The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase ...inhibitor with MK‐2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6–12 mg/m2 i.v.) and MK‐2206 (60–135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty‐nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK‐2206 135 mg. Treatment‐related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post‐treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK‐2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.
Tumor involvement of major vascular structures limits surgical options in pancreatic adenocarcinoma (PDAC), which in turn limits opportunities for cure. Despite advances in locoregional approaches, ...there is currently no role for incomplete resection. This study evaluated a gelatinized neoantigen-targeted vaccine applied to a grossly positive resection margin in preventing local recurrence. Incomplete surgical resection was performed in mice bearing syngeneic flank Panc02 tumors, leaving a 1 mm rim adherent to the muscle bed. A previously validated vaccine consisting of neoantigen peptides, a stimulator of interferon genes (STING) agonist and AddaVax
TM
(termed PancVax) was embedded in a hyaluronic acid hydrogel and applied to the tumor bed. Tumor remnants, regional lymph nodes, and spleens were analyzed using histology, flow cytometry, gene expression profiling, and ELISPOT assays. The immune microenvironment at the tumor margin after surgery alone was characterized by a transient influx of myeloid-derived suppressor cells (MDSCs), prolonged neutrophil influx, and near complete loss of cytotoxic T cells. Application of PancVax gel was associated with enhanced T cell activation in the draining lymph node and expansion of neoantigen-specific T cells in the spleen. Mice implanted with PancVax gel demonstrated no evidence of residual tumor at two weeks postoperatively and healed incisions at two months postoperatively without local recurrence. In summary, application of PancVax gel at a grossly positive tumor margin led to systemic expansion of neoantigen-specific T cells and effectively prevented local recurrence. These findings support further work into locoregional adjuncts to immune modulation in PDAC.
We previously reported CHFR methylation in a subset of colorectal cancer (CRC; ∼30%) with high concordance with microsatellite instability (MSI). We also showed that CHFR methylation predicted for ...sensitivity to docetaxel, whereas the MSI‐high phenotypes were sensitive to gemcitabine. We hypothesized that this subset of patients with CRC would be selectively sensitive to gemcitabine and docetaxel. We enrolled a Phase 2 trial of gemcitabine and docetaxel in patients with MSI‐high and/or CHFR methylated CRC. The primary objective was Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 response rate. Enrolled patients were treated with gemcitabine 800 mg/m2 on days 1 and 8 and docetaxel 70 mg/m2 on day 8 of each 21‐day cycle. A total of 6 patients with CHFR‐methylated, MSI‐high CRC were enrolled from September 2012 to August 2016. The study was closed in September of 2017 due to poor accrual prior to reaching the first interim assessment of response rate, which would have occurred at 10 patients. No RECIST criteria tumor responses were observed, with 3 patients (50%) having stable disease as best response, 1 lasting more than 9 months. Median progression‐free survival (PFS) was 1.79 months (95% confidence interval CI = 1.28, not available NA) and median overall survival (OS) was 15.67 months (95% CI = 4.24, NA). Common grade 3 toxicities were lymphopenia (67%), leukopenia (33%), and anemia (33%). Although negative, this study establishes a proof‐of‐concept for the implementation of epigenetic biomarkers (CHFR methylation/MSI) as inclusion criteria in a prospective clinical trial to optimize combinatorial strategies in the era of personalized medicine.
Study Highlights
WHAT IS THE CURRENT KNOWLEDGE ON THE TOPIC?
CHFR silencing via DNA methylation has been suggested to be predictive of taxane sensitivity in diverse tumors. The frequent association of CHFR methylation with microsatellite instability (MSI) suggested a possible combination therapy with gemcitabine, because the MSI phenotype may result in sensitivity to nucleoside analogues.
WHAT QUESTION DID THIS STUDY ADDRESS?
We hypothesized that metastatic colorectal cancer (mCRC), which have CHFR methylation and MSI phenotype were sensitive to gemcitabine and docetaxel, and have designed this Phase 2 trial in biomarker‐selected mCRC to test this prediction.
WHAT DOES THIS STUDY ADD TO OUR KNOWLEDGE?
The study enrolled a molecularly defined subgroup of patients with colorectal cancer (CRC) and showed that the combination is safe in this population. Nevertheless, due to poor enrollment and early termination, no conclusions on the primary and secondary end points could be made.
HOW MIGHT THIS CHANGE CLINICAL PHARMACOLOGY OR TRANSLATIONAL SCIENCE?
This study supports the feasibility of implementing DNA methylation markers in a prospective clinical trial and further efforts toward their application as predictive biomarkers for therapeutic agents in defined subsets of patients are warranted.
The #MeToo movement has taken on sexual harassment in the workplace and served to inform the world that these unacceptable and illegal acts have become commonplace, including in academic settings. ...Through this platform, women are empowering each other to fight back against egregious behaviors that have infiltrated the workplace for decades. However, there are more subtle ways in which women can be demeaned in the workplace. Historically, women have been excluded from leadership positions in academic medicine. Importantly, while it is clear that gender-based and racial disparities are pervasive, concrete solutions to rectify these disparities are emerging and should be enacted broadly throughout academia. The percentage of women medical students has been steadily increasing with slightly more (52%) women enrolled in US medical schools in 2018. In fact, the 2019 medical student class at the Johns Hopkins University School of Medicine is predominantly female at 58%.
Background
Readmission has received attention as a potential healthcare quality metric. No studies have investigated the relationship between readmission and survival in patients undergoing rectal ...cancer surgery. The aims of this study were to identify factors associated with 30-day readmission after rectal cancer surgery and to determine the impact of readmission on overall survival (OS).
Methods
Patients who underwent surgical treatment for rectal/rectosigmoid adenocarcinoma stages I–IV were identified using the National Cancer Database (2004–2014). Multivariable logistic regression was used to identify factors for readmission. 2:1 nearest neighbor caliper matching without replacement was used to ensure similarity of patients being compared. Survival analyses were performed using Kaplan–Meier method along with log-rank test and Cox proportional hazards model.
Results
Of 110,167 patients, 7045 (6.39%) were readmitted. Factors associated with readmission included higher Charlson comorbidity score, non-private or no insurance, procedure type, hospitals in the Northeast, South, and Midwest regions, and prolonged length of stay. Within the matched cohort (13,756 non-readmitted and 6878 readmitted), readmitted patients had worse 5- and 10-year OS regardless of cancer stage (
p
< 0.001) and procedure type. Five- and 10-year OS were 58.98% and 41.01% for readmitted patients, 64.96% and 43.50% for non-readmitted patients. Readmitted patients had shorter OS by 13.14 months and increased risk of mortality (HR 1.20, 95% CI 1.15–1.25,
p
< 0.001).
Conclusions
Thirty-day readmission after rectal cancer surgery is associated with decreased OS. Efforts to reduce readmissions should be considered to advance cancer care and enhance the potential for improved patient survival.
Multidisciplinary care has been associated with improved survival in patients with primary liver cancers. We report the practice patterns and real world clinical outcomes for patients presenting to ...the Johns Hopkins Hospital (JHH) multidisciplinary liver clinic (MDLC). We analyzed hepatocellular carcinoma (HCC, n = 100) and biliary tract cancer (BTC, n = 76) patients evaluated at the JHH MDLC in 2019. We describe the conduct of the clinic, consensus decisions for patient management based on stage categories, and describe treatment approaches and outcomes based on these categories. We describe subclassification of BCLC stage C into 2 parts, and subclassification of cholangiocarcinoma into 4 stages. A treatment consensus was finalized on the day of MDLC for the majority of patients (89% in HCC, 87% in BTC), with high adherence to MDLC recommendations (91% in HCC, 100% in BTC). Among patients presenting for a second opinion regarding management, 28% of HCC and 31% of BTC patients were given new therapeutic recommendations. For HCC patients, at a median follow up of 11.7 months (0.7-19.4 months), median OS was not reached in BCLC A and B patients. In BTC patients, at a median follow up of 14.2 months (0.9-21.1 months) the median OS was not reached in patients with resectable or borderline resectable disease, and was 11.9 months in patients with unresectable or metastatic disease. Coordinated expert multidisciplinary care is feasible for primary liver cancers with high adherence to recommendations and a change in treatment for a sizeable minority of patients.
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