who died of adrenocortical carcinoma) in the open surgery group and 37 (88%) of 42 patients treated laparoscopically were normotensive. Post-operative values were 3.6 to 5.0 of serum potassium per liter and 3.5 to 4.9 of serum potassium per liter in the open and laparoscopic groups, respectively. CONCLUSIONS: Patients who are treated with laparoscopic adrenalectomy for primary hyperaldosteronism are being referred with less severe hypertension and hypokalemia than patients formerly treated with open adrenalectomy. Patients treated laparoscopically had fewer postoperative complications and were equally likely to improve in blood pressure and hypokalemia. Laparoscopic adrenalectomy has become the treatment of choice for patients with primary hyperaldosteronism because of lower morbidity.

Selective nonoperative management of blunt liver injury using computed tomography.

Computed tomographic (CT) scans are used to evaluate victims of blunt trauma for abdominal injury when reasons for immediate laparotomy are not present. Twenty-four patients whose CT scans showed liver injuries that were small parenchymal lacerations or intrahepatic hematomas were managed without laparotomy. Intra-abdominal blood was absent or estimated to be less than 250 mL in volume. None of the patients were in shock; six patients required transfusions, none for acute abdominal bleeding. None of these patients subsequently required laparotomy or showed hepatobiliary problems at a follow-up examination less than one year later. Five follow-up scans showed varying degrees of resolution. Two patients died of severe head injury, but the liver injury did not contribute to the cause of death. Other patients with more severe blunt liver injury who were treated nonoperatively developed significant complications that required delayed surgery. It seems that patients with limited liver injury diagnosed by CT scan and selected by strictly applied criteria can be managed safely without laparotomy in a setting where rapid evaluation and treatment of any potential complication is available.

Advances in management of splenic injuries.

Because there is no such thing as "minor splenic injury", the diagnosis of splenic rupture is a major problem after abdominal trauma. Since it is our policy to explore all penetrating abdominal injuries, the problem of early recognition arises in patients with blunt trauma. When abdominal evaluation is difficult because of associated injuries, we increasingly use peritoneal dialysis. This has been particularly helpful in patients with head injury or drug intoxication and has also contributed to earlier operation in patients with signs of hypovolemia but minimal abdominal findings. Angiography has been useful in doubtful cases. Review of our experience in the last five years with splenectomy (298 cases) has revealed complications, particularly thromboembolic, that have changed our management of these patients. The incidence of clinical pulmonary embolism was 4 per cent in patients having splenectomy for trauma as contrasted with 0.5 per cent in patients having laparotomy for trauma without splenectomy. Postoperative platelet evaluations in patients after splenectomy for trauma revealed thrombocytosis. Detailed follow-up platelet studies showed a peak thrombocytosis at about two weeks, averaging 976,000/mm3. In contrast, similar studies in other patients having laparotomy for trauma showed counts of about 200,000/mm3. Because of the high incidence of thromboembolic complications, a low-dose heparin regimen was initiated. There was a 30 per cent incidence of infection postoperatively.

Prevention of complications after liver trauma.

Treatment of 681 cases of liver trauma during the past ten years at the San Francisco General Hospital was reviewed. The mortality was 14.7 per cent and the morbidity rate 18.9 per cent. The complications relating specifically to liver injury were bleeding subphrenic or subhepatic abscesses, intrahepatic abscess, biliary fistula, and liver failure. These complications and the recommended management of the liver injury are discussed.

Pharyngoesophageal caustic stricture. Treatment by pharyngogastrostomy compared to colon interposition combined with free bowel graft.

Four cases of combined hypopharyngeal and cervical esophageal stricture secondary to caustic ingestion are presented. Although gastropharyngostomy has rarely been used for treatment of patients with caustic stricture of the pharynx and cervical esophagus, we believe that it is a useful procedure and has several advantages over use of the colon. We prefer total esophagectomy and posterior mediastinal transposition of the stomach to the neck followed by gastropharyngostomy in those patients who have minimal stomach involvement.

Morbidity and mortality in hepatic trauma. A 5 year study.

The records of 443 cases of liver trauma operated on at San Francisco General Hospital from 1976 to 1981 were reviewed. Forty-two percent of the injuries were due to blunt trauma, 32 percent to stabbings, and 26 percent to gunshot wounds. Seventy-two percent of the patients were treated by simple repair and only 8 percent of patients had to undergo major resection. Infections and pulmonary problems were the most common complications, and the overall morbidity was 38 percent. Associated injuries occurred in 84 percent of patients. Our overall mortality was 9 percent; mortality for blunt trauma was 14 percent, for gunshot wounds 8 percent, and for stab wounds 2.8 percent. Most deaths were intraoperative (58 percent), with the primary cause of death being exsanguination. Multiple organ failure accounted for most of the postoperative deaths. Our 5 years study and comparison with previous studies reaffirms our belief in a conservative approach to the traumatized patient with liver injury. Utilizing the aforementioned principles, we have managed to show a continual decrease in mortality in spite of treating a more severely traumatized group of patients. We believe that continued improvement in mortality and morbidity is possible through the prevention of trauma, adherence to our basic guidelines, and the implementation of new technological advances now on the horizon.