A Comprehensive Review of Diagnostic and Therapeutic Strategies for the Management of Pancreatic Cancer.

Pancreatic cancer is one of the fastest-growing fatal solid tumors across the world. The challenges with pancreatic cancer are delayed diagnosis and lack of effective treatment strategies. Pancreatic cancer is expected to become the third leading cause of cancer-related mortality in high-income countries in the coming decade. In most cases, patients are diagnosed at advanced stages, due to a lack of early symptoms, whereby the tumor is unresectable. Imaging, histopathology, and biomarker approaches are currently used for pancreatic cancer diagnosis. Imaging modalities for pancreatic cancer diagnosis include endoscopy, ultrasound, computed tomography, magnetic resonance imaging, and positron emission tomography scanning. Along with imaging, histopathology helps in the identification of cancer stages and in therapeutic decisions. The multidisciplinary treatment option is the most common choice for pancreatic cancer and includes surgery, chemotherapy, chemoradiotherapy, and supportive care. Immunotherapy is the emerging approach for the treatment of pancreatic cancers. The present review summarizes the current literature and provides an overview of both the diagnostic and therapeutic options for the effective management of pancreatic carcinoma.

Epigenetic Modifiers and Their Potential Application in Colorectal Cancer Diagnosis and Therapy.

Colorectal cancer (CRC) is the second leading cause of mortality in western countries. Delayed diagnosis of CRC is among the major reasons for its high mortality rate and progression to advanced stages. Early diagnosis of CRC is considered very important for timely treatment. Therefore, identification of accurate biomarkers holds the potential of laying a structural foundation for successful clinical management. A multistep process including genetic and epigenetic alterations, drives the development of early premalignant lesions to advanced metastatic CRC. These genetic and epi-genetic alterations accumulated over the course of malignant transformation favor the growth of neoplastic cells and an aggressive phenotype of malignant cells. Several epigenetic modifications have been shown to play a critical role in regulating gene expression, not only causing belligerent malignant cells but also impelling the initial stages of oncogenesis. The present review discusses the diagnostic, prognostic, and predictive applications of epigenetic biomarkers along with therapeutic strategies targeting such epigenetic alterations.

Laparoscopic Peritoneal Dialysis Catheter Placement with Chest Wall Exit Site for Neonate with Stoma.

Neonates requiring peritoneal dialysis (PD) catheters have been shown to have complication rates up to 70%. The presence of a concurrent stoma significantly increases the risk of peritonitis, exit-site infection, and catheter failure. As such, multiple techniques have been proposed to reduce these risks, including a chest wall exit site. In this case, the patient was born with bilateral hypoplastic kidneys and an anorectal malformation, requiring a colostomy soon after birth. At 4 weeks of life, he required placement of a PD catheter for dialysis. Given the high risk of infection, a laparoscopic-assisted PD catheter placement with a chest wall exit remote from the colostomy was performed. This report describes the operative technique including omentectomy, placement of a percutaneous stitch between the catheter cuffs, and fibrin glue injection around the catheter. The patient had no catheter-related infections. Laparoscopic-assisted PD catheter placement with chest wall exit site is a safe alternative in patients with any type of abdominal stoma.

Incidence and Outcomes of Perforated Peptic Ulcers in Children: Analysis of the Kid's Inpatient Database and Report of Two Cases Treated by Laparoscopic Omental Patch Repair.

INTRODUCTION: Peptic ulcer disease (PUD) is a rare condition in children. Perforated peptic ulcer (PPU), a complication of PUD has an estimated mortality between 1.3% and 20%. We evaluate incidence and outcomes of PPU in children using an administrative database, perform a review of the literature, and report our technique for laparoscopic omental patch repair for PPU in two pediatric patients. MATERIALS AND METHODS: Kids' inpatient database (KID's) was analyzed for demographics, incidence, and outcomes. Incidence for each year was calculated based on the reported pediatric population in the United States for 2000, 2003, 2006, 2009, and 2012 by the U.S. Census Bureau. Additionally, we present two PPU cases, accompanied by a comprehensive review of the literature. RESULTS: The annual number of primary discharge diagnosis of PPU in the KID was 178 cases for 2000, 252 for 2003, 255 for 2006, 299 for 2009, and 266 for 2012. An increase trend over time was noted between 2000 and 2009; however, it was not statistically significant (0.05). PPU appears to be more common in Caucasian teenage boys. The mean length of stay was 8.02 days and with a statistically significant increase in healthcare charges ($33,187 versus $78,142, P = .002) when comparing year 2000-2012. DISCUSSION: PPU is a rare cause of abdominal pain in children, but still a PUD complication that requires surgery. PPU should be included in the differential diagnosis in patients presenting with acute abdominal pain of uncertain etiology and pneumoperitoneum. Laparoscopy is both diagnostic and therapeutic. Laparoscopic omental patch repair is a safe and effective treatment for PPUs.

Laparoscopic Division of Median Sacral Artery and Dissection of Types III and IV Sacrococcygeal Teratomas to Decrease Intraoperative Hemorrhagic Complications: Case Series and Review of the Literature.

INTRODUCTION: Sacrococcygeal teratoma (SCT) is the most common teratoma presenting at birth. Life-threatening bleeding is a major complication during tumor excision in children. In this study we demonstrate our technique for laparoscopic division of median sacral artery (MSA) during dissection of SCT in 2 pediatric patients as a safe technique to minimize risk of hemorrhage. METHODS: Two female infants diagnosed with types III and IV SCTs underwent preoperative evaluation in the postnatal period. The first patient was an 18-month-old girl who presented with metastatic type IV teratoma, resected after neoadjuvant therapy, and the second patient was a 6-day-old girl with prenatal diagnosis of cystic type III teratoma. Using laparoscopy in both patients, the presacral space was reached by opening the peritoneal reflection with blunt dissection and the MSA was identified. Then it was carefully isolated and divided with 3 or 5 mm sealing device. The pelvic components of the tumors were partially dissected using laparoscopy. The first patient's tumor resection was completed using a posterior sagittal approach and the second patient required a standard Chevron incision. Along with the description of our technique, a review of the current literature for the management of SCT and MSA was performed. RESULTS: Both patients underwent successful laparoscopic division of the MSA and resection of the SCTs without complications. CONCLUSION: Laparoscopic MSA division before SCT excision offers a safe approach that can reduce the risk of hemorrhage during surgery.

Peritoneal Nodules in a Pediatric Patient with Benign Teratoma. A Case Report and Review of Literature.

BACKGROUND: Mature ovarian teratomas are common in children. These well differentiated tumors are typically confined to the ovary. In rare cases, they can rupture leading to granulomatous peritonitis that mimics carcinomatosis. Ovarian tumors with peritoneal/omental implants suggest malignant pathology with a different prognosis. CASE: A 15-year-old girl presented with 5 months of abdominal pain, and weight loss. Computed tomography (CT) imaging of the abdomen revealed a large mass filling the abdomen. Slightly elevated lactate dehydrogenase (LDH) and carcinoma antigen 125 (CA125). On laparotomy an ovarian tumor with peritoneal and omental implants was identified. Left salpingo-oophorectomy, omentectomy, and peritoneal washing were performed. Pathology revealed a benign cystic teratoma. SUMMARY AND CONCLUSION: Although ovarian teratomas are typically benign, they might mimic carcinomatosis. In patients with unexpected finding of peritoneal implants, histologic diagnosis is recommended before proceeding with a full oncologic ovarian resection.

Laparoscopic-assisted divided colostomy for anorectal malformation case series: a description of technique, clinical outcomes and a review of the literature.

OBJECTIVE: To present a case series of pediatric patients who underwent a laparoscopic-assisted divided colostomy for anorectal malformations, describe our technique, and provide a review of the literature on laparoscopic-assisted colostomy in pediatric patients. METHODS: We performed a retrospective review of six patients born with anorectal malformations, who received a laparoscopic-assisted colostomy from 2012 to 2016 at Cardinal Glennon Children's Medical Center. RESULTS: The average operating time was 74.5 min. Laparoscopic colostomy types included divided (n = 5) and end colostomy with Hartmann's (n = 1). Location of the colostomy was selected just distal to the descending colon (n = 5) or at the sigmoid flexure (n = 1). Feeds and stoma production was achieved within 24 h from surgery in most patients. There were no major complications except one patient having a mucosal fistula prolapse that was easily reduced. CONCLUSIONS: Laparoscopic-assisted colostomy in the management of anorectal malformations is a safe and effective technique. It offers similar advantages of the open technique, with the added benefits of avoiding wound-related complications and improved cosmetic results.

Optimal timing of cholecystectomy in children with gallstone pancreatitis.

BACKGROUND: Little data exist regarding the recurrence of pancreatitis in pediatric patients with gallstone pancreatitis awaiting cholecystectomy. This study evaluates the recurrence rate of pancreatitis after acute gallstone pancreatitis based on the timing of cholecystectomy in pediatric patients. MATERIALS AND METHODS: A retrospective chart review of all patients admitted with gallstone pancreatitis from 2007 to 2015 was performed. Children were divided into the following five groups. Group 1 had surgery during the index admission. Group 2 had surgery within 2 wk of discharge. Group 3 had surgery between 2 and 6 wk postdischarge. Group 4 had surgery 6 wk after discharge, and group 5 patients had no surgery. The recurrence rates of pancreatitis were calculated for all groups. RESULTS: Forty-eight patients with gallstone pancreatitis were identified in this study. The 19 patients in group 1 had no recurrence of their pancreatitis. Of the remaining 29 patients, nine (31%) had recurrence of pancreatitis or required readmission for abdominal pain prior to their cholecystectomy. In group 2, two of the eight patients (25%) had recurrent pancreatitis. In group 3, three of eight patients (37.5%) developed recurrent pancreatitis. In group 4, three of five patients (60%), and in group 5, one of eight. No children in group 5 had demonstrable gallstones at presentation, only sludge in their gallbladder. CONCLUSIONS: Cholecystectomy during the index admission is associated with no recurrence or readmission for pancreatitis. Therefore, we recommend that cholecystectomy be performed after resolution of an episode of gallstone pancreatitis during index admission.

(1)H, (15)N, (13)C resonance assignment of human osteopontin.

Osteopontin (OPN) is a 33.7 kDa intrinsically disordered protein and a member of the SIBLING family of proteins. OPN is bearing a signal peptide for secretion into the extracellular space, where it exerts its main physiological function, the control of calcium biomineralization. It is often involved in tumorigenic processes influencing proliferation, migration and survival, as well as the adhesive properties of cancer cells via CD44 and integrin signaling pathways. Here we report the nearly complete NMR chemical shift assignment of recombinant human osteopontin.

Minimally invasive, nonendoscopic thyroidectomy: a cosmetic alternative to robotic-assisted thyroidectomy.

BACKGROUND: The desire to improve cosmesis has driven the introduction of robotic-assisted and video-assisted thyroidectomy techniques. We report on minimally invasive thyroidectomy (MIT) through a 2-cm incision without the added need for video assistance and hypothesize similar clinical results to standard open thyroidectomy. METHODS: Between May 2012 and December 2013, 62 nonendoscopic MIT were evaluated for demographics, clinical outcomes, and patient satisfaction on a 1-10 scale. The results were compared with a case-matched control group who underwent conventional open thyroidectomy by the same surgeon. RESULTS: The 124 study patients demonstrated no differences between groups for demographics or clinical outcomes except a smaller thyroid lobe in the MIT group (9.2 vs 11.7 g; P = .05). There were longer operative times in the MIT group (135.4 vs 119.6 minutes; P = .07) that were not equivalent by equivalence testing (P = .534). In MIT patients, transient recurrent laryngeal nerve injury occurred per nerves at risk (1.1% vs 3.4%; P = .62) with no permanent injuries in either group. There was no difference in symptomatic hypocalcemia (9.7% vs 11.3%; P = .77) and postoperative hematoma (0% vs 3.2%; P = .50). On follow-up, the measured MIT scar was significantly shorter (2.22 vs 3.98 cm; P < .00001), which resulted in significantly improved cosmetic satisfaction ratings (9.56 vs 8.66; P = .03). CONCLUSION: In selected patients, MIT through a 2-cm incision without endoscopic assistance is a safe alternative to standard open thyroidectomy in the hands of an experienced endocrine surgeon. The operating time is slightly increased, but clinical results are equivalent and patient satisfaction is significantly improved.

Protonation-dependent conformational variability of intrinsically disordered proteins.

Intrinsically disordered proteins (IDPs) are characterized by substantial conformational plasticity and undergo rearrangements of the time-averaged conformational ensemble on changes of environmental conditions (e.g., in ionic strength, pH, molecular crowding). In contrast to stably folded proteins, IDPs often form compact conformations at acidic pH. The biological relevance of this process was, for example, demonstrated by nuclear magnetic resonance studies of the aggregation prone (low pH) state of α-synuclein. In this study, we report a large-scale analysis of the pH dependence of disordered proteins using the recently developed meta-structure approach. The meta-structure analysis of a large set of IDPs revealed a significant tendency of IDPs to form α-helical secondary structure elements and to preferentially fold into more compact structures under acidic conditions. The predictive validity of this novel approach was demonstrated with applications to the tumor-suppressor BASP1 and the transcription factor Tcf4.

Probing local backbone geometries in intrinsically disordered proteins by cross-correlated NMR relaxation.

An ultra-high-resolution NMR experiment for the measurement of intraresidue (1)H(i)-(15)N(i)-(13)C'(i) dipolar-chemical shift anisotropy relaxation interference is employed to extract information about local backbone geometries in intrinsically disordered proteins. The study of tumor suppressor BASP1 revealed a population shift of ß-turn geometries at low pH conditions and a compaction of the BASP1 structural ensemble.

¹H, ¹³C and ¹5N resonance assignments of human BASP1.

Brain acid-soluble protein 1 (BASP1, CAP-23, NAP-22) appears to be implicated in diverse cellular processes. An N-terminally myristoylated form of BASP1 has been discovered to participate in the regulation of actin cytoskeleton dynamics in neurons, whereas non-myristoylated nuclear BASP1 acts as co-suppressor of the potent transcription regulator WT1 (Wilms' Tumor suppressor protein 1). Here we report NMR chemical shift assignment of recombinant human BASP1 fused to an N-terminal cleavable His6-tag.

¹H, ¹³C, and ¹5N backbone and side chain resonance assignments of the C-terminal DNA binding and dimerization domain of v-Myc.

The oncogenic transcription factor Myc is one of the most interesting members of the basic-helix-loop-helix-zipper (bHLHZip) protein family. Deregulation of Myc via gene amplification, chromosomal translocation or other mechanisms lead to tumorigenesis including Burkitt lymphoma, multiple myeloma, and many other malignancies. The oncogene myc is a highly potent transforming gene and capable to transform various cell types in vivo and in vitro. Its oncogenic activity initialized by deregulated expression leads to a shift of the equilibrium in the Myc/Max/Mad network towards Myc/Max complexes. The Myc/Max heterodimerization is a prerequisite for transcriptional functionality of Myc. Primarily, we are focusing on the apo-state of the C-terminal domain of v-Myc, the retroviral homolog of human c-Myc. Based on multi-dimensional NMR measurements v-Myc appears to be neither a fully structured nor a completely unstructured protein. The bHLHZip domain of v-Myc does not exist as a random coil but exhibits partially pre-formed α-helical regions in its apo-state. In order to elucidate the structural propensities of Myc in more detail, the backbone and side-chain assignments obtained here for apo-Myc are a crucial prerequisite for further NMR measurements.

Hypoxic preconditioning with cobalt ameliorates hypobaric hypoxia induced pulmonary edema in rat.

Exposure to high altitude results in hypobaric hypoxia which is considered as an acute physiological stress and often leads to high altitude maladies such as high altitude pulmonary edema (HAPE) and high altitude cerebral edema (HACE). The best way to prevent high altitude injuries is hypoxic preconditioning which has potential clinical usefulness and can be mimicked by cobalt chloride. Preconditioning with cobalt has been reported to provide protection in various tissues against ischemic injury. However, the effect of preconditioning with cobalt against high altitude induced pulmonary edema has not been investigated in vivo. Therefore, in the present study, rats pretreated with saline or cobalt (12.5mg/kg body weight) for 7days were exposed to hypobaric hypoxia of 9142m for 5h at 24°C. Formation of pulmonary edema was assessed by measuring transvascular leakage of sodium fluorescein dye and lung water content. Total protein content, albumin content, vascular endothelial growth factor (VEGF) and cytokine levels were measured in bronchoalveolar lavage fluid. Expression of HO-1, MT, NF-κB DNA binding activity and lung tissue pathology were evaluated to determine the effect of preconditioning on HAPE. Hypobaric hypoxia induced increase in transvascular leakage of sodium fluorescein dye, lung water content, lavage total protein, albumin, VEGF levels, pro-inflammatory cytokine levels, tissue expression of cell adhesion molecules and NF-κB DNA binding activity were reduced significantly after hypoxic preconditioning with cobalt. Expression of anti-inflammatory protein HO-1, MT, TGF-ß and IL-6 were increased after hypoxic preconditioning. These data suggest that hypoxic preconditioning with cobalt has protective effect against HAPE.

Hypoxic preconditioning facilitates acclimatization to hypobaric hypoxia in rat heart.

OBJECTIVES: Acute systemic hypoxia induces delayed cardioprotection against ischaemia-reperfusion injury in the heart. As cobalt chloride (CoCl2) is known to elicit hypoxia-like responses, it was hypothesized that this chemical would mimic the preconditioning effect and facilitate acclimatization to hypobaric hypoxia in rat heart. METHODS: Male Sprague-Dawley rats treated with distilled water or cobalt chloride (12.5 mg Co/kg for 7 days) were exposed to simulated altitude at 7622 m for different time periods (1, 2, 3 and 5 days). KEY FINDINGS: Hypoxic preconditioning with cobalt appreciably attenuated hypobaric hypoxia-induced oxidative damage as observed by a decrease in free radical (reactive oxygen species) generation, oxidation of lipids and proteins. Interestingly, the observed effect was due to increased expression of the antioxidant proteins hemeoxygenase and metallothionein, as no significant change was observed in antioxidant enzyme activity. Hypoxic preconditioning with cobalt increased hypoxia-inducible factor 1α (HIF-1α) expression as well as HIF-1 DNA binding activity, which further resulted in increased expression of HIF-1 regulated genes such as erythropoietin, vascular endothelial growth factor and glucose transporter. A significant decrease was observed in lactate dehydrogenase activity and lactate levels in the heart of preconditioned animals compared with non-preconditioned animals exposed to hypoxia. CONCLUSIONS: The results showed that hypoxic preconditioning with cobalt induces acclimatization by up-regulation of hemeoxygenase 1 and metallothionein 1 via HIF-1 stabilization.

Hypoxic preconditioning with cobalt attenuates hypobaric hypoxia-induced oxidative damage in rat lungs.

Shukla, Dhananjay, Saurabh Saxena, Purushotman Jayamurthy, Mustoori Sairam, Mrinalini, Singh, Swatantra Kumar Jain, Anju Bansal, and Govindaswamy Ilavazaghan. High Alt. Med. Biol. 10:57-69, 2009.-Hypoxic preco759nditioning (HPC) provides robust protection against injury from subsequent prolonged hypobaric hypoxia, which is a characteristic of high altitude and is known to induce oxidative injury in lung by increasing the generation of reactive oxygen species (ROS) and decreasing the effectiveness of the antioxidant defense system. We hypothesize that HPC with cobalt might protect the lung from subsequent hypobaric hypoxia-induced lung injury. HPC with cobalt can be achieved by oral feeding of CoCl(2) (12.5 mg kg(-1)) in rats for 7 days. Nonpreconditioned rats responded to hypobaric hypoxia (7619 m) by increased reactive oxygen species (ROS) generation and a decreased GSH/GSSG ratio. They also showed a marked increase in lipid peroxidation, heat-shock proteins (HSP32, HSP70), metallothionins (MT), levels of inflammatory cytokines (TNF-alpha, IFN-gamma, MCP-1), and SOD, GPx, and GST enzyme activity. In contrast, rats preconditioned with cobalt were far less impaired by severe hypobaric hypoxia, as observed by decreased ROS generation, lipid peroxidation, and inflammatory cytokine release and an inceased GSH/GSSG ratio. Increased expression of antioxidative proeins Nrf-1, HSP-32, and MT was also observed in cobalt- preconditioned animals. A marked increase in the protein expression and DNA binding activity of hypoxia-inducible transcriptional factor (HIF-1alpha) and its regulated genes, such as erythropoietin (EPO) and glucose transporter-1 (glut-1), was observed after HPC with cobalt. We conclude that HPC with cobalt enhances antioxidant status in the lung and protects from subsequent hypobaric hypoxia-induced oxidative stress.