TRP53 Mutants Drive Neuroendocrine Lung Cancer Through Loss-of-Function Mechanisms with Gain-of-Function Effects on Chemotherapy Response.

Lung cancer is the leading cause of cancer-related deaths with small-cell lung cancer (SCLC) as the most aggressive subtype. Preferential occurrence of TP53 missense mutations rather than loss implicates a selective advantage for TP53-mutant expression in SCLC pathogenesis. We show that lung epithelial expression of R270H and R172H (R273H and R175H in humans), common TRP53 mutants in lung cancer, combined with RB1 loss selectively results in two subtypes of neuroendocrine carcinoma, SCLC and large cell neuroendocrine carcinoma (LCNEC). Tumor initiation and progression occur in a remarkably consistent time frame with short latency and uniform progression to lethal metastatic disease by 7 months. R270H or R172H expression and TRP53 loss result in similar phenotypes demonstrating that TRP53 mutants promote lung carcinogenesis through loss-of-function and not gain-of-function mechanisms. Tumor responses to targeted and cytotoxic therapeutics were discordant in mice and corresponding tumor cell cultures demonstrating need to assess therapeutic response at the organismal level. Rapamycin did not have therapeutic efficacy in the mouse model despite inhibiting mTOR signaling and markedly suppressing tumor cell growth in culture. In contrast, cisplatin/etoposide treatment using a patient regimen prolonged survival with development of chemoresistance recapitulating human responses. R270H, but not R172H, expression conferred gain-of-function activity in attenuating chemotherapeutic efficacy. These data demonstrate a causative role for TRP53 mutants in development of chemoresistant lung cancer, and provide tractable preclinical models to test novel therapeutics for refractory disease. Mol Cancer Ther; 16(12); 2913-26. ©2017 AACR.

Fistulojejunostomy Versus Distal Pancreatectomy for the Management of the Disconnected Pancreas Remnant Following Necrotizing Pancreatitis.

BACKGROUND: A disconnected distal pancreas (DDP) remnant is a morbid sequela of necrotizing pancreatitis. Definitive surgical management can be accomplished by either fistulojejunostomy (FJ) or distal pancreatectomy (DP). It is unclear which operative approach is superior with regard to short- and long-term outcomes. METHODS: Between 2002 and 2014, patients undergoing either FJ or DP for DDP were retrospectively identified at a center specializing in pancreatic diseases. Patient demographics, perioperative, and postoperative variables were evaluated. RESULTS: Forty-two patients with DDP secondary to necrotizing pancreatitis underwent either a FJ (n = 21) or DP (n = 21). Between the two cohorts, there were no significant differences in overall lengths of stay, pancreatic leak rates, or readmission rates (all p > 0.05). DP was associated with higher estimated blood loss, increased transfusion requirements, and worsening endocrine function (all p < 0.05). At a median follow-up of 18 months, four patients that underwent a FJ developed a recurrent fluid collection requiring re-intervention. Overall, FJ was successful in 80% of patients as compared to a 95% success rate for DP (p = 0.15). CONCLUSIONS: Although DP was associated with higher intraoperative blood loss, increased transfusion requirements, and worsening of preoperative diabetes, this procedure provides superior long-term resolution of a DDP when compared to FJ.

Routine use of U-tube drainage for necrotizing pancreatitis: a step toward less morbidity and resource utilization.

BACKGROUND: A U-tube drainage catheter (UTDC) is a novel intervention for necrotizing pancreatitis, with multiple benefits: bidirectional flushing, greater interface with large fluid collections, less risk of dislodgement, and creation of a large-diameter fistula tract for potential fistulojejunostomy. We report the first clinical experience with UTDC for necrotizing pancreatitis. METHODS: From 2011 to 2014, all patients undergoing UTDC for necrotizing pancreatitis at our institution were identified. Clinical variables including patient, disease, and intervention-specific characteristics as well as long-term outcomes populated our dataset. RESULTS: Twenty-two patients underwent UTDC for necrotizing pancreatitis; the median follow-up was 10.2 months. Necrotizing pancreatitis was most commonly owing to gallstones (n = 9; 41%), idiopathic disease (n = 5; 23%), and alcohol abuse (n = 4; 18%). During the course of UTDC and definitive operative therapy (when required), patients had median hospital stays of 31 days, 6 interventional radiology procedures, and 6 CT scans. Operative intervention was not necessary in 9 patients (41%). Among the other 13 patients, 4 patients underwent distal pancreatectomy/splenectomy, 8 had a fistulojejunostomy performed, and 1 underwent both procedures. CONCLUSION: UTDC for necrotizing pancreatitis patients is associated with effective drainage and low morbidity/hospital resource utilization. With skilled interventional radiologists and multidisciplinary coordination, this technique is a valuable means of minimizing morbidity for patients with necrotizing pancreatitis.

Post-traumatic pseudoaneurysm of the thyrocervical trunk.

Pseudoaneurysms of the thyrocervical trunk or its branches are extremely rare. They are often the result of a penetrating injury and commonly iatrogenic in origin. Pseudoaneurysm formation following blunt trauma has twice been reported in the English-language literature. We report a case of a 56-year-old man involved in a motor vehicle collision who presented with a slowly growing mass over the course of 4 months. A magnetic resonance (MR) examination was requested to evaluate the cause of this slowly growing mass. Our case is unique in that MR imaging correctly diagnosed the lesion, which was subsequently treated with ultrasound-guided percutaneous thrombin injection. Our case is the only published instance of treatment of a thyrocervical trunk pseudoaneurysm by direct ultrasound-guided percutaneous thrombin injection.

Imaging-guided prostate biopsy: conventional and emerging techniques.

Transrectal ultrasonography (US)-guided biopsy is the standard approach for histopathologic diagnosis of prostate cancer. However, this technique has multiple limitations owing to the operator's inability in most cases to directly visualize and target prostate lesions. Magnetic resonance (MR) imaging of the prostate overcomes many of these limitations by directly depicting areas of abnormality and allowing targeted biopsies. Accuracy in the detection of prostate cancer is improved by the combined use of standard T2-weighted MR imaging and advanced MR imaging techniques such as diffusion-weighted imaging, dynamic contrast-enhanced imaging, and MR spectroscopy. Suspicious-appearing regions of the prostate seen on MR images can be targeted at real-time transrectal US-guided biopsy to improve the diagnostic yield. MR imaging also can be performed for real-time guidance of transrectal prostate biopsy. Studies among patients who underwent at least one transrectal US-guided biopsy with a negative result before undergoing an MR imaging-guided biopsy showed improved detection rates with MR imaging-guided biopsy in comparison with the detection rates achieved with a repeat transrectal US-guided biopsy; however, MR imaging-guided biopsy is a more time-consuming procedure. A technique known as fused MR imaging- and transrectal US-guided biopsy, which relies on the coregistration of previously acquired MR images with real-time transrectal US images acquired during the procedure, shows promise but is limited by deformation of the prostate; this limitation is the subject of ongoing investigation. Another technique that is currently under investigation, MR imaging-guided prostate biopsy with robotic assistance, may one day help improve the accuracy of biopsy needle placement.

Efficacy of intrapleural tissue-type plasminogen activator in the treatment of loculated parapneumonic effusions.

PURPOSE: To assess the feasibility and effectiveness of intrapleural recombinant tissue-type plasminogen activator (r-tPA) in the treatment of loculated parapneumonic effusions (PPEs). MATERIALS AND METHODS: A single-arm prospective study of 25 consecutive patients with loculated PPEs was analyzed. All patients received 6-mg doses of intrapleural r-tPA on a defined schedule via a thoracostomy tube. The volume of output from the tubes was recorded and analysis of the fluid composition performed. Follow-up was both clinical and radiographic, with all patients undergoing pre- and postprocedural computed tomography. RESULTS: Eighteen of the 25 patients (72%) required no additional intervention and had a complete clinical and radiographic response with the fibrinolytic therapy. Seven patients (28%) were treated with video-assisted thoracoscopic surgery, but no patient required thoracotomy for total decortication. There were no hemorrhagic complications. CONCLUSIONS: Intrapleural r-tPA is effective in the treatment of loculated PPEs. It can be performed safely and in some patients may avoid the need for additional surgical intervention.

Overnight resident preliminary interpretations on CT examinations: should the process continue?

We report our experience with resident preliminary interpretations given at night on both abdominal and neurological CT scans to quantify the discrepancy rate when compared to the final report. An attempt was also made to document any adverse clinical outcomes as a result of the preliminary interpretation. From January 1, 2004 to December 31, 2004, adult CT examinations were prospectively interpreted by residents at night at a level I trauma center. Both the neurological and body CT scans were reviewed beginning at 7:00 a.m. the following morning by the respective subspecialty staff and discrepancies were noted. Adult CT examinations (6,858) were prospectively interpreted by residents: 5,206 cranial spinal CT examinations and 1,652 body CT examinations. Among the neurological studies, there were six cases identified as major discrepancies (0.1%) and 185 minor discrepancies (3.5%). Among the body CT cases, there were seven cases identified as major discrepancies (0.4%) and 23 cases of minor discrepancies (1.4%). There is a low discrepancy rate (0.2% major and 3.1% minor) in the preliminary resident interpretations from the final report. The process of overnight preliminary CT interpretations should continue as it is not substandard care.

Multiple focal nodular hyperplasia of the liver in a 21-year-old woman.

Focal nodular hyperplasia (FNH) is a relatively common condition, the diagnosis of which is now regularly made with diagnostic imaging. Cases of multiple FNH (more than four lesions) are rare, however, and the presence of numerous lesions may complicate the workup and diagnosis. We recently treated a young woman with multiple FNH. We report this case to highlight the clinical issues presented by this rare variant of a common benign hepatic disease.

An algorithm for the accurate identification of benign liver lesions.

BACKGROUND: Benign liver lesions may be difficult to characterize preoperatively. In most instances, determination of the etiology of a hepatic mass makes its management decisions clear-cut. We present our experience using an algorithm for the management of liver masses of suspected benign or uncertain pathology and highlight this approach along with our surgical experience in benign liver lesions. METHODS: Seventy-one patients underwent hepatectomy with a preoperative diagnosis of benign disease or unknown etiology from December 1992 to February 2002. Patients were preoperatively assessed with computed tomography, along with other imaging studies, as indicated. Final pathology was reviewed to confirm the preoperative diagnosis. RESULTS: Ninety-two percent (65 of 71) were correctly characterized preoperatively. Diagnosis was inaccurate in 6 patients. Of these patients, final pathology revealed focal nodular hyperplasia in 4 patients. The remaining 2 patients, who had adenoma, were found to harbor malignancy within the surgical specimens. CONCLUSIONS: An algorithm to manage liver lesions resulted in a high diagnostic accuracy of a preoperative evaluation. Hepatic resection for benign disease can be performed with low morbidity and mortality and is highly successful in achieving relief for symptomatic patients.

Total pancreatectomy and autologous islet cell transplantation as a means to treat severe chronic pancreatitis.

Autologous islet cell transplantation after near-total or total pancreatic resection can alleviate pain in patients with severe chronic pancreatitis and preserve endocrine function. From February 2000 to February 2003, a total of 22 patients, whose median age was 38 years, underwent pancreatectomy and autologous islet cell transplantation. Postoperative complications, metabolic studies, insulin usage, pain scores, and quality of life were recorded for all of these patients. The average number of islet cells harvested was 245,457 (range 20,850 to 607,466). Operative data revealed a mean estimated blood loss of 635 ml, an average operative time of 9 hours, and a mean length of hospital stay of 15 days. Sixty-eight percent of the patients had either a minor or major complication. Major complications included acute respiratory distress syndrome (n=2), intra-abdominal abscess (n=1), and pulmonary embolism (n=1). There were no deaths in our series. All patients demonstrated C-peptide and insulin production indicating graft function. Forty-one percent are insulin independent, and 27% required minimal amount of insulin or a sliding scale. All patients had preoperative pain and had been taking opioid analgesics; 82% no longer required analgesics postoperatively. Pancreatectomy with autologous islet cell transplantation can alleviate pain for patients with chronic pancreatitis and preserve endocrine function.

Prevalence and predictors of severity as defined by atlanta criteria among patients presenting with acute pancreatitis.

INTRODUCTION: Effective triage of patients with acute pancreatitis is dependent on the ability to accurately predict a severe course. Predictors (e.g., APACHE II score of >8) have been tested against wide-ranging definitions of severity (prevalence, 15%-40%). To ensure uniformity in defining a severe course of acute pancreatitis, the Atlanta symposium of 1992 adopted all-encompassing criteria (local complications, systemic complications, need for surgery, or death). AIMS: To assess the prevalence of each Atlanta criteria for severe acute pancreatitis and to determine the sensitivity, specificity, and positive and negative predictive values of the APACHE II score as a predictor of these criteria for severe acute pancreatitis. METHODOLOGY: We reviewed records of patients admitted to the University of Cincinnati Medical Center (Cincinnati, OH, U.S.A.) between 1994 and 1998 with acute pancreatitis. Exclusion criteria included referral from an outside hospital, immunocompromised state, and chronic pancreatitis. RESULTS: Seventy-four consecutive patients met our inclusion criteria. Ten patients (13.5%) had a severe course. Seven patients developed only local complications. Three patients had systemic complications. Pancreatic surgical intervention was required in four patients. No deaths occurred. An APACHE II score of >8 exhibited 50% sensitivity and 69% specificity (positive predictive value, 20%; negative predictive value, 89%). All patients with systemic complications and two of seven patients with only local complications had an APACHE II score of >8. CONCLUSIONS: The prevalence of severity among our nonreferred patients with acute pancreatitis was less than previously reported. The APACHE II scoring system exhibited reasonable sensitivity in predicting systemic complications and/or the need for surgery, with a low positive predictive value. This most certainly is a function of the low pretest probability of severe pancreatitis. Future studies attempting to identify predictive systems that triage patients in a more cost-effective manner should restrict their analysis to Atlanta criteria other than local complications.