BackgroundAnti-CD19 CAR T cell therapy has demonstrated high response rates in patients with relapsed or refractory (r/r) B cell malignancies but is associated with significant toxicity. Cytokine release syndrome (CRS) is the most significant complication associated with CAR T cell therapy, and it is critical to have a reproducible and easy method to grade CRS after CAR T cell infusions.DiscussionThe Common Terminology Criteria for Adverse Events scale is inadequate for grading CRS associated with cellular therapy. Clinical experience with the anti-CD19 CAR T cell therapy tisagenlecleucel at the University of Pennsylvania (Penn) was used to develop the Penn grading scale for CRS. The Penn grading scale depends on easily accessible clinical features; does not rely on location of care or quantitation of supportive care; assigns grades to guide CRS management; distinguishes between mild, moderate, severe, and life-threatening CRS; and applies to both early-onset and delayed-onset CRS associated with T cell therapies. Clinical data from 55 pediatric patients with r/r B cell acute lymphoblastic leukemia and 42 patients with r/r chronic lymphocytic lymphoma treated with tisagenlecleucel were used to demonstrate the current application of the Penn grading scale.ConclusionWe show that the Penn grading scale provides reproducible CRS grading that can be useful to guide therapy and that can be applied across clinical trials and treatment platforms.

Permuted block design is the most popular randomization method used in clinical trials, especially for trials with more than two treatments and unbalanced allocation, because of its consistent imbalance control and simplicity in implementation. However, the risk of selection biases caused by high proportion of deterministic assignments is a cause of concern. Efron’s biased coin design and Wei’s urn design provide better allocation randomness without deterministic assignments, but they do not consistently control treatment imbalances. Alternative randomization designs with improved performances have been proposed over the past few decades, including Soares and Wu’s big stick design, which has high allocation randomness, but is limited to two-treatment balanced allocation scenarios only, and Berger’s maximal procedure design which has a high allocation randomness and a potential for more general trial scenarios, but lacks the explicit function for the conditional allocation probability and is more complex to implement than most other designs. The block urn design proposed in this paper combines the advantages of existing randomization designs while overcoming their limitations. Statistical properties of the new algorithm are assessed and compared to currently available designs via analytical and computer simulation approaches. The results suggest that the block urn design simultaneously provides consistent imbalance control and high allocation randomness. It can be easily implemented for sequential clinical trials with two or more treatments and balanced or unbalanced allocation.

BackgroundAccumulating evidence links colorectal cancer (CRC) with the intestinal microbiota. However, the disturbance of intestinal microbiota and the role of Fusobacterium nucleatum during the colorectal adenoma-carcinoma sequence have not yet been evaluated.Methods454 FLX pyrosequencing was used to evaluate the disturbance of intestinal microbiota during the adenoma-carcinoma sequence pathway of CRC. Intestinal microbiota and mucosa tumor-immune cytokines were detected in mice after introducing 1,2-dimethylhydrazine (DMH), F. nucleatum or Berberine (BBR), using pyrosequencing and Bio-Plex Pro™ cytokine assays, respectively. Protein expressions were detected by western blotting.ResultsThe levels of opportunistic pathogens, such as Fusobacterium, Streptococcus and Enterococcus spp. gradually increased during the colorectal adenoma-carcinoma sequence in human fecal and mucosal samples. F. nucleatum treatment significantly altered lumen microbial structures, with increased Tenericutes and Verrucomicrobia (opportunistic pathogens) (P < 0.05 = in wild-type C57BL/6 and mice with DMH treatment). BBR intervention reversed the F. nucleatum-mediated increase in opportunistic pathogens, and the secretion of IL-21/22/31, CD40L and the expression of p-STAT3, p-STAT5 and p-ERK1/2 in mice, compared with mice fed with F. nucleatum alone.ConclusionsF. nucleatum colonization in the intestine may prompt colorectal tumorigenesis. BBR could rescue F. nucleatum-induced colorectal tumorigenesis by modulating the tumor microenvironment and blocking the activation of tumorigenesis-related pathways.

To evaluate the performance of randomization designs under various parameter settings and trial sample sizes, and identify optimal designs with respect to both treatment imbalance and allocation randomness, we evaluate 260 design scenarios from 14 randomization designs under 15 sample sizes range from 10 to 300, using three measures for imbalance and three measures for randomness. The maximum absolute imbalance and the correct guess (CG) probability are selected to assess the trade-off performance of each randomization design. As measured by the maximum absolute imbalance and the CG probability, we found that performances of the 14 randomization designs are located in a closed region with the upper boundary (worst case) given by Efron’s biased coin design (BCD) and the lower boundary (best case) from the Soares and Wu’s big stick design (BSD). Designs close to the lower boundary provide a smaller imbalance and a higher randomness than designs close to the upper boundary. Our research suggested that optimization of randomization design is possible based on quantified evaluation of imbalance and randomness. Based on the maximum imbalance and CG probability, the BSD, Chen’s biased coin design with imbalance tolerance method, and Chen’s Ehrenfest urn design perform better than popularly used permuted block design, EBCD, and Wei’s urn design.

Objective: We aimed to describe our experience and the learning curve of 450 cases of robot-assisted pancreaticoduodenectomy (RPD) and optimize the surgical process so that our findings can be useful for surgeons starting to perform RPD. Summary Background Data: Robotic surgical systems were first introduced 20 years ago. Pancreaticoduodenectomy (PD) is a challenging surgery because of its technical difficulty. RPD may overcome some of these difficulties. Methods: The medical records of 450 patients who underwent RPD between May 2010 and December 2018 at the Shanghai Ruijin Hospital were retrospectively analyzed. Operative times and estimated blood loss (EBL) were analyzed and the learning curve was determined. A cumulative sum (CUSUM) analysis was used to identify the inflexion points. Other postoperative outcomes, postoperative complications, and long-term follow-up were also analyzed. Results: Operative time improved gradually over time from 405.4 AE 112.9 minutes (case 1-50) to 273.6 AE 70 minutes (case 301-350) (P < 0.001). EBL improved from 410 AE 563.5 mL (case 1-50) to 149.0 AE 103.3 mL (case 351-400) (P < 0.001). According to the CUSUM curve, there were 3 phases in the RPD learning curve. The inflexion points were around cases 100 and 250. The incidence of pancreatic leak in the last 350 cases was significantly lower than that in the first 100 cases (30.0% vs 15.1%, P ¼ 0.003). Conclusions: RPD is safe and feasible for selected patients. Operative and oncologic outcomes were much improved after experience of 250 cases. Our optimization of the surgical process may have also contributed to this. Future prospective and randomized studies are needed to confirm our results.

The structural proteins cytokeratin 18 (CK18) and its coexpressed complementary partner CK8 are expressed in a variety of adult epithelial organs and may play a role in carcinogenesis. In this study, we focused on the biological functions of CK18, which is thought to modulate intracellular signaling and operates in conjunction with various related proteins. CK18 may affect carcinogenesis through several signaling pathways, including the phosphoinositide 3-kinase (PI3K)/Akt, Wnt, and extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) signaling pathways. CK18 acts as an identical target of Akt in the PI3K/Akt pathway and of ERK1/2 in the ERK MAPK pathway, and regulation of CK18 by Wnt is involved in Akt activation. Finally, we discuss the importance of gaining a more complete understanding of the expression of CK18 during carcinogenesis, and suggest potential clinical applications of that understanding. Mol Cancer Res; 10(4); 485-93. Ó2012 AACR.

IMPORTANCE Robot-assisted pancreaticoduodenectomy (RPD) has been reported to be safe and feasible. As a new technique, RPD has a learning curve similar to that of other types of minimally invasive pancreatic surgery such as laparoscopic pancreaticoduodenectomy. To our knowledge, no reports exist on the outcomes of open pancreaticoduodenectomy (OPD) and RPD after the learning curve. OBJECTIVE To analyze and evaluate the actual advantages of RPD. DESIGN, SETTING, AND PARTICIPANTS Between May 2010 and December 2018, 450 patients underwent RPD in the Shanghai Ruijin Hospital affiliated with Shanghai Jiaotong University in Shanghai, China, a high-volume pancreatic disease center. According to our previous study, an important flexion point in the learning curve is 250 cases. Data on the last 200 RPD cases were collected from January 2017 to December 2018. During that period, 634 patients underwent OPD. These patients were divided into 2 groups, and propensity score matching was used to minimize bias. The demographic data and operative outcomes were collected and analyzed. Analysis began May 2019. EXPOSURES Robot-assisted pancreaticoduodenectomy and OPD. MAIN OUTCOMES AND MEASURES The short-term operative outcomes of RPD and OPD. RESULTS After 1:1 matching, 187 cases of RPD and OPD were recorded. In the RPD group, 78 patients (41.7%) were women, and the mean (SD) age was 60.9 (11.4) years. In the OPD group, 80 patients (42.8%) were women, and the mean (SD) age was 60.1 (10.8) years. Robot-assisted pancreaticoduodenectomy had advantages in operative time (mean [SD], 279.7 [76.3] minutes vs 298.2 [78.3] minutes; P = .02), estimated blood loss (mean [SD], 297.3 [246.8] mL vs 415.2 [497.9] mL; P = .002), and postoperative length of hospital stay (mean [SD], 22.4 [16.7] days vs 26.1 [16.3] days; P = .03). However, there was no significant difference in the R0 resection rate and incidence rate of postoperative complications, such as postoperative pancreatic fistula, bile leak, and delayed gastric emptying. The incidence rates of postoperative bleeding and reoperation in the RPD group were similar to those in the OPD group, with no statistically significant difference. CONCLUSIONS AND RELEVANCE After passing the learning curve, RPD had advantages in operative time and blood loss compared with OPD. There were no differences in postoperative complications such as postoperative pancreatic fistula, bile leak, and delayed gastric emptying. However, patients recovered more quickly after RPD than after OPD. A prospective randomized clinical trial is needed in the future to verify these results.

No abstract