Abrogation of taxol-induced G2-M arrest and apoptosis in human ovarian cancer cells grown as multicellular tumor spheroids.

Tumor cells grown as multicellular spheroids are known to be intrinsically more resistant to a large and diverse array of anticancer chemotherapeutic drugs compared to the same cells grown as dispersed monolayer cell cultures. Some drugs, however, seem relatively insensitive to this multicellular drug resistance, e.g., cisplatinum. Whether the cytotoxic effects of Taxol, an anticancer drug of growing importance in the treatment of breast and ovarian carcinomas, are diminished by multicellular growth conditions is unknown. To study this question, we examined the relative sensitivity of a panel of four different human ovarian carcinoma cell lines to either Taxol or cisplatinum. Upon exposure to Taxol, all the cell lines manifested a relative drug-resistant phenotype when grown as multicellular tumor spheroids, compared to the same cells grown as sparse monolayer cultures. This multicellular-dependent drug-resistant phenotype was not observed when the same cells were exposed to cisplatinum for an equivalent length of time. Monolayer but not spheroid cultures exposed to Taxol demonstrated an accumulation of cells at G2-M and a sub-G1 apoptotic region. In addition, Taxol-induced apoptosis was detected in monolayer conditions but not in the spheroid cultures. The relative sensitivity of the monolayer cell cultures was associated with a decrease in bcl-X(L) protein levels after Taxol exposure, an effect not observed in drug-exposed spheroids. Taken together, these results suggest that some aspects of intrinsic Taxol resistance in ovarian carcinoma may be due to multicellular-dependent or -associated mechanisms. This raises the possibility of using antiadhesive agents to reverse multicellular-dependent Taxol resistance in certain circumstances as a potential means of increasing the initial efficiency of Taxol therapy against ovarian carcinoma.

In vitro and in vivo effects of a monoclonal antibody-toxin conjugate for use in autologous bone marrow transplantation for patients with breast cancer.

We have devised a method utilizing a monoclonal antibody-toxin conjugate (LICR-LON-Fib75/abrin A-chain) for ridding bone marrow of infiltrating breast cancer cells to rescue patients with autologous bone marrow following high dose therapy. Initially we examined the activity of this conjugate in vitro. Five of seven human breast cancer cell lines were killed following exposure at 10(-8) M for 2 h; this concentration only reduced bone marrow colony formation to 83% (range, 50-100%) of control bone marrow. We then examined the pattern of bone marrow recovery after high dose melphalan (200 mg/m2) in patients with advanced breast cancer who were in remission following combination chemotherapy. To do this we compared the time of recovery of the blood count in three patients who received treated marrow and seven who received untreated marrow. Mean time to recovery of the peripheral white count (greater than 1.5 X 10(9)/liter) was 16.7 days (treated) and 18.3 days (untreated), respectively. Mean time to recovery of peripheral platelet count (greater than 50 X 10(9)/liter) was 23.7 days (treated) and 18.9 days (untreated), respectively. Patients continued in remission for 1-greater than 14 mo after high dose melphalan, and remission duration was similar in patients who received treated (6.2 mo) and untreated (7.3 mo) bone marrow. These findings indicate that treatment of bone marrow with LICR-LON-Fib75/abrin A-chain conjugate does not significantly impair bone marrow recovery, and it is, therefore, possible to rescue breast cancer patients with bone marrow that has been cleansed of infiltrating cancer cells. This may have an application in patients with poor-risk primary breast cancer who have micrometastases and who may benefit from intensive therapy, but it has minimal application in patients with more advanced disease.

Phase II study of weekly edatrexate as first-line chemotherapy for metastatic breast cancer: a National Cancer Institute of Canada Clinical Trials Group study.

PURPOSE: The National Cancer Institute of Canada (NCIC) Clinical Trials Group conducted a phase II study to assess the efficacy and toxicity of edatrexate, a folate antagonist, in 35 patients with metastatic breast cancer. PATIENTS AND METHODS: The planned dose of edatrexate was 80 mg/m2/wk administered intravenously as first-line therapy. Prior adjuvant chemotherapy was allowed provided at least 12 months had elapsed from the completion of treatment to the development of recurrence. RESULTS: Mucositis was the dose-limiting toxicity in 34 assessable patients, resulting in a mean delivered dose-intensity of 57 mg/m2/wk. Other toxicities included myelosuppression, rash, pneumonitis, and increased AST. Side effects were generally mild to moderate. The complete plus partial remission rate (13 patients; 41%) was impressive. CONCLUSION: Edatrexate is an active agent against metastatic breast cancer, with acceptable toxicity. A lower than planned delivered dose-intensity was mainly due to mucositis.

High-dose cyclophosphamide in small-cell carcinoma of the lung.

Eighteen patients with untreated small-cell cancer of the lung have been treated with cyclophosphamide 200 mg/kg on two occasions at an interval of four weeks. An additional eight patients received etoposide in addition to cyclophosphamide. Measurements of tumor volume were made by thoracic computed tomographic (CT) scan before and after each cycle. When compared with our previous study in which only one cycle of cyclophosphamide was given, the double procedure did not increase response rate, decrease the incidence of local relapse, or prolong the relapse-free interval. Survival after relapse was shorter with two cycles of chemotherapy mainly due to greater difficulty in administering further chemotherapy. The CT scans showed a decrease in tumor volume from 99.2 cc to 21 cc after the first cycle, but a smaller decrease to 14.1 cc after the second. These results show that the rapid emergence of drug resistance imposes limitations on the use of very high-dose cytotoxic chemotherapy.

Randomized trial of cyclophosphamide, methotrexate, and fluorouracil chemotherapy added to tamoxifen as adjuvant therapy in postmenopausal women with node-positive estrogen and/or progesterone receptor-positive breast cancer: a report of the National Cancer Institute of Canada Clinical Trials Group. Breast Cancer Site Group.

PURPOSE AND METHODS: By the mid 1980s, tamoxifen alone was considered standard adjuvant therapy for postmenopausal women with node-positive, estrogen receptor (ER)- or progesterone receptor (PgR)-positive breast cancer. From 1984 through 1990, 705 eligible postmenopausal women with node-positive, ER- or PgR-positive breast cancer were randomized to a National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) study that compared tamoxifen 30 mg by mouth daily for 2 years (TAM) versus TAM plus chemotherapy with all-intravenous cyclophosphamide 600 mg/m2, methotrexate 40 mg/m2, and fluorouracil 600 mg/m2 given every 21 days for eight cycles (CMF). RESULTS: There were no significant differences in overall survival, recurrence-free survival, locoregional recurrence-free survival, or distant recurrence-free survival between the two treatment arms. However, there was significantly greater severe toxicity, which included leukopenia (P < .0001), nausea and vomiting (P < .0001), and thromboembolic events (P < .0001), as well as significantly more mild or greater toxicity, which included thrombocytopenia (P = .04), anemia (P = .02), infection (P = .0004), mucositis (P = .0001), diarrhea (P = .0001), and neurologic toxicity (P = .006), in women who received TAM plus CMF. CONCLUSION: The addition of CMF to TAM adds no benefit and considerable toxicity in this group of women.

Clozapine for refractory schizophrenia: the Illinois experience.

Based upon the Illinois Department of Mental Health and Developmental Disabilities' computerized clinical information system, with its integration of client-specific clinical data, a 5-year retrospective study was designed to determine the clinical effectiveness and economic impact of the use of clozapine for treatment-resistant schizophrenia. The study sample consisted of 518 hospitalized, treatment-resistant patients. At the end of 5 years, 78% were well maintained on clozapine. Two hundred forty-three patients had been discharged to the community, and 62 had been transferred for treatment of medical or surgical problems. Clozapine treatment was discontinued in 115 patients (22%). The drug was well tolerated, with a very low incidence of agranulocytosis. Cost savings resulting from the discharge of the 243 clozapine-treated patients amounts to approximately $20 million per year. A disease management algorithm has been developed allowing physicians to begin clozapine treatment for patients not successfully treated with 2 prior antipsychotic agents. Adherence to this protocol throughout the state's mental health system would result in even greater savings.

William Cowper.

William Cowper, now virtually forgotten, was the first of the surgeon-scientists of Great Britain. He was the first to bring the power of the experimental method to bear on practical surgical problems and to urge that the principles of surgery be drawn from an understanding of the "animal oeconomy." In these areas he anticipated the celebrated Hunterian school of surgery by more than half a century and by his example he actually set the foundation on which that school was built. Cowper was a scientist of a high order. He was the first to prove the existence of capillaries in higher mammals, to describe naturally occurring arteriovenous shunts in the lungs and spleen, to define the essential physiology of aortic valvular disease, and to recognize the nature and consequences of arteriosclerotic vascular disease. He was the author of two important anatomy books and the first English language treatise on general physiology available to surgeons. He was one of the first two surgeons ever honored by election to the prestigious Royal Society of London. An analysis of the works and doctrines of William Cowper appears to cast serious doubt on the common teaching that the idea of "scientific surgery" was the sole creation of John Hunter.

Percutaneous diagnosis and drainage of pylephlebitis: a case report.

Suppurative pylephlebitis is a rare complication of intra-abdominal inflammatory processes, but it carries a high mortality rate. Even in this modern era, diagnosis and treatment are difficult because of the nonspecificity of clinical signs and symptoms, as well as laboratory tests. We present a case in which the diagnosis of pylephlebitis was made in the radiology department by percutaneous needle aspiration of the portal venous system. Computerized tomography is very helpful in the diagnosis of pylephlebitis but requires that the radiologist be familiar with this rare entity. The computerized tomographic findings in this case are described and discussed. This patient was treated with percutaneous transhepatic drainage of the portal venous system and antibiotics only since we thought he would not survive a surgical procedure. To the best of our knowledge, there have been no previous reports of percutaneous therapy of pylephlebitis. The patient had an uneventful recovery.

Some effects of Bunnell suture on otherwise uninjured tendons in subhuman primates.

An experimental study was performed in rhesus monkeys (M. mulatta) to examine the contribution of Bunnell tendon suture to the production of postoperative tendon adhesions. It was found that Bunnell suture used with atraumatic technique caused a significant depression of in vitro tendon surface plasminogen activator activity, allowing the in vivo persistence and fibrous organization of fibrinous postoperative adhesions to sutured areas. Bunnell suture also produced coagulation necrosis of the sutured area of tendon. Collagen, which replaced the destroyed areas, was oriented randomly and frequently was continuous with surface tendon adhesions to surrounding connective tissues. Bunnell suture appears to be a cause of tendon adhesions in subhuman primates. The importance of fibrin and depressed local fibrinolysis in the relationship of tendon ischemia and adhesion formation is discussed.

Anatomic considerations in penetrating gluteal wounds.

A retrospective study of 81 patients with penetrating gluteal wounds was performed to determine if the site of penetration was useful in predicting the likelihood of associated vascular or visceral injury. There were 53 gunshot wounds and 28 stab wounds, including one impalement. The gluteal region was divided into upper and lower zones by determining whether entry occurred above or below the greater trochanters. Sixty-six percent of all penetrating gluteal wounds entered the upper zone. Thirty-two percent of patients with upper zone penetration had associated vascular or visceral injury. Only one of 27 patients with lower zone penetration sustained major injury. The site of entry plays a critical role in determining the likelihood of serious injury associated with penetrating gluteal wounds. Wounds penetrating above the greater trochanters demand thorough evaluation, especially gunshot wounds.

Direct cardiac massage without major thoracotomy: feasibility and systemic blood flow.

BACKGROUND: Open-chest cardiac massage (OC-CM) provides higher blood pressure and flow than closed-chest compression and may improve the probability of successful resuscitation from cardiac arrest. Its clinical use has been limited by its requirement for a major thoracotomy. The present pilot study tested the technical feasibility of performing effective direct cardiac massage without a major thoracic incision, by using a simple, manually-powered plunger-like device, inserted through a small thoracic incision, to cyclically compress the cardiac ventricles. The method was termed minimally-invasive direct cardiac massage (MID-CM). Systemic blood flow using MID-CM was compared to that with OC-CM, by both direct systemic hemodynamic measurements, cumulative metabolic indicators of the ratio of whole body oxygen delivery and oxygen consumption, and a metabolic index of pulmonary blood flow. METHODS: In 12 large swine, baseline systemic and pulmonary hemodynamic measurements were performed. Arterial and mixed venous blood gases and metabolic indicators of systemic blood flow were measured. Ventricular fibrillation was induced and after 4 min, animals underwent either bimanual OC-CM (N = 6) or MID-CM (N = 6). At 10, 20 and 30 min, hemodynamic and metabolic measurements were repeated. RESULTS: Systemic Blood Pressure: Aortic systolic and diastolic blood pressures were reduced from baseline levels with both OC-CM and MID-CM. No difference in pressure was noted between OC-CM and MID-CM groups. Pulmonary Artery Pressure: Pulmonary artery systolic pressure was elevated from baseline during OC-CM and MID-CM. Pulmonary artery diastolic pressures remained constant throughout the resuscitation period in both groups. No differences in pulmonary systolic or diastolic pressure were noted between OC-CM and MID-CM groups. A trend towards higher pulmonary systolic pressures appeared with MID-CM. Thermodilution Blood Flow: Cardiac index fell from baseline levels with OC-CM and MID-CM. No difference in cardiac index was noted between OC-CM and MID-CM groups. Metabolic Indices: Mixed venous O2 saturation decreased from baseline levels during resuscitation in both experimental groups, with a further decrease at 30 min compared to 10- and 20-min levels. No difference was noted between OC-CM and MID-CM groups at any point. Arterial pH was reduced from baseline levels at 30 min in both groups compared to baseline but no difference was noted between groups.(ABSTRACT TRUNCATED AT 400 WORDS)

Open-chest cardiac massage without major thoracotomy: metabolic indicators of coronary and cerebral perfusion.

OBJECTIVE: To compare the coronary and cerebral perfusion achieved using a novel method of minimally-invasive, direct cardiac massage to that obtained using bimanual, open-chest cardiac massage. DESIGN: Prospective, controlled animal study with repeated measures. SETTING: University research laboratory. SUBJECTS: Large domestic swine. INTERVENTIONS: Aortic, coronary sinus, jugular venous and pulmonary artery catheters were placed. Following an equilibration period, ventricular fibrillation was induced. After 4 min of untreated ventricular fibrillation, animals underwent bimanual, open-chest cardiac massage (N = 6) or minimally-invasive, direct cardiac massage using a novel device for direct cardiac compression (N = 6). Adrenaline was administered at a dose of 1 mg intravenously every 5 min. MEASUREMENTS: Systemic metabolic parameters, (arterial PO2, PCO2 and lactate concentration) and coronary sinus and jugular venous metabolic parameters (pH, PVO2, SVO2, PVCO2 and lactate concentration) were measured and calculated (coronary sinus/jugular-arterial SVO2, coronary sinus/jugular-arterial PCO2 and lactate differences) at baseline and at 10, 20 and 30 min following induction of ventricular fibrillation. Animals were euthanised after 30 min with no attempt at defibrillation. MAIN RESULTS: Oxygen tension and oxygen saturation of coronary sinus blood declined significantly during the experimental period, but no differences were noted between treatment groups. The coronary sinus-arterial oxygen saturation difference increased during the study with no significant differences between groups. Coronary sinus PCO2 and the coronary sinus-arterial PCO2 difference increased significantly in both experimental groups during cardiac massage. No inter-group differences were noted. A similar relationship was noted in coronary sinus lactate values. The coronary sinus-arterial lactate difference displayed a positive balance at all intervals with no differences noted between group values. The oxygen tension and oxygen saturation of jugular venous blood, were reduced from baseline levels with both treatments. The jugular-arterial oxygen saturation difference increased in both groups compared to baseline values. Between group values were significantly different only at the 20 min interval. Both the jugular venous PCO2 and the jugular-arterial PCO2 gradient were elevated at all intervals, but no inter-group differences were noted. Jugular venous lactate concentration rose steadily with time in both groups. No significant increase in the jugular-arterial lactate gradient was noted at any time point. CONCLUSIONS: Minimally-invasive, direct cardiac massage provides coronary and cerebral perfusion similar to that achieved using standard open-chest cardiac massage. This method may provide a more effective substitute for standard, closed-chest cardiac massage in cases of refractory cardiac arrest.

Future directions for resuscitation research. V. Ultra-advanced life support.

Standard external cardiopulmonary resuscitation (SECPR) frequently produces very low perfusion pressures, which are inadequate to achieve restoration of spontaneous circulation (ROSC) and intact survival, particularly when the heart is diseased. Ultra-advanced life support (UALS) techniques may allow support of vital organ systems until either the heart recovers or cardiac repair or replacement is performed. Closed-chest emergency cardiopulmonary bypass (CPB) provides control of blood flow, pressure, composition and temperature, but has so far been applied relatively late. This additional low-flow time may preclude conscious survival. An easy, quick method for vessel access and a small preprimed system that could be taken into the field are needed. Open-chest CPR (OCCPR) is physiologically superior to SECPR, but has also been initiated too late in prior studies. Its application in the field has recently proven feasible. Variations of OCCPR, which deserve clinical trials inside and outside hospitals, include 'minimally invasive direct cardiac massage' (MIDCM), using a pocket-size plunger-like device inserted via a small incision and 'direct mechanical ventricular actuation' (DMVA), using a machine that pneumatically drives a cup placed around the heart. Other novel UALS approaches for further research include the use of an aortic balloon catheter to improve coronary and cerebral blood flow during SECPR, aortic flush techniques and a double-balloon aortic catheter that could allow separate perfusion (and cooling) of the heart, brain and viscera for optimal resuscitation of each. Decision-making, initiation of UALS methods and diagnostic evaluations must be rapid to maximize the potential for ROSC and facilitate decision-making regarding long-term circulatory support versus withdrawal of life support for hopeless cases. Research and development of UALS techniques needs to be coordinated with cerebral resuscitation research.

Clamp control of the right ventricular angle to facilitate exposure and repair of cardiac wounds.

Penetrating cardiac wounds, especially those of the posterior surface, present a major challenge to the trauma surgeon. Previously described methods to assist in cardiac exposure include manual control and apex stitch. The authors describe a simple technique to facilitate exposure during acute control and repair of traumatic cardiac wounds. Using an atraumatic vascular clamp in the fashion described allows for improved exposure and easier repair of heart surface wounds.

Vertical deceleration trauma. Principles of management.

A highly complex interaction of several physical and biomechanical factors determines the patterns of injury and probability of survival in free falls. Falls from extreme heights result in massive visceral and vascular injuries, which are usually lethal. Urban falls tend to result in severe lower extremity, spinal, and pelvic fractures. Retroperitoneal hemorrhage is a significant cause of death and is best managed by emergency angiography and embolization. Early fixation of fractures reduces morbidity.

Injuries of the inferior vena cava.

Injuries of the IVC, whether caused by blunt or penetrating mechanisms, are usually fatal. Patients who arrive in shock and fail to respond to initial resuscitative measures, those who are still actively bleeding at the time of laparotomy, and those with wounds of the retrohepatic vena cava have a low probability of survival. Death most commonly is caused by intraoperative exsanguination. Knowledge of the anatomy and exposure techniques for the five different segments of the intra-abdominal vena cava is very important to trauma surgeons. Although some wounds of the vena cava, especially those of the retrohepatic vena cava, are best left unexplored, most injuries inferior to this level can be exposed and repaired by lateral suture technique. Preservation of a lumen of at least 25% of normal is probably important in the suprarenal vena cava but is of no provable value inferior to the renal veins. No evidence supports the need to expose and repair vena caval wounds that have spontaneously stopped bleeding. Such wounds, especially in the retrohepatic area, may be managed expectantly provided that there is no strong suspicion of an associated injury to a major artery or hollow viscus.

Portal vein injuries.

Wounds of the portal vein are caused most commonly by penetrating trauma and carry a very high mortality rate. Most deaths are caused by exsanguination, occurring intraoperatively as surgeons struggle to control the hemorrhage from the portal vein and associated vascular injuries. A thorough knowledge of the anatomy of the area and of the likely patterns of wounding is important. At surgery, surgeons must be prepared to deal with multiple vessel wounding. Although most investigators have advocated lateral repair of the portal vein when it can be accomplished, portal ligation seems to be a safe alternative. Complex repairs are justified only when a contraindication to ligation exists. Postoperative care must recognize the need for extraordinary fluid replacement and the small risk for postoperative bowel infarction after repair or ligation of the portal vein.

Communication skills in palliative care: a practical guide.

Communication skills are frequently regarded as innate and intuitive. Many studies, however, now show that most components of communication techniques can be taught and that these learned skills have an impact on the physician's ability to communicate. This article sets out two fundamental protocols that act as templates or strategies for communication. One, (the C-L-A-S-S strategy) highlights the five central factors in all clinician-patient interviews. The second (the S-P-I-K-E-S protocol) is a variant for the specific task of breaking bad news.

Penetrating neck trauma in children: an urban hospital's experience.

OBJECTIVE: As the incidence of violent crime increases in our society, the rate of penetrating head and neck trauma in children also rises. The methods of management of pediatric penetrating neck wounds are addressed. METHODS: All clinical records of children younger than 18 years admitted with penetrating neck injuries between 1990 and 1997 were reviewed. The injuries were classified according to type and location of the neck wound. Demographic data, clinical presentation, diagnostic studies, and management techniques were evaluated. RESULTS: Thirty-five children aged 6 to 18 years old were evaluated for 31 missile wounds and 4 stab wounds. There were 30 boys and 5 girls. Fourteen percent of injuries were in zone 1, 60% in zone II, and 26% in zone III. Of the 33% of children with zone II penetrating neck traumas who underwent selective neck explorations, 86% had significant intraoperative findings. The mortality rates for zones I, II, and III were 60%, 29%, and 56%, respectively. The overall mortality rate was 40%. CONCLUSIONS: Penetrating neck trauma in children may lead to potentially life-threatening injuries. Selective management of penetrating head and neck injuries in children can be a safe and effective policy in an experienced trauma center.

Extended intravascular shunting in an experimental model of vascular injury.

PURPOSE: To examine the extended patency (> 24 hrs) of heparin-bonded intravascular shunts in a porcine model of vascular injury. PROCEDURES: Adult swine underwent bilateral, common iliac artery resection (n = 5) or bilateral common iliac vein resection (n = 5) and vessel replacement with interposition, heparin-bonded shunts. Three control swine had vessel dissection only. Hematologic and coagulation profiles were measured at baseline and 24 hrs. Limb perfusion was assessed at 24 hrs by clinical exam and angiography. RESULTS: At 24 hrs, all limbs in both shunt groups were well perfused. All arterial shunts were angiographically patent. No distal emboli were detected. Nine of 10 venous shunts were patent, seven were lined with non-occluding thrombus. No alterations in hematologic or coagulation profiles were noted. CONCLUSIONS: Heparin-bonded shunts remained patent in arteries for 24 hours. Shunts placed in the venous system were prone to thrombus formation but most remained patent.