Cancer cells surviving hypoxia obtain hypoxia resistance and maintain anti-apoptotic potential under reoxygenation.

In solid tumors hypoxia and reoxygenation may be important factors in secondary expansion after anti-cancer therapy. Our study examined the effect of hypoxia and reoxygenation on the apoptotic potential of cancer cells. Four experimental groups were studied using a human colorectal cancer cell line (HCT116) that is apoptosis-competent in conventional culture: (1) sham, cells grown under conventional conditions; (2) hypoxic, cells cultured in 95% N2 and 5% CO2 for 24 hr; (3) continued hypoxic, cells cultured for 48 hr; and (4) reoxygenation, cells grown in hypoxic conditions for 24 hr followed by another 24 hr under conventional conditions. Protein expression of p53, bcl-2 and PCNA were determined by immunohistochemistry and immunoblotting (p53), and viable cell growth rate was determined. Hypoxia for 24 hr induced significant up-regulation of p53 and bcl-2 expression, accompanied by significant decreases of cell growth rate and PCNA expression. Up-regulation of p53 and bcl-2 expression persisted with both continued hypoxia and reoxygenation, despite increased cell growth rate and PCNA expression. Cells escaping hypoxia acquired sustained resistance to apoptosis and proliferate despite an elevated p53 level, suggesting that p53 transfer to hypoxic solid tumor should be reevaluated as a cancer gene therapy approach.

The potential role of fecal carbonic anhydrase II in screening for colorectal cancer.

Several studies have demonstrated a relationship between mucosal carbonic anhydrase (CA) isoenzymes, particularly CA II, and cancer of the large intestine. Recent work has suggested the potential usefulness of fecal CA assay for colorectal cancer screening. This clinical study examined the accuracy of fecal CA II as a marker of adenocarcinoma of the colon and rectum. An enzyme-linked immunosorbent assay was used to measure CA II in urine, serum, and stool samples from 31 colorectal cancer patients and 26 control subjects. An immunochemical fecal occult blood test was also performed in all study participants. Urine and serum CA II were similar in the two study groups. However, both the prevalence and the mean level of fecal CA II in the cancer patients were significantly higher than those in the control group. The detection rate for CA II in the stool was 65 per cent for the cancer patients versus 4 per cent for the control population. The fecal CA II test was similar in sensitivity and specificity to the immunochemical fecal occult blood test (65 vs 48%; 96 vs 100%). Measurement of fecal CA II might be useful in screening for colorectal cancer.

ICU scoring systems do not allow prediction of patient outcomes or comparison of ICU performance.

Recent revisions of the major ICU scoring systems have broadened their database markedly and increased their statistical accuracy. For a specific patient, however, the systems cannot be accurate enough to direct management decisions. Significant questions remain about the reliability of these systems for comparing different ICUs and different patient populations, especially in surgical and trauma patients. Current scoring systems, therefore, cannot be used reliably in either the management of the individual patient or in the making of quality comparisons between ICUs.

Perforated jejunal diverticula.

Jejunal diverticular (JD) perforation is an uncommon cause of acute abdominal pain in the elderly. From 1971 to 1994 we treated 13 such patients, 9 men and 4 women, with a mean age of 68 years. All patients experienced sudden onset of abdominal pain, nausea and vomiting, and leukocytosis (range of white blood cell counts, 14,000-21,000). On physical examination, three patients had localized peritonitis, were thought to have appendicitis, and underwent immediate laparotomy and segmental jejunal resection for perforated JD. The remaining 10 patients had abdominal tenderness without peritoneal signs. They were hospitalized and managed expectantly. All experienced worsening signs and symptoms and underwent exploratory laparotomy and resection of the involved jejunal segment 13 hours to 8 days after admission. Although 6 of 13 patients had had JD documented previously, in only 2 patients was perforated JD diagnosed preoperatively. In 8 of 13 patients peritoneal contamination was minimal and was contained within the leaves of the mesentery. Soilage was severe with abscess formation in 5 patients. The longer the delay in operative intervention, the greater the peritoneal soilage. The 3 patients undergoing immediate surgery had minimal contamination. Of the 10 patients initially observed, the mean interval before operation was 74 hours in the 5 patients with severe soilage versus 21 hours in those with minimal contamination. The postoperative course was uneventful in 11 patients. Two patients died. Surgical consultation was delayed (8 days, 12 days) in both patients, who had severe peritoneal contamination and died of sepsis. In conclusion, JD perforation is an uncommon and frequently overlooked cause of acute abdominal pain in elderly patients. Timely operative intervention and resection of the involved jejunum are the keys to a successful outcome. Because the presentation and physical findings of perforated JD can be highly variable, a history of preexisting JD should arouse suspicion for JD perforation as the etiology of acute abdominal pain in the elderly.

The safety of orotracheal intubation in patients with unstable cervical spine fracture or high spinal cord injury.

BACKGROUND: The potential merits and dangers of orotracheal and nasotracheal intubation in patients with injury to the cervical spine or spinal cord continue to be debated. To address this issue, a prospective study was conducted at a level 1 trauma center in patients with respiratory embarrassment and either or both of these injuries. MATERIALS AND METHODS: Over a 7-year period, all such patients underwent neurologic examination by a trauma surgeon on arrival at the trauma center, immediately after endotracheal intubation, and at frequent intervals throughout hospitalization. Cervical immobilization was maintained manually during endotracheal intubation. When necessary, patients were sedated or paralyzed with short-acting pharmacologic agents. RESULTS: During the study period, there were 81 patients with 98 cervical vertebral body fractures, but without evidence of spinal cord injury on initial examination. Sixty-seven patients (83%) were legally intoxicated, and 12 patients had closed head injury. Endotracheal intubation was performed in 26 patients with unstable fractures, and 22 patients were intubated via the oral route. No patient manifested a subsequent neurologic deficit. Sixty-nine additional patients presented with high spinal cord injury; 16 had no cervical spine fracture, and 53 patients had 61 fractures of the cervical vertebrae. Sixty patients (87%) were intoxicated, and 8 patients had closed head injury. Endotracheal intubation was performed in 29 of these patients, and 26 patients were intubated via the oral route. No patient experienced further neurologic deficit following endotracheal intubation. CONCLUSION: In trauma victims with or at high risk of cervical spinal cord injury, orotracheal intubation is a rapid, safe means of achieving airway control.

Long-term results of curative resection of "minimally invasive" colorectal cancer.

PURPOSE: The aim of this study was to determine the long-term outcome after curative resection of colorectal cancers that extend only into the submucosa ("minimally invasive") and to evaluate potential histologic predictors of lymph node metastases. METHODS: Seventy-nine patients who underwent curative resection of minimally invasive colorectal cancer and were followed for at least five years were studied retrospectively. RESULTS: The series was comprised of 53 men and 26 women, with a mean age of 61 years. The lesion was in the colon in 47 patients and the rectosigmoid or rectum in 32 patients. Open surgery followed attempted endoscopic tumor removal in 25 patients. Lymph node metastasis, found in 11/79 patients (13.9 percent), was associated with worse outcome: 36.4 percent of node(+) patients developed recurrence, vs. only 5.9 percent of node(-) patients (P < 0.005). The cumulative survival rate was also worse in node(+) vs. node(-) patients: 72.7 percent vs. 91.1 percent at five years (P < 0.05) and 45.5 percent vs. 65.3 percent at ten years (P < 0.05). Five histopathologic characteristics were identified as risk factors for lymph node metastasis: 1) small clusters of undifferentiated cancer cells ahead of the invasive front of the lesion ("tumor budding"); 2) a poorly demarcated invasive front; 3) moderately or poorly differentiated cancer cells in the invasive front; 4) extension of the tumor to the middle or deep submucosal layer; 5) cancer cells in lymphatics. Whereas patients with three or fewer risk factors had no nodal spread, the rate of lymph node involvement with four or more risk factors was 33.3 percent and 66.7 percent, respectively. CONCLUSIONS: Metastasis is not infrequent in "minimally invasive" colorectal cancer. Appropriate bowel resection with lymph node dissection is indicated if such a lesion exhibits more than three histologic risk factors for metastasis.

Trauma team activation for 'mechanism of injury' blunt trauma victims: time for a change?

Excessive overtriage prompted a review of all stable blunt trauma victims < or = age 65 years transported to our trauma center from 1990 through 1992 only by virtue of mechanism of injury. Of 4392 blunt trauma patients, 2298 (52%) met review criteria. In this group 1712 (75%) were discharged home from the emergency room, and 586 were hospitalized: 367 (63%) for < or = 1 day; 465 (79%) for < or = 2 days. Of 93 ICU patients, 61 (66%) stayed < or = 24 hours, and 78 (84%) < or = 48 hours. Most ICU admissions were for neurologic or cardiac monitoring. The mean ISS of the population was < or = 2.8; only 15 patients had an ISS > or = 16. No patient required urgent transfer from the emergency room to the operating room for hemodynamic or neurologic instability. Four patients (0.17%) had early surgery following appropriate radiologic evaluation and underwent hemisplenectomy; brachial artery repair; ligation of a mesenteric bleeder; or evacuation of a subdural hematoma. Early open reduction/internal fixation of extremity fractures was done in 22 other patients (0.96%). Initial trauma team evaluation of hemodynamically stable blunt trauma victims whose only reason for trauma center transport is mechanism of injury is needlessly labor intensive and is not cost effective. Rather, a competent trauma center emergency medicine physician should be able to safely perform an initial assessment of such patients and summon the surgery team for specific clinical or radiologic indicators.

Surgical scar endometrioma.

Relatively few instances of surgical scar endometrioma have been reported. Herein we review 24 patients treated for this condition at the institutions at which we work between 1972 and 1992. The age of the patients ranged from 17 to 47 years, with an average age of 31.7 years. Surgical scar endometriomas occurred after operations including cesarean section (19 patients), appendectomy (two patients), episiotomy (two patients) and hysterectomy (one patient). The interval between prior surgical treatment and the onset of symptoms ranged from one to 20 years, with an average of 4.8 years. All patients were treated by wide excision. Seventeen of 24 patients were available for follow-up evaluation. The interval between excision and follow-up evaluation ranged from 1.2 to 14.0 years, with an average of 6.4 years. None of the patients had recurrence of surgical scar endometrioma. Patients with the classic presentation of a painful surgical scar mass that increases in size or tenderness during menstruation need no further evaluation of the lesion before excision. Ultrasonographic examination and fine needle aspiration biopsy should be used preoperatively in women who have a constantly painful or asymptomatic mass in a surgical scar. Because medical management yields poor results, wide excision of surgical scar endometriomas is the treatment of choice.

Prospective, randomized trial of the biofragmentable anastomosis ring. The BAR Investigational Group.

A randomized trial was undertaken to compare the biofragmental anastomotic ring (BAR) with conventional intraperitoneal colorectal anastomotic techniques. Patients were randomized into one of two schemes: BAR versus sutured or BAR versus stapled anastomosis. There were 782 patients entered into the study and 283 patients (36%) had a sutured anastomosis, 104 patients (13%) had a stapled anastomosis, and 395 (51%) had the BAR. Comparison of the BAR with combined suture and stapled controls revealed no significant differences in wound complication, abscess rate, bleeding, anastomotic leaks, ileus, obstruction, or deaths. There were no differences in return of bowel function, return to normal diet, or hospital stay. Intraoperative difficulties occurred in 46 BAR patients (17%), and this was significantly higher (p less than 0.001) than for sutured (3%) but not for stapled anastomoses (11%). The occurrence of these problems did not adversely effect the outcome. The data suggest that the BAR is a safe, satisfactory alternative to sutured or stapled colorectal anastomoses.

Impact of encephalopathy on mortality in the sepsis syndrome. The Veterans Administration Systemic Sepsis Cooperative Study Group.

Sepsis, an important cause of hospital mortality, continues to be a diagnostic and therapeutic challenge. To define more clearly the impact of encephalopathy on the course of sepsis, the various clinical signs of sepsis, blood culture results, and mortality rates were examined in relation to mental status in septic patients. Patients were classified as having an acutely altered mental status due to sepsis (AAMS), preexisting altered mental status (PAMS), or normal mental status (NMS). Twenty-three (307/1333) percent of the study patients had an acutely altered sensorium secondary to sepsis. Patients with AAMS had a higher mortality (49%) than patients with PAMS (41%) or patients with NMS (26%) (p less than .000001). Multivariate analysis disclosed that altered mental status, hypothermia, hypotension, thrombocytopenia, and the absence of shaking chills were independent predictors of increased mortality in the sepsis syndrome. Patients with Gram-negative bacteremia (28%) were as likely to have AAMS as patients with Gram-positive bacteremia (25%) or patients with negative blood cultures (23%). In summary, alterations in mental status are common in septic patients, and are associated with significantly higher mortality.

Surgical significance of acquired ileal diverticulosis.

Acquired (non-Meckel's) ileal diverticular disease is uncommon, and most surgeons have limited, if any, experience with this condition. To gain insight into the frequency of surgical complications of ileal diverticula, we reviewed our experience during the past ten years with 21 patients, 12 women, and nine men. The mean patient age was 62 years; 16 patients (76%) were more than 50 years of age. Thirteen patients had associated diverticula in another segment of the small intestine. In 15 patients ileal diverticulosis was diagnosed during gastrointestinal (GI) radiologic evaluation of abdominal symptomatology. Ileal diverticula were identified intraoperatively in the remaining six patients. In three patients ileal diverticulosis was an incidental finding. Documented surgical complications of acquired ileal diverticula occurred in four patients (19%). Three patients had acute diverticular perforation, and one patient had diverticulitis without perforation. These patients underwent successful operative intervention. Three other patients, all managed nonoperatively, had abdominal symptoms that may have been related to ileal diverticula and were of potential surgical significance. Two patients experienced recurrent rectal bleeding, and the third patient had severe chronic abdominal pain. Although the majority of patients with acquired ileal diverticula do not require surgical treatment, complications such as perforation, bleeding, or incapacitating abdominal pain may necessitate ileal resection.

Blunt injuries of the cervical trachea: review of 51 patients.

The low incidence of blunt trauma to the cervical portion of the trachea limits management experience in most centers. Hence, we combined our patients with those in published reports containing essential information on injury, treatment, and results. Among 51 patients (93% male), ages ranged from 3 to 65 years. There were 32 complete transections, 15 partial transections, and four tears. There were associated injuries of the recurrent laryngeal nerve (49%), esophagus (21%), larynx (14%), and cervical spine (9%). Presenting signs and symptoms included subcutaneous emphysema in 84%, respiratory distress in 76%, hoarseness/dysphonia in 46%, and hemoptysis in 21%. Tracheostomy was the best means of airway control; 13 of 17 (76%) attempted oral/nasotracheal intubations failed, necessitating emergency tracheostomy. Five patients with no respiratory distress and minimal tissue injury were successfully managed without tracheal repair. Ten patients had tracheal repair without tracheostomy. The only poor result occurred in a patient with a treatment delay of several days. Tracheal repair with tracheostomy was used in 27 patients, with good results in 19. Two patients died of other injuries, and six patients (four with delayed repair) required subsequent tracheal reconstruction. Repair over a stent was used in seven patients, four of whom had satisfactory results. From this review we conclude that (1) the diagnosis of blunt trauma to the cervical trachea requires a high index of suspicion, since this injury can easily be overlooked; (2) tracheostomy (vs intubation or cricothyroidotomy) is the preferred means of airway control; (3) preoperative laryngoscopy/bronchoscopy should be done to assess vocal cord function, possible laryngeal damage, and level of tracheal injury; (4) good long-term results, measured by voice and airway quality, are best obtained by immediate repair of significant injuries.

Triiodothyronine (T3) antagonizes adverse effects of high circulating reverse-T3 (rT3) during hemorrhagic shock.

To examine whether triiodothyronine (T3) could counteract the lethal effect of exogenous reverse T3 (rT3) in hemorrhagic shock, 21 anesthetized, heparinized mongrel dogs were given 15 micrograms/kg of rT3 IV. Thirty minutes later, the dogs were bled rapidly into a reservoir to achieve and maintain a mean arterial pressure of 40 mm Hg. After 60 minutes at 40 mm Hg (compensated shock), the reservoir line was clamped for 30 minutes (uncompensated shock). The shed blood was then reinfused over 30 minutes, and the dogs were monitored for an additional 60 minutes. At the start of uncompensated shock, 11 dogs were given at least 15 micrograms/kg of T3 IV, and 10 animals received saline. Before T3 treatment, there were no significant intergroup differences in the measured hemodynamic and blood gas variables. In the untreated group, 8 of 10 dogs (80%) died during uncompensated shock, in comparison to 3 of 11 dogs (27%) that received T3 (P less than 0.01). Long-term survival in the T3 group was 5/11 (45%), significantly higher than that (1/10, 10%) in the untreated group (P less than 0.05). These results, interpreted in relationship to previous studies, suggest that the therapeutic efficacy of T3 in canine hemorrhagic shock may be related to antagonism of adverse effects of endogenous rT3.

Surgical implications of jejunal diverticula.

To gain insight into the surgical significance of acquired jejunal diverticula, we reviewed the experience at the teaching hospitals in our city during the past ten years. An antemortem diagnosis of jejunal diverticulosis was made in 27 men and 59 women with a mean age of 69.6 years. In 71 patients the diagnosis was made during upper gastrointestinal roentgenologic evaluation for abdominal symptoms, in three it was made during mesenteric arteriography or bleeding scan for massive rectal bleeding, in six it was made during exploratory laparotomy for acute abdominal signs and symptoms, and in the remaining six it was an incidental intraoperative finding. Surgical indications occurred in 13 patients (15%) and consisted of massive lower gastrointestinal bleeding in four patients, blind loop syndrome in three, small bowel obstruction in three, diverticular perforation in two, and chronic abdominal pain requiring jejunal resection in one. In three additional patients with melena and nine with chronic abdominal pain, jejunal diverticulosis was the only abnormality detected; none of these patients had operation. Although the majority of patients with jejunal diverticula do not require surgical treatment, it may be necessitated by complications such as bleeding, perforation, obstruction, blind loop syndrome, or intractable abdominal pain.

[The effect of triiodothyronine (T3) and reverse triiodothyronine (rT3) on canine hemorrhagic shock].

The euthyroid sick ("low T3") syndrome occurs in circulatory collapse and could influence survival. To evaluate the role of T3 and rT3 in shock, 36 mongrel dogs were subjected to hemorrhagic shock. In 13 dogs 15 micrograms/kg of T3 was given after 60 min of hypotension and 15 micrograms/kg of rT3 was administered IV 30 min before hemorrhage in 10 dogs. An equal volume of saline was injected in 13 dogs for control study. These dogs were bled rapidly into a reservoir to a mean arterial pressure (MAP) of 40 mmHg. After 60 min of hypotension the reservoir line was clamped for 30 min. The shed blood was then reinfused over 30 min. T3 administration caused significant increases during the clamped period in cardiac output, stroke volume, MAP, right and left ventricular stroke work and systemic vascular resistance, with a decrease in pulmonary vascular resistance (PVR). In the group receiving rT3 the only significant hemodynamic-metabolic differences were PVR and mean arterial pH. In the control group, 6 of 13 dogs died, whereas 9 of 10 dogs given rT3 died (p less than 0.03) and only one of 13 T3 dogs died (p less than 0.05). This study strongly suggests that T3 improves survival by acting on cardiovascular receptors or via the hypothalamic-pituitary-thyroid axis and that exogeneous rT3 is detrimental during the stress of shock and may play a biologically causative role in the sick euthyroid syndrome.

Initial resuscitation and assessment of patients with multisystem blunt trauma.

In the vast majority of blunt trauma victims, shock is due to blood loss. Whereas the diagnosis of circulatory collapse is clear-cut, the rapid identification and control of the bleeding source may not be. Such patients often have injuries to several body systems and thus have numerous possible sources of hemorrhage. Ideally, the injury pattern should be defined during resuscitation, preferably by a trauma team using standardized protocols. Airway patency and adequacy of ventilation have top priority. The cervical spine must be immobilized until fracture has been ruled out. In concert with respiratory management, other members of the trauma team should secure adequate vascular access, resuscitate the patient, and perform a physical examination. Physical findings dictate the order of further diagnostic and therapeutic maneuvers. Patients in unstable condition may need emergency surgery.

Creatine phosphokinase-MB assays in patients with suspected myocardial contusion: diagnostic test or test of diagnosis?

To clarify the role of serum CPK-MB assays in the diagnosis of myocardial contusion, we reviewed the hospital records of 182 patients with significant blunt chest trauma and serial CPK-MB determinations. In our laboratory a serum CPK-MB/CPK ratio less than 2.2% is abnormal. The study group was composed of 131 men and 51 women, with a mean age of 35 years. Only six patients had histories of cardiac disease. Of 159 patients injured in vehicular accidents, 143 were drivers, nine were pedestrians, and seven were passengers. There was no relationship between the MB fraction and soft (nonspecific changes) or strongly suggestive (ectopy, focal changes) ECG signs of myocardial contusion. Two of the three patients with power failure had CPK-MB/CPK ratios less than 2.2%. MUGA scans, performed in 18 patients, indicated myocardial injury in seven patients; only 1/7 had abnormal 2D echocardiography, and only 2/7 had elevated MB fractions. In summary, we found no relationship between serum CPK-MB and the presence of clinically significant myocardial contusion. CPK-MB determination in patients with suspected blunt myocardial injury is unjustifiably expensive ($108/assay) and adds confusion to an already vague clinical area.

Triiodothyronine increases survival in canine hemorrhagic shock.

The euthyroid sick (low T3) syndrome occurs in shock and could influence survival. To evaluate the potential therapeutic value of triiodothyronine (T3) in circulatory collapse, 26 anesthetized, heparinized mongrel dogs were bled rapidly into a reservoir until mean arterial blood pressure (MAP) = 40 mmHg. After 60 min of hypotension, the animals were given 15 micrograms/kg of T3 i.v. (13 dogs) or an equal volume of normal saline (13 dogs), and the reservoir line was clamped for 30 min (uncompensated shock). The shed blood was then reinfused over 30 min. After 1 h of monitoring the dogs were returned to the kennel and observed for 3 days. T3 (15 micrograms/kg) or normal saline was administered i.v. on each of the first 3 postshock days. T3 administration caused significant increases during uncompensated shock in cardiac output, stroke volume, mean arterial pressure, right and left ventricular stroke work and systemic vascular resistance, with a decrease in pulmonary vascular resistance. Shortly after reinfusion of shed blood, hemodynamic values were similar in T3 and untreated animals. In the control group, 6 of 13 dogs died. However, only one of 13 T3 dogs died (P less than 0.05). Although the mechanism by which T3 enhances shock survival was not clearly identified, T3 might exert beneficial effects via the hypothalamic-pituitary-thyroid axis or by acting on cardiovascular receptors to improve hemodynamic function at a critical stage of shock. Additional studies of T3 therapy in clinical shock appear warranted.

The reliability of excretory urography as a screening examination for blunt renal trauma.

A prospective study was designed to evaluate the reliability of excretory urography (EU) in excluding renal damage in patients with blunt abdominal trauma, using contrast-enhanced computed tomography (CECT) as the "gold standard" of diagnostic studies. Sixty patients with indications for genitourinary evaluation and with normal EU underwent CECT. Five renal injuries were demonstrated by CECT in patients with negative EU: one contusion, one subcapsular hematoma, two perirenal hematomas, and one renal laceration. All of these lesions resolved with conservative patient management. Thus, the CECT findings did not alter treatment in these five patients.