CREB: A Key Regulator of Normal and Neoplastic Hematopoiesis

The cAMP response element-binding protein (CREB) is a nuclear transcription factor downstream of cell surface receptors and mitogens that is critical for normal and neoplastic hematopoiesis. Previous work from our laboratory demonstrated that a majority of patients with acute myeloid leukemia (AML) and acute lymphoid leukemia (ALL) overexpress CREB in the bone marrow. To understand the role of CREB in leukemogenesis, we examined the biological effect of CREB overexpression on primary leukemia cells, leukemia cell lines, and CREB overexpressing transgenic mice. Our results demonstrated that CREB overexpression leads to an increase in cellular proliferation and survival. Furthermore, CREB transgenic mice develop a myeloproliferative disorder with aberrant myelopoiesis in both the bone marrow and spleen. Additional research from other groups has shown that the expression of the cAMP early inducible repressor (ICER), a CREB repressor, is also deregulated in leukemias. And, miR-34b, a microRNA that negative regulates CREB expression, is expressed at lower levels in myeloid leukemia cell lines compared to that of healthy bone marrow. Taken together, these data suggest that CREB plays a role in cellular transformation. The data also suggest that CREB-specific signaling pathways could possibly serve as potential targets for therapeutic intervention

Extracorporeal Versus Intracorporeal Anastomosis for Laparoscopic Right Hemicolectomy

Background: During laparoscopic right hemicolectomy, the anastomosis can be created intra- or extracorporeally. This study aimed to determine whether a difference exists in short-term outcomes between these techniques.Methods: Prospectively collected data of 80 consecutive patients who underwent laparoscopic right hemicolectomies since 2004 were reviewed retrospectively. An intracorporeal anastomosis was performed in 23 patients, an extracorporeal anastomosis in 57.Results: There were no significant differences in median length of stay (4 days), number of removed lymph nodes, estimated blood loss, operative time (190 minutes intracorporeal vs. 180 minutes) and postoperative ileus (22% intracorporeal vs. 16%). The incision length was significantly shorter in the intracorporeal group (4cm vs. 5cm; P=0.004). Complications related to the anastomosis including twisting of the mesentery (n=2), anastomotic volvulus (n=1), or leak (n=1) occurred in 4 patients in the extracorporeal group compared with one minor anastomotic leak in the intracorporeal group. Major complication rates were similar between the 2 groups (4.3% intracorporeal vs. 5.3% extracorporeal).Conclusion: The type of anastomosis does not influence short-term outcomes after laparoscopic right hemicolectomy. An intracorporeal anastomosis results in shorter incision length and may decrease wound-related complications

Two consecutive immunophenotypic switches in a child with MLL-rearranged acute lymphoblastic leukemia.

An 18-month-old girl was diagnosed with prepre-B ALL/t(4;11) leukemia, which during thetreatment and after matched bone marrow transplantation(BMT), underwent two consecutiveswitches from lymphoid to myeloid lineage andvice versa. The high expression of HOXA9 andFLT3 genes remaining genotypically stable in aleukemia throughout phenotypic switches, suggeststhat this leukemia may have originated as acommon B/myeloid progenitors

CREB engages C/EBPδ to initiate leukemogenesis.

cAMP response element binding protein (CREB) is frequently overexpressed in acute myeloid leukemia (AML) and acts as a proto-oncogene; however, it is still debated whether such overactivation alone is able to induce leukemia as its pathogenetic downstream signaling is still unclear. We generated a zebrafish model overexpressing CREB in the myeloid lineage, which showed an aberrant regulation of primitive hematopoiesis, and in 79% of adult CREB-zebrafish a block of myeloid differentiation, triggering to a monocytic leukemia akin the human counterpart. Gene expression analysis of CREB-zebrafish revealed a signature of 20 differentially expressed human homologous CREB targets in common with pediatric AML. Among them, we demonstrated that CREB overexpression increased CCAAT-enhancer-binding protein-δ (C/EBPδ) levels to cause myeloid differentiation arrest, and the silencing of CREB-C/EBPδ axis restored myeloid terminal differentiation. Then, C/EBPδ overexpression was found to identify a subset of pediatric AML affected by a block of myeloid differentiation at monocytic stage who presented a significant higher relapse risk and the enrichment of aggressive signatures. Finally, this study unveils the aberrant activation of CREB-C/EBPδ axis concurring to AML onset by disrupting the myeloid cell differentiation process. We provide a novel in vivo model to perform high-throughput drug screening for AML cure improvement

Robotic-assisted surgery compared with laparoscopic resection surgery for rectal cancer: the ROLARR RCT

This is the final version. Available from NIHR Journals Library via the DOI in this recordData-sharing statement: All available data can be obtained by contacting the corresponding author.Background Robotic rectal cancer surgery is gaining popularity, but there are limited data about its safety and efficacy. Objective To undertake an evaluation of robotic compared with laparoscopic rectal cancer surgery to determine its safety, efficacy and cost-effectiveness. Design This was a multicentre, randomised trial comparing robotic with laparoscopic rectal resection in patients with rectal adenocarcinoma. Setting The study was conducted at 26 sites across 10 countries and involved 40 surgeons. Participants The study involved 471 patients with rectal adenocarcinoma. Recruitment took place from 7 January 2011 to 30 September 2014 with final follow-up on 16 June 2015. Interventions Robotic and laparoscopic rectal cancer resections were performed by high anterior resection, low anterior resection or abdominoperineal resection. There were 237 patients randomised to robotic and 234 to laparoscopic surgery. Follow-up was at 30 days, at 6 months and annually until 3 years after surgery. Main outcome measures The primary outcome was conversion to laparotomy. Secondary end points included intra- and postoperative complications, pathological outcomes, quality of life (QoL) [measured using the Short Form questionnaire-36 items version 2 (SF-36v2) and the Multidimensional Fatigue Inventory-20 (MFI-20)], bladder and sexual dysfunction [measured using the International Prostatic Symptom Score (I-PSS), the International Index of Erectile Function (IIEF) and the Female Sexual Function Index (FSFI)], and oncological outcomes. An economic evaluation considered the costs of robotic and laparoscopic surgery, including primary and secondary care costs up to 6 months post operation. Results Among 471 randomised patients [mean age 64.9 years, standard deviation (SD) 11.0 years; 320 (67.9%) men], 466 (98.9%) patients completed the study. Data were analysed on an intention-to-treat basis. The overall rate of conversion to laparotomy was 10.1% and occurred in 19 (8.1%) patients in the robotic-assisted group and in 28 (12.2%) patients in the conventional laparoscopic group {unadjusted risk difference 4.12% [95% confidence interval (CI) –1.35% to 9.59%], adjusted odds ratio 0.61 [95% CI 0.31 to –1.21]; p = 0.16}. Of the nine prespecified secondary end points, including circumferential resection margin positivity, intraoperative complications, postoperative complications, plane of surgery, 30-day mortality and bladder and sexual dysfunction, none showed a statistically significant difference between the groups. No difference between the treatment groups was observed for longer-term outcomes, disease-free and overall survival (OS). Males were at a greater risk of local recurrence than females and had worse OS rates. The costs of robotic and laparoscopic surgery, excluding capital costs, were £11,853 (SD £2940) and £10,874 (SD £2676) respectively. Conclusions There is insufficient evidence to conclude that robotic rectal surgery compared with laparoscopic rectal surgery reduces the risk of conversion to laparotomy. There were no statistically significant differences in resection margin positivity, complication rates or QoL at 6 months between the treatment groups. Robotic rectal cancer surgery was on average £980 more expensive than laparoscopic surgery, even when the acquisition and maintenance costs for the robot were excluded. Future work The lower rate of conversion to laparotomy in males undergoing robotic rectal cancer surgery deserves further investigation. The introduction of new robotic systems into the market may alter the cost-effectiveness of robotic rectal cancer surgery.National Institute for Health Research (NIHR

Optimal Total Mesorectal Excision for Rectal Cancer: the Role of Robotic Surgery from an Expert's View

Total mesorectal excision (TME) has gained worldwide acceptance as a standard surgical technique in the treatment of rectal cancer. Ever since laparoscopic surgery was first applied to TME for rectal cancer, with increasing penetration rates, especially in Asia, an unstable camera platform, the limited mobility of straight laparoscopic instruments, the two-dimensional imaging, and a poor ergonomic position for surgeons have been regarded as limitations. Robotic technology was developed in an attempt to reduce the limitations of laparoscopic surgery. The robotic system has many advantages, including a more ergonomic position, stable camera platform and stereoscopic view, as well as elimination of tremor and subsequent improved dexterity. Current comparison data between robotic and laparoscopic rectal cancer surgery show similar intraoperative results and morbidity, postoperative recovery, and short-term oncologic outcomes. Potential benefits of a robotic system include reduction of surgeon's fatigue during surgery, improved performance and safety for intracorporeal suture, reduction of postoperative complications, sharper and more meticulous dissection, and completion of autonomic nerve preservation techniques. However, the higher cost for a robotic system still remains an obstacle to wide application, and many socioeconomic issues remain to be solved in the future. In addition, we need more concrete evidence regarding the merits for both patients and surgeons, as well as the merits compared to conventional laparoscopic techniques. Therefore, we need large-scale prospective randomized clinical trials to prove the potential benefits of robot TME for the treatment of rectal cancer