Tumours with elevated levels of the Notch and Wnt pathways exhibit efficacy to PF-03084014, a γ-secretase inhibitor, in a preclinical colorectal explant model.

BACKGROUND: Dysregulation of the Notch pathway has been identified to play an important role in the development and progression of colorectal cancer (CRC). In this study, we used a patient-derived CRC explant model to investigate the efficacy of the clinical γ-secretase inhibitor (GSI) PF-03084014. METHODS: A total of 16 CRC explants were treated with PF-03084014. Knockdown of RBPjκ gene was used to determine the specificity of PF-03084014. Evaluation of the Notch and Wnt pathways in CRC explant tumours was performed by gene array and immunoblotting. RESULTS: We identified a subset of CRC tumours that exhibited elevations of the Notch and Wnt pathways sensitive to PF-03084014. Treatment with the GSI resulted in a significant reduction in cleaved Notch, Axin2 (Wnt-dependent gene) and active ß-catenin. In addition, knockdown of the RBPjκ gene showed that PF-03084014 has specificity for the Notch pathway in an HCT116 cell line xenograft model. Finally, an increase in apoptosis was observed in CRC001- and CRC021-sensitive tumours. CONCLUSION: This study provides evidence that inhibition of γ-secretase may be beneficial in a subset of patients with elevated levels of the Wnt and Notch pathways.

Strongyloidiasis in immunosuppressed hosts. Presentation as massive lower gastrointestinal bleeding.

Two cases of massive lower gastrointestinal hemorrhage in immunosuppressed patients were due to complicated infestation with Strongyloides stercoralis. The very high mortality of disseminated strongyloidiasis may in part be attributed to delays in diagnosis and treatment resulting from the complex life cycle of this nematode. Successful therapy in the cases presented consisted of reduction of corticosteroid dosage, use of thiabendazole in excess of that recommended for uncomplicated infestation, parenterally administered nutrition, multiple transfusion of blood products, and vigorous supportive management. Emphasis is given to proper categorization of patients and measures designed to prevent, detect, and treat hyperinfection in patients in whom immunosuppression is anticipated.

Modified technique for radical transmediastinal forequarter amputation and chest wall resection.

Forequarter or interscapulothoracic amputation is a major surgical procedure indicated primarily in the treatment of malignant lesions involving the bony and soft tissue parieties of the upper part of the arm, shoulder, and scapula. It is also indicated in extensive trauma with irreparable damage to the shoulder area and as a palliative measure in intractable pain caused by incurable tumors of the shoulder girdle. Several operative techniques have been described: the classical Berger approach, an anterior pectoral approach, and posterior retroscapular approaches. A radical transthoracic approach has been described in cases in which the tumor had spread through the chest wall. The two main goals of these approaches have been early ligation of the subclavian vessels and immediate exploration for operability. This report details our experience with a modified technique for radical forequarter amputation and chest wall resection in which a transmediastinal approach is employed. This approach was used in two patients: One had a radiation-induced fibrosarcoma of the left axilla and adjacent chest wall following a radical mastectomy 19 years earlier, and the other patient had a recurrent rhabdomyosarcoma of the right axilla with invasion of the chest wall. This technique avoids time-consuming and individual excision of ribs and minimizes the amount of blood loss by early ligation of the internal mammary vessels. Safe and excellent exposure and division of the subclavian vessels and early exploration for mediastinal and intrathoracic involvement are made possible. Details of the procedure with illustrations are described.

Breast masses in young women.

To better define the risk of breast cancer in young patients, a retrospective review of all breast biopsies in women under age 40 years at Grady Memorial Hospital, Atlanta, from Dec 1, 1981, to Aug 15, 1987, was performed. During this time, 751 biopsies were performed on patients aged 9 to 40 years. None of the 128 patients aged 20 years or less had carcinoma. Of 150 patients aged 21 to 25 years, two had carcinoma. At age 26, there began a steady rise in the incidence of carcinoma, such that in the 36- to 40-year age group, carcinoma was present in 24.4% of the specimens. This retrospective review confirms previous reports that suggest that carcinoma of the breast is distinctly unusual in patients under age 20 and that breast masses in these young patients should be managed conservatively. As the incidence of carcinoma increases with the age of the patient, one's threshold for excisional biopsy should decrease.

Paget disease of the male breast.

Twenty-two fully documented cases of Paget disease of the male breast are reviewed, and an additional patient is reported. The most common initial symptom was ulceration and excoriation, while a breast mass was palpable in the majority of patients. Nipple changes were surprisingly rare, in contrast to the female. The prognosis of the disease in the male appears to be worse than in the female, with the Paget carcinoma carrying a worse prognosis than the "ordinary" male breast cancer. The subareolar location and the meager volume of tissue interposed between the tumor and chest wall may be an important factor in this regard. Nipple changes or symptoms (ulceration, discharge, enlargement) are mroe apt to be due to cancer in the male than in the female. Therefore, prompt diagnosis is mandatory.

Diagnostic pneumoperitoneum in the pediatric patient with a unilateral inguinal hernia.

Controversy continues among surgeons over the management of pediatric patients with unilateral groin hernias. Currently, advocated treatment modalities include repair of only the clinically apparent side, exploration of the contralateral side when the ipsilateral hernia is repaired, or performance of contrast herniography before surgery. Another technique for consideration--diagnostic intraoperative pneumoperitoneum--is a simple, quick, safe, and highly accurate means of detecting a clinically inapparent contralateral inguinal hernia during the initial surgery. This technique, the results of its use, and a review of the literature are included.

Pseudotorsion of testis.

Unilateral scrotal inflammation was noted in an otherwise asymptomatic three-day-old male and was initially believed to be due to testicular torsion. It proved, however, to be the result of peritonitis from a thermometer-induced rectal perforation presenting via a communicating hydrocele. Treatment included primary closure of the rectal perforation with colostomy diversion combined with parenteral antibiotics. Preoperative evaluation of neonates with acute unilateral inflammation of the scrotum and a known hydrocele or hernia with flat and oblique x-ray films may reveal significant unsuspected intra-abdominal pathology.

Intraoperative diagnostic pneumoperitoneum (Goldstein test) in the infant and child with unilateral inguinal hernia.

Over a 3 year period, 191 infants and children underwent operative repair of inguinal or communicating hydroceles or both. Of these patients, 131 underwent the Goldstein test to determine the presence or absence of a contralateral hernia sac. The Goldstein test was performed by introducing a soft rubber catheter through the hernia sac into the abdominal cavity and distending the peritoneal cavity with air. The contralateral groin and, in males, the scrotum were then palpated for crepitance. The presence of crepitance constituted a positive test result. Of the 131 tests performed, the results were positive in 38 (29 percent) and negative in 93 (71 percent). There was one false-positive test result (2 percent) and no false-negative results. The test was not performed in 60 patients because of technical problems in passing the catheter (22 percent), presence of a ventriculoperitoneal shunt (2 percent), previous contralateral herniorrhaphy (1.6 percent), presentation with bilateral hernias (26 percent), and patient age of 12 years (1 percent). Continued differences in approaches to the management of pediatric patients who present with unilateral groin hernias prompted this study. We believe that the Goldstein test represents a safe, economical, rapid, accurate, and humane approach to this common problem.

Surgical problems in the fetus: a multidisciplinary approach.

Over a 2 year period, 90 cases of potential fetal pathologic conditions were presented to a multidisciplinary fetal board. Members, including persons from perinatology, neonatology, genetics, radiology, pathology, pediatric surgery, neurosurgery, and urology, met monthly to discuss new referrals, follow-up ongoing cases, and present findings and treatment in delivered cases. Of 90 referred cases, 76 surgical diagnoses occurred in 71 fetuses (79 percent), with central nervous system and genitourinary anomalies predominating. A formal presentation during a single meeting with the variety of specialists necessary to manage surgical problems in the fetus facilitated perinatal management and allowed for the appropriate specialist to counsel the parents as early as possible.

Pediatric maxillofacial trauma: unique features in diagnosis and treatment.

The purpose of this study was to review mechanisms, etiologies, associated injuries, and treatment of maxillofacial trauma in children and to compare them to similar adult injuries. Thirty blunt injuries (1984-1986) comprised the children's group, and 176 injuries, the adult group. Multiple associated injuries were more common in children, the most frequent being CNS and orthopedic injuries. Detailed anatomy of mandibular fractures required pleuridirectional tomography in 63% of the pediatric cases compared to 12% in adults. In the children's group, the mandibular fractures were favorable in 56% of cases compared to 15% in adults. Children required shorter periods of intermaxillary fixation with no child requiring reapplication of fixation. Based on these comparisons, a protocol for the management of pediatric maxillofacial injuries has been developed.

Conservative treatment of early-stage breast cancer. The Emory experience.

Between January 1983 and December 1991, 80 women with AJCC clinical stage I or II breast cancer were treated with conservative surgery and radiation therapy. Reexcision of the primary was performed in 40 breasts, and residual tumor was identified in 40% of these. Margins of resection were assessed in 80% and, of these, 46 patients had final margins of resection that were negative, 86% had axillary node dissection, 45 patients had histologically negative axillary nodes, and 24 had histologically positive axillary nodes. Of patients with histologically positive lymph nodes, 92% received systemic adjuvant treatment consisting of chemotherapy in 19/24 and tamoxifen in 14/24. Median follow-up was 34 months (range: 6-90 months). The adjusted 5-year actuarial Overall Survival for the group was 92%, and Disease-Free Survival was 80%. The 5-year Local Recurrence-Free Survival was 96%. The present study confirms the excellent results that can be obtained with conservative surgery plus radiation therapy.

Hirschsprung's disease in adolescents. Misadventures in diagnosis and management.

Three male adolescents, ages 13, 15, and 17 years, presented with complications of their Hirschsprung's disease, including acute enterocolitis with sepsis, chronic enterocolitis with anemia and leukocytosis, and severe fecal impaction. All had experienced delay in diagnosis resulting from either physician error in diagnosis or physician misinformation concerning the surgical treatment of the disease. These three patients illustrate some of the pitfalls in the diagnosis and surgical management of patients with Hirschsprung's disease. Misinformation concerning the surgical correction of this disease still exists, and these patients emphasize the necessity of continued, updated information in the diagnosis, management, and outcome of patients with Hirschsprung's disease.

Atlanto-occipital subluxation/dislocation: a "survivable" injury in children.

Atlanto-occipital dislocation occurs more often in children due to the laxity of the ligamentous structures anchoring the occiput to the axial skeleton. The mechanism of action usually involves a sudden acceleration-deceleration force on the head of the child. The dislocation usually severs the spinal cord at the foramen magnum, resulting in acute respiratory arrest. We have managed four patients who sustained this injury and arrived at our trauma center with signs of life. Two patients were hemodynamically unstable, had positive diagnostic peritoneal lavage, and underwent splenectomy. Both patients had obvious separation of the occiput and C1 on lateral cervical spine films. Both remained very unstable and died soon after celiotomy. The other two patients were stabilized, and both met criteria for brain death; one family agreed to organ donation. A 5-year analysis revealed 57 pediatric deaths, with 10 patients sustaining atlanto-occipital dislocations (17.5%). Nine of 10 patients sustained other injuries, but in only 2 patients were the injuries immediately life-threatening. With continued improvement in emergency medical systems and pediatric trauma care, we can expect to see more pediatric patients with this injury arriving in trauma centers with signs of life. In our experience, 50 per cent of patients may meet organ donor criteria, and our incidence of this injury (17.5%) reveals atlanto-occipital dislocation as a major contributor to pediatric trauma mortality.

Injury severity score as a guide to nutritional management of the pediatric trauma patient.

Age, degree of injury, different metabolic rates, and growth complicate the estimation of nutritional requirements in the pediatric trauma victim. This study was designed to determine energy requirements of the injured child in relation to injury severity. Fourteen patients of 600 seen in a 5-year period met our criteria for evaluation with significant weight loss, caloric deficit recorded to the lowest weight, and details of injury. There were 10 males and four females with a mean age of 11.24 years (+/- 5.5). Mean injury scores included ISS 24.24 +/- 5.96, PTS 4.8 +/- 1.7, and TSS 11.79 +/- 2.78. The closest Theoretical Caloric Requirement (ThCR) that would have produced the Cumulative Caloric Deficit was calculated from the actual weight loss and Caloric Intake. Eighty-six per cent of the ThCR were less than or equal to the 1989 Recommended Dietary Allowances (RDA) (mean -16.43 +/- 24%). The per cent increase of the ThCR above the basal was significantly higher for lower ISS scores (P < 0.05). When compared to RDA, the per cent change of the ThCR for mild injuries were 1.8 +/- 27.9% above the RDA and were 26.5 +/- 17.2% below the RDA for the severe injuries. These findings are consistent with the child with milder injuries resuming activity and the growth process earlier than a severely injured child. We would recommend calculating caloric requirements based on the RDA for milder injuries and on 0.75 RDA for the more severely injured child (ISS > 25).

Tntraoperative vesical pressure measurements as a guide in the closure of abdominal wall defects.

Increased intra-abdominal pressure represents a difficult problem when closing abdominal wall defects (AWD) and can cause renal insufficiency and vascular injury to the intestine with the development of necrotizing enterocolitis. Urinary bladder pressure measurements have been shown to accurately reflect intra-abdominal pressure in animal models. This study compares outcomes with and without vesical pressure measurements in AWD. Since its description in 1987, these vesical pressure measurements have guided the closure of AWDs. A pressure of <20 cm H2O allows closure by primary fascial, skin, or staged prosthetic closure. All charts of patients who underwent AWD closure from 1981 to 1993 were reviewed and data collected including type of defect and closure, gestational age, weight, age at operation, fluid requirements and urinary outputs, ventilator requirements, days to first and total feeding, total parenteral nutrition (TPN) days, hospital days, hospital charges, morbidity, and mortality. Results were analyzed by paired or unpaired Student's t test or Fisher's exact test. Twenty-seven infants did not receive vesical pressure measurements, whereas 13 did. No significant differences occurred in the parameters recorded in these two diverse groups. When gastroschisis patients only were compared, a significant decrease in intravenous fluid requirements in the vesical measurement group occurred on postoperative Day 2 (155.3+/- 37.5 versus 109.6 +/- 34.3; P = 0.016), and a significant decrease in urinary output occurred on postoperative Day 3 (4.2 +/- 112 versus 3.1+/- 1.1; P=0.044). Ventilator support, TPN days, and oral feeding data were all lower in the vesical measurement group but did not reach statistical significance. Hospital days and hospital changes showed a trend to lower values in the measured group (P values 0.052 and 0.095, respectively). Intraoperative vesical pressure measurements represent a simple, safe, effective method to guide the closing of AWD and result in less capillary leak and more prompt diuresis, and may result in significantly less morbidity, mortality, and cost.

Vaginal agenesis discovered during repair of high imperforate anus: operative management.

A girl born with laryngeal stenosis, tracheal esophageal fistula and esophageal atresia, imperforate anus, duodenal atresia, and Mayer-Rokitansky-Kuster-Hauser syndrome is presented. An explanation of the abnormalities and the surgical approach are presented.

Management of exposed inguinofemoral arterial conduits by skeletal muscular rotational flaps.

Peripheral vascular reconstructions are common operations for the treatment of occlusive atherosclerosis, and the vast majority are uncomplicated. However, despite all precautionary measures, a small percentage of patients will manifest wound infection and graft exposure that may evolve to loss of limb and/or life. Treatment has traditionally consisted of systemic administration of antibiotic medication(s), graft extirpation, and extra-anatomic arterial bypass; yet despite use of these more radical modalities, morbidity and mortality have remained high. An additional meritorious adjunct for the treatment of exposed prosthetic or autogenous saphenous vein arterial bypass grafts is the use of local/regional autogenous skeletal muscular rotational flaps. Reported herein are the results of this technique applied to the inguinofemoral regions of eight patients. Rectus abdominis (1 patient), rectus femoris (4), and sartorius (4) skeletal muscular rotational flaps were employed. Seven of eight (88%) patients convalesced well at mean duration of follow-up measuring 24 months, although one patient subsequently required major amputation due to progression of occlusive atherosclerosis. One of eight (12%) patients succumbed secondary to irreversible sepsis, despite radical amputation. The data suggest that use of local/regional skeletal muscular rotational flaps is a useful adjunct for the treatment of patients with exposed arterial conduits.

Resuscitative thoracotomy in children and adolescents.

Accidental injury continues as the leading cause of mortality in children and adolescents. With the recent push for improvement in emergency medical services and specialized trauma centers for this age group, more moribund patients can be expected to reach these centers. Multiple reports document the efficacy of resuscitative thoracotomy in the moribund adult trauma victim, but published reports of this technique in children and adolescents are lacking. From January 1981 to July 1986, 19 patients ranging in age from 4 to 18 years (mean 14) underwent resuscitative thoracotomy. Eleven patients sustained penetrating trauma while eight sustained injuries from blunt trauma. Five patients survived and were discharged from the hospital (26%). There were no survivors in the 0-15 year age group in five penetrating injuries and four blunt trauma victims. This review confirms the efficacy of resuscitative thoracotomy in the patient with penetrating trauma. Salvage in the blunt trauma victim is possible, but less than in penetrating injuries (12.5% versus 36%). Further studies in this age group will be necessary to establish appropriate guidelines for the use of RT in children and adolescents.

Determination of ambulatory blood pressure control in treated patients with controlled office blood pressures.

Office blood pressure measurement is the standard for assessing blood pressure control. Many patients, however, take their antihypertensive medication in the morning, so they are likely to have their office blood pressure measured during the maximal antihypertensive effect. It is therefore unknown whether patients deemed by office blood pressure to be controlled do in fact have 24h blood pressure control. The objectives of this study were to determine blood pressure control, including blood pressure control while the patients were awake and during the first 6 hours after awakening, by ambulatory blood pressure monitoring (ABPM) in treated hypertensive patients deemed by office blood pressure measurements to be controlled. A total of 103 patients on a stable antihypertensive regimen and deemed to be controlled in terms of office blood pressure values (mean office blood pressure <140/90mmHg) were enrolled. Patients were stratified by cardiovascular risk status and the number of antihypertensive medications that they were taking. Seventy-eight out of 103 participants successfully completed ABPM. The mean ambulatory blood pressure was greater than 135/85mmHg and 140/90mmHg while awake for 37% (95% confidence interval [CI] 26-48%) and 23% (95% CI 14-32%) of all patients respectively. Forty-eight per cent (95% CI 33-63%) of patients taking monotherapy versus 25% (95% CI 11-39%) of patients on multiple antihypertensive medications were uncontrolled (P=0.039) using 135/85mmHg as the reference value. Thirty-one per cent (95% CI, 17-44%) of patients on monotherapy versus 14% (95% CI 3-25%) of patients on multiple antihypertensive medication were uncontrolled (P=0.064) using 140/90mmHg instead. These results demonstrate that a high number of patients deemed by office blood pressure to be under control do not have adequate blood pressure control based on ABPM.