C-Jun N-terminal kinases are required for oncolytic adenovirus-mediated autophagy.

Oncolytic adenoviruses, such as Delta-24-RGD (Δ24RGD), are replication-competent viruses that are genetically engineered to induce selective cancer cell lysis. In cancer cells, Δ24RGD induces massive autophagy, which is required for efficient cell lysis and adenoviral spread. Understanding the cellular mechanisms underlying the regulation of autophagy in cells treated with oncolytic adenoviruses may provide new avenues to improve the therapeutic effect. In this work, we showed that cancer cells infected with Δ24RGDundergo autophagy despite the concurrent activation of the AKT/mTOR pathway. Moreover, adenovirus replication induced sustained activation of JNK proteins in vitro. ERK1/2 phosphorylation remained unchanged during adenoviral infection, suggesting specificity of JNK activation. Using genetic ablation and pharmacological inactivation of JNK, we unequivocally demonstrated that cells infected with Δ24RGD required JNK activation. Thus, genetic co-ablation of JNK1 and JNK2 genes or inhibition of JNK kinase function rendered Δ24RGD-treated cells resistant to autophagy. Accordingly, JNK activation induced phosphorylation of Bcl-2 and prevented the formation of Bcl-2/Beclin 1 autophagy suppressor complexes. Using an orthotopic model of human glioma xenograft, we showed that treatment with Δ24RGD induced phosphorylation and nuclear translocation of JNK, as well as phosphorylation of Bcl-2. Collectively, our data identified JNK proteins as an essential mechanistic link between Δ24RGD infection and autophagy in cancer cells. Activation of JNK without inactivation of the AKT/mTOR pathway constitutes a distinct molecular signature of autophagy regulation that differentiates Δ24RGD adenovirus from the mechanism used by other oncolytic viruses to induce autophagy and provides a new rationale for the combination of oncolytic viruses and chemotherapy.

The clinical utility of Tc-99m sestamibi scintimammography in detecting multicentric breast cancer.

The ability to recognize multicentric breast cancer preoperatively would assist in identifying appropriate candidates for breast conservation surgery. Tc-99m scintimammography (SMM) is an adjunct to conventional mammography in identifying selected patients with breast cancer. The purpose of this study is to report the utility of SMM in identifying patients with multicentric breast cancer. Breast cancer patients treated by mastectomy who underwent a preoperative SMM between 1992 and 1999 were identified using the institution's Tumor Registry. The pathology report of each patient was reviewed for multicentric disease defined as an additional focus of cancer within a different quadrant of the breast or greater than 2.5 cm from the dominant tumor mass. Each patient's preoperative SMM was reviewed and compared with the pathologic findings to obtain correlative data. Fifty-eight women treated by mastectomy had preoperative SMM (age range 35-78 years; median 52 years). Pathology revealed infiltrating ductal carcinoma in 49 patients (84.5%), infiltrating lobular carcinoma in five patients (8.6%), ductal carcinoma in situ in three patients (5.1%), and colloid carcinoma in one patient (1.7%). Multicentric disease was present in the specimens of eight patients for a prevalence of 10.3 per cent. SMM was positive for uptake in 36 of 58 patients (sensitivity 62.1%). The sensitivity, specificity, positive predictive value, and negative predictive value of SMM in the detection of multicentric disease were 62.5, 96, 71, and 94 per cent, respectively. Although the overall sensitivity of SMM in the detection of breast cancer is superior to that of conventional mammography and physical examination in identifying multicentric breast cancer it is not an accurate modality for detecting multicentric disease in this study group. However, it may have limited applications in specific cases.

Objective criteria may assist in distinguishing necrotizing fasciitis from nonnecrotizing soft tissue infection.

BACKGROUND: Optimal treatment of necrotizing fasciitis (NF) requires rapid diagnosis. The purpose of the study was to identify objective admission measurements that help differentiate NF from nonnecrotizing (non-NF) infection and, among NF patients, to identify admission factors that predict mortality. METHODS: Twenty-one NF cases were paired with matched non-NF controls. Statistical comparison of admission vital signs, laboratory values, and radiographic studies was performed. RESULTS: On multivariate analysis, admission white blood cell count (WBC) >14 x 10(9)/L, serum sodium <135 mmol/L, and blood urea nitrogen (BUN) >15 mg/dL separated NF from non-NF patients. Mortality for NF patients was predicted by admission WBC >30 x 10(9)/L. Mortality was also significantly increased for patients transferred from an outside institution prior to definitive therapy. CONCLUSIONS: Objective admission criteria (elevated WBC and BUN and decreased serum sodium) can assist in distinguishing NF from non-NF infections. The best objective predictor of mortality in NF patients is marked elevation of admission WBC.

Objective assessment of axillary morbidity in breast cancer treatment.

Historically, axillary lymph node dissection (ALND) was a critical aspect of the operative management of breast cancer. Recently, the role of ALND has been questioned, with postoperative morbidity possibly overshadowing patient benefit. Our objective was to quantitatively assess the long-term morbidity of ALND in patients with breast cancer. We conducted a cross-sectional study of patients being followed by the Breast Surgery Clinic at a university-affiliated urban hospital. Ninety-five patients with unilateral breast cancer who had undergone ALND were evaluated at routine follow-up visits in the latter half of 1998. A questionnaire was used to quantify the degree of subjective findings, including arm swelling, chest wall pain, decreased mobility, and weakness. Upper extremity strength, active range of motion, and circumference were measured. Overall, 70 per cent of patients had at least one complaint, with 18 per cent having moderate to severe symptoms. Twenty-one per cent had notable decrements in strength or range of motion, 9.3 per cent of patients required chronic compression garments for lymphedema, and 6.4 per cent changed their vocational status because of surgical morbidity. We conclude that adverse effects from ALND occur commonly. Objective findings are less common, perhaps causing clinicians to underappreciate postoperative morbidity. A significant subset of patients had enduring disability.

Central venous injuries of the subclavian-jugular and innominate-caval confluences.

Injuries to the central venous system can result from penetrating trauma or iatrogenic causes. Injuries to major venous confluences can be particularly problematic, because the clavicle and sternum seriously limit exposure of the injury site. We report our institution's experience with central venous injuries of the subclavian-jugular and innominate-caval venous confluences. Significant injuries of the subclavian-jugular venous confluence frequently result from penetrating trauma, while injuries to the innominate-caval confluence are usually catheter-related. Median sternotomy provides adequate exposure of the innominate-caval confluence, while exposure of the subclavian-jugular venous confluence requires extension of the median sternotomy incision into the neck and resection of the clavicle. The literature is reviewed.

Iliac to popliteal artery bypass through the iliac wing: An alternative extracavitary route for management of complex groin injuries.

Extracavitary bypass through the iliac wing allows placement of the grafts into the posterior thigh and is another alternative route when an obturator bypass is not possible, or an axillary-popliteal bypass is to be avoided. The transiliac wing bypass is relatively simple and easy to perform. The bypass route is short and direct, has excellent inflow, and is accompanied by minimal neurological or bleeding risks. An illustrative case is presented with a complete description of the operative technique. Review of the literature is also included.

Scintimammographic analysis of nonpalpable breast lesions previously identified by conventional mammography.

BACKGROUND: In randomized trials, screening mammography has led to decreased mortality from breast cancer. However, the low positive predictive value of mammography (i.e., the proportion of patients with a positive test result who actually have breast cancer) results in a large number of unnecessary biopsies. We determined whether scintimammography with technetium-99m-sestamibi is a useful supplemental diagnostic tool for women with nonpalpable breast abnormalities identified by conventional mammography. METHODS: Scintimammography was performed preoperatively on 70 women who were 31-66 years of age (mean age and median age = 51 years). These women had nonpalpable breast abnormalities identified by conventional mammography; subsequently, a needle-localization excisional biopsy of each suspicious lesion was performed. Scintimammographic images were interpreted independently by two nuclear medicine physicians who were blinded to all clinical and pathologic data, and an interobserver variation analysis was performed. RESULTS: Interobserver variation analysis of the scintimammographic findings showed an agreement for breast diagnosis of 97% and a kappa coefficient of 0.90. Comparison of scintimammographic findings and histopathologic results revealed that the sensitivity (proportion of patients with breast cancer who had a positive test result), the specificity (proportion of patients without breast cancer who had a negative test result), the positive predictive value and the negative predictive value (proportion of patients with a negative test result who actually did not have breast cancer) of scintimammography were 56% (95% confidence interval [CI] = 23%-85%), 87% (95% CI = 75%-94%), 38% (95% CI = 15%-68%), and 93% (95% CI = 82%-98%), respectively. Four of nine breast cancers were not detected by scintimammography. CONCLUSION: Because of excellent interobserver agreement, scintimammography provides an objective way of detecting primary breast carcinoma. In view of its low sensitivity and positive predictive value, however, scintimammography is not currently recommended as a screening test in patients with nonpalpable positive mammographic findings.

The laparoscopic approach for repair of Morgagni hernias.

BACKGROUND AND OBJECTIVES: Morgagni hernias are unusual congenital diaphragmatic hernias that are generally asymptomatic and discovered incidentally. Surgical treatment is indicated once the diagnosis is made. These hernias have traditionally been repaired by the open abdominal or thoracic approaches. We report a case of Morgagni hernia repaired successfully via the laparoscopic approach. METHODS AND RESULTS: The patient was noted to have a large anteromedial diaphragmatic hernia by chest radiograph and CT imaging. He underwent laparoscopy, during which the hernia was reduced and the defect repaired with mesh placement. We used intracorporeal suture placement to anchor the mesh. The patient recovered uneventfully after a short hospitalization. CONCLUSIONS: The laparoscopic approach for repair of Morgagni hernias offers diagnostic advantages as well as the potential for reduced morbidity when compared to laparotomy. We report intracorporeal knot-tying for fixation of the mesh to be a secure and satisfactory means to achieve the laparoscopic repair.

Intraoperative ultrasound assessment in management of complex pancreatic pseudocysts.

Preoperative imaging studies and operative inspection may provide insufficient information to appropriately manage certain complex pancreatic pseudocysts. Intraoperative ultrasound accurately identifies and localizes peripancreatic fluid collections, cyst wall thickness, parenchymal and ductal anatomy, and relationships to adjacent visceral and vascular structures. Adjunctive use of intraoperative ultrasonography altered the surgical management in the clinical case described herein and is advocated for assessment of problematic pancreatic pseudocysts.

Radionuclide-guided stereotactic prebiopsy localization of nonpalpable breast lesions with normal mammograms.

UNLABELLED: Scintimammography with 99mTc-sestamibi can be used as a complementary technique to improve the mammogram's sensitivity and specificity for detection of breast carcinoma. We have observed in some patients focal areas of increased 99mTc-sestamibi uptake with no corresponding abnormalities on physical examination or mammogram. A phantom device and a special needle were designed to stereotactically localize these lesions before biopsy. METHODS: After intravenous injection of 30 mCI (1110 MBq) of 99m Tc-sestamibi, a prone lateral image of the abnormal breast was obtained. With the patient in the prone position, the breast was compressed with two fenestrated plates in the prone position. The x and y coordinates of the abnormal hot spot of the breast were determined. The z coordinate of focal 99mTc-sestamibi uptake was determined by advancing a localizer needle through a selected predetermined hole of the fenestrated plate using real-time visualization on the persistence monitor. The tip of the opturator inside the needle is welded with 57Co to determine the depth of the hot spot in the breast. RESULTS: Three women, all of whom had normal mammogram and breast physical examinations, were studied using 99mTc-sestamibi prone breast imaging. Pre-excisional biopsy needle localization of abnormal focal uptake was performed. Two women demonstrated infiltrative ductal carcinoma, and the third had proliferative fibrocystic disease of the breast. CONCLUSION: Our initial experience demonstrates that nuclear medicine guided stereotactic needle biopsy of the breast in patients with positive scintimammograms is technically feasible. In the future, this technology will enable us to detect breast carcinoma in the absence of clear-cut clinical and mammographic findings.

Detection and evaluation of aerodigestive tract injuries caused by cervical and transmediastinal gunshot wounds.

BACKGROUND: Aerodigestive tract penetrations occurring with gunshot wounds to the neck and thorax are uncommon but are frequently associated with multiple organ injury and contribute to significant morbidity. METHODS: The selective management strategy used at our institution for suspected aerodigestive tract involvement with cervical, thoracic inlet, and transmediastinal gunshot wounds is reviewed with reference to eight clinical cases from 1989 to 1995. RESULTS: Seven pharyngoesophageal and four laryngotracheal injuries are described with three patients sustaining combined aerodigestive organ wounds. Associated injuries occurred in seven of the eight cases. Diagnosis of aerodigestive tract penetrations were made by triple endoscopy in five patients, by contrast esophagography in one case, and at operation for associated injuries in two patients. No injuries were missed during endoscopy or contrast studies. Two patients suffered complications including delayed recognition of an esophageal injury and pneumonia in one case and dehiscence of a distal esophageal repair in another. An associated vascular injury resulted in a single death in the series. CONCLUSIONS: A high index of suspicion must be maintained for aerodigestive tract involvement with cervicothoracic gunshot wounds. We advocate operative endoscopic inspection during emergent exploration in unstable patients or arteriography with endoscopy in stable patients. Adjunctive contrast pharyngoesophagography is performed to confirm equivocal endoscopic findings, evaluate the extent of leak, or completely exclude injury.

Scintimammography with Tc-99m sestamibi.

Mammography and physical breast examination are currently the most frequently and recognized screening tools for detection of breast carcinoma. These methods have been proved successful for early detection of breast cancer. Considering the 85% sensitivity associated with combined mammography and physical examination and a low positive predictive value of 20%-30% for diagnosis of breast carcinoma, there is a critical need for a more accurate, noninvasive imaging test to improve the sensitivity and specificity of mammography (7, 19, 20). Since early 1992, we have studied over 1200 women with clinically and/or mammographic abnormalities prior to breast biopsy and/or fine needle aspiration cytology of the breast. We have evaluated the role of Tc 99m Sestamibi as a complimentary procedure to conventional mammography in detection of breast carcinoma. The preliminary results of our studies have been published elsewhere (14, 17, 18). DuPont Merck Pharmaceutical Company in the USA on that basis, determined to conduct a multicenter clinical trial for the role of this radiopharmaceutical for the diagnosis of breast carcinoma in women with mammographically and/or clinically palpable abnormalities. This study was conducted at 42 institutions throughout the United States and Canada enrolling 673 women who where otherwise scheduled for breast biopsy and/or mastectomy. The preliminary results of this trial in both palpable and nonpalpable breast abnormalities are encouraging (24). Our most recent study on 157 women (mean age 47.9 years +/- 10.2) with 164 lesions with indications for histologic and cytologic analysis who underwent scintimammography with Tc 99m Sestamibi demonstrated the sensitivity of 92.3% and the specificity 87.5% (15). We have concluded that Scintimammography with Tc 99m Sestamibi can be used in conjunction with mammography to improve its specificity.

Comparative stress hormone changes during helium versus carbon dioxide laparoscopic cholecystectomy.

Laparoscopic surgery has been termed minimally invasive surgery by advocates of this technology. It has been demonstrated previously that using carbon dioxide for insufflation produces a respiratory acidosis due to transperitoneal absorption of gas. Insufflation with helium does not create this acidosis. We questioned whether laparoscopic surgery would elicit a stress response and whether the absence of acidosis with helium might prevent or reduce the levels of stress hormones. Sixteen female patients undergoing laparoscopic cholecystectomy were randomly assigned to helium (n = 8) or CO2 (n = 8) insufflation. Serum cortisol, epinephrine, and norepinephrine were measured preoperatively, after induction of anesthesia but before insufflation, at 45 min of surgery, and after desufflation. There were increases in epinephrine, norepinephrine, plasma cortisol, and urine cortisol at 45 min and at the conclusion of the procedure over the preoperative value. With ANOVA, each variable showed significant increases from preoperative values, at 45 min, and at the end of the case. Except for the increased epinephrine when helium was used, there were no significant differences in the other variables between helium and CO2. Laparoscopic cholecystectomy produces significant increases in stress hormone levels. Prevention of acidosis with helium insufflation does not appear to protect against increases in stress hormones. Epinephrine levels with helium insufflation are higher than with CO2, and elevations in stress hormones suggest that laparoscopic cholecystectomy is not physiologically minimally invasive.

Laparoscopic inguinal herniorrhaphy in two stallions.

Two mature stallions that were used for breeding purposes were admitted for evaluation of inguinal hernias. In 1 horse, the hernia was reduced per rectum by gentle traction applied to the intestine. In the other horse, the hernia was reduced by placing the horse in dorsal recumbency and applying external pressure over the scrotum. Both horses were observed for recurrence of the hernia. Seven days later, an elective laparoscopic technique for inguinal herniorrhaphy was performed on each horse, using polypropylene mesh. Complications did not develop, and both horses have successfully completed 2 full breeding seasons. Laparoscopic inguinal herniorrhaphy allows preservation of the testis on the affected side and precludes many complications associated with open surgical techniques used on inguinal rings.

Scintimammography: the complementary role of Tc-99m sestamibi prone breast imaging for the diagnosis of breast carcinoma.

PURPOSE: To evaluate the complementary role of technetium-99m sestamibi scintimammography in improvement of the sensitivity and specificity of mammography in detection of carcinoma of the breast. MATERIALS AND METHODS: At 5 and 60 minutes after intravenous injection of Tc-99m sestamibi, scintimammograms were obtained in 147 women (age range, 18-73 years; mean age, 47.9 years +/- 10.2 [standard deviation]) with 153 lesions that warranted breast biopsy (102 lesions) or fine-needle aspiration cytologic analysis (51 lesions). There were 113 palpable and 40 nonpalpable lesions. Lesion size on mammograms was 0.8 x 0.6 cm to 15.0 x 11.0 cm (mean, 2.82 cm +/- 1.71 x 2.39 cm +/- 1.56). RESULTS: Scintimammographic findings were true-positive in 47 biopsy-confirmed carcinomas, true-negative in 91 benign lesions, false-positive in 11 lesions with benign histopathologic findings (fibrocystic disease [n = 8] or fibroadenoma [n = 3]), and false-negative in four lesions of infiltrating ductal carcinoma. The sensitivity of scintimammography was 92.2%; specificity, 89.2%; positive predictive value, 81.0%; and negative predictive value, 95.8%. CONCLUSION: The authors conclude that scintimammography is a sensitive test that can improve the detection of breast carcinoma.

Balloon dissection facilitated laparoscopic extraperitoneal hernioplasty.

BACKGROUND: With the goals of minimizing perioperative morbidity and obtaining direct inguinal access without transgressing the peritoneal cavity, we developed a balloon dissection device to facilitate laparoscopic extraperitoneal hernioplasty. PATIENTS AND METHODS: We have performed balloon facilitated dissection on 113 patients (105 males) on an outpatient basis. Some patients were repaired under regional anesthesia. A total of 150 hernias have been repaired: 72 indirect, 70 direct, 3 scrotal, 2 sliding, 2 spigelian, and 1 femoral. RESULTS: Mean operating time was 60 minutes. All patients were ambulatory on discharge. Half reported minimal or no immediate postoperative pain. Over 80% had only minimal irritation or discomfort on the third postoperative day. Nearly 60% returned to work within 2 weeks. None required hospital readmission for an immediate complication of hernioplasty. With a mean follow-up of 6.3 months, only three recurrences are reported. Except for one persistent neuropathy which resolved after staple removal, there were no significant complications. CONCLUSIONS: We conclude that balloon dissection facilitates laparoscopic extraperitoneal hernioplasty and obviates the need for general anesthesia. Our approach minimizes perioperative pain. It can be done on an outpatient basis and permits prompt return to full activity including physical work.