Seattle, Washington, is an epicenter of the coronavirus disease 2019 epidemic in the United States. In response, the Division of General Surgery at the University of Washington Department of Surgery ...in Seattle has designed and implemented an emergency restructuring of the facility’s general surgery resident care teams in an attempt to optimize workforce well-being, comply with physical distancing requirements, and continue excellent patient care. This article introduces a unique approach to general surgery resident allocation by dividing patient care into separate inpatient care, operating care, and clinic care teams. Separate teams made up of all resident levels will work in each setting for a 1-week period. By creating this emergency structure, we have limited the number of surgery residents with direct patient contact and have created teams working in isolation from one another to optimize physical distancing while still performing required work. This also provides a resident reserve without exposure to the virus, theoretically flattening the curve among our general surgery resident cohort. Surgical resident team restructuring is critical during a pandemic to optimize patient care and ensure the well-being and vitality of the resident workforce while ensuring the entire workforce is not compromised.
Pancreatic ductal adenocarcinoma (PDA) frequently presents at an advanced and incurable stage of the disease. Common signs and symptoms of PDA include abdominal or back pain, jaundice, weight loss, ...pruritus, and nausea/vomiting. Diagnostic workup includes serum chemistries and CA19-9, primarily to monitor disease status and response to treatment. Imaging studies are performed to assess resectability and stage disease, and pancreatic protocol computed tomography (CT) scan or magnetic resonance imaging (MRI) are the preferred imaging studies for this purpose. Conventional staging is based on the American Joint Cancer Committee (AJCC) Staging System, 7th Edition and informs prognosis, while surgical staging systems focus specifically on assessing the likelihood of a complete (negative margins) resection with operative management. Herein, we review the presenting signs and symptoms, the diagnostic evaluation, and staging of PDA.
Genomic methods can identify homologous recombination deficiency (HRD). Rigorous evaluation of their outcome association to DNA damage response-targeted therapies like platinum in pancreatic ductal ...adenocarcinoma (PDAC) is essential in maximizing therapeutic outcome.
We evaluated progression-free survival (PFS) and overall survival (OS) of patients with advanced-stage PDAC, who had both germline- and somatic-targeted gene sequencing. Homologous recombination gene mutations (HRm) were evaluated:
, and
HRm status was grouped as: (i) germline versus somatic; (ii) core (
and
versus non-core (other HRm); and (iii) monoallelic versus biallelic. Genomic instability was compared using large-scale state transition, signature 3, and tumor mutation burden.
Among 262 patients, 50 (19%) had HRD (15% germline and 4% somatic). Both groups were analyzed together due to lack of difference in their genomic instability and outcome. Median 95% confidence interval (CI) follow-up was 21.9 (1.4-57.0) months. Median OS and PFS were 15.5 (14.6-19) and 7 (6.1-8.1) months, respectively. Patients with HRD had improved PFS compared with no HRD when treated with first-line (1L) platinum HR, 0.44 (95% CI: 0.29-0.67);
< 0.01, but not with 1L-non-platinum. Multivariate analysis showed HRD patients had improved OS regardless of their first-line treatment, but most had platinum exposure during their course. Biallelic HRm (11%) and core HRm (12%) had higher genomic instability, which translated to improved PFS on first-line platinum (1L-platinum) versus 1L-non-platinum.
Pathogenic HRm identifies HRD in patients with PDAC with the best outcome when treated with 1L-platinum. Biallelic HRm and core HRm further enriched benefit from 1L-platinum from HRD.
Despite insights gained by bulk DNA sequencing of cancer it remains challenging to resolve the admixture of normal and tumor cells, and/or of distinct tumor subclones; high-throughput single-cell DNA ...sequencing circumvents these and brings cancer genomic studies to higher resolution. However, its application has been limited to liquid tumors or a small batch of solid tumors, mainly because of the lack of a scalable workflow to process solid tumor samples. Here we optimize a highly automated nuclei extraction workflow that achieves fast and reliable targeted single-nucleus DNA library preparation of 38 samples from 16 pancreatic ductal adenocarcinoma patients, with an average library yield per sample of 2867 single nuclei. We demonstrate that this workflow not only performs well using low cellularity or low tumor purity samples but reveals genomic evolution patterns of pancreatic ductal adenocarcinoma as well.
Background
Liver metastasis (LM) after pancreatic ductal adenocarcinoma (PDAC) resection is common but difficult to predict and has grave prognosis. We combined preoperative clinicopathological ...variables and quantitative analysis of computed tomography (CT) imaging to predict early LM.
Methods
We retrospectively evaluated patients with PDAC submitted to resection between 2005 and 2014 and identified clinicopathological variables associated with early LM. We performed liver radiomic analysis on preoperative contrast-enhanced CT scans and developed a logistic regression classifier to predict early LM (< 6 months).
Results
In 688 resected PDAC patients, there were 516 recurrences (75%). The cumulative incidence of LM at 5 years was 41%, and patients who developed LM first (
n
= 194) had the lowest 1-year overall survival (OS) (34%), compared with 322 patients who developed extrahepatic recurrence first (61%). Independent predictors of time to LM included poor tumor differentiation (hazard ratio (HR) = 2.30;
P
< 0.001), large tumor size (HR = 1.17 per 2-cm increase;
P
= 0.048), lymphovascular invasion (HR = 1.50;
P
= 0.015), and liver Fibrosis-4 score (HR = 0.89 per 1-unit increase;
P
= 0.029) on multivariate analysis. A model using radiomic variables that reflect hepatic parenchymal heterogeneity identified patients at risk for early LM with an area under the receiver operating characteristic curve (AUC) of 0.71; the performance of the model was improved by incorporating preoperative clinicopathological variables (tumor size and differentiation status; AUC = 0.74, negative predictive value (NPV) = 0.86).
Conclusions
We confirm the adverse survival impact of early LM after resection of PDAC. We further show that a model using radiomic data from preoperative imaging combined with tumor-related variables has great potential for identifying patients at high risk for LM and may help guide treatment selection.
Background
While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly ...characterized.
Methods
One thousand one hundred seven patients underwent pancreatectomy at Thomas Jefferson University between 2006 and 2013. Attempts were made to contact all living patients by telephone and a DM-focused questionnaire was administered.
Results
Two hundred fifty-nine of 691 (37 %) surviving patients completed the survey, including 179 pancreaticoduodenectomies (PD), 78 distal pancreatectomies (DP), and 2 total pancreatectomies. In the PD group, 44 (25 %) patients reported having DM prior to resection. Of these, 5 (12 %) had improved glucose control after resection and 21 (48 %) reported escalated DM medication requirements post-resection. Of 135 PD patients without preoperative DM, 24 (18 %) had new-onset DM postoperatively. In the DP group, 23 patients (29 %) had DM preoperatively. None had improved glucose control after resection, while six (26 %) had worse control after resection. Seventeen of 55 DP patients (31 %) without preoperative DM developed new-onset DM postoperatively (
p
= 0.04 vs. PD). Preoperative HgbA1C >6.0 %, glucose >124 mg/dL, and insulin use >2 units per day were associated with an increased risk of new-onset postoperative DM.
Conclusions
The development or worsening of DM after pancreatic resection is extremely common, with different types of resections conveying different risks for disease progression. DP places patients at a greater risk for the development of new-onset postoperative diabetes when compared to PD. In contrast, patients with preoperative diabetes are more likely to experience worsening of their disease after PD as compared to DP. Patients should be screened prospectively, particularly those at highest risk, and informed of and educated about the potential for post-resection DM.
Entosis is a type of regulated cell death that promotes cancer cell competition. Though several studies have revealed the molecular mechanisms that govern entosis, the clinical and genetic correlates ...of entosis in human tumors is less well understood. Here we reviewed entotic cell-in-cell (CIC) patterns in a large single institution sequencing cohort (MSK IMPACT clinical sequencing cohort) of more than 1600 human pancreatic ductal adenocarcinoma (PDAC) samples to identify the genetic and clinical correlates of this cellular feature. After case selection, 516 conventional PDACs and 21 ASCs entered this study and ~45,000 HPFs (median 80 HPFs per sample) were reviewed; 549 entotic-CICs were detected through our cohort. We observed that entotic-CIC occurred more frequently in liver metastasis compared with primary in PDAC. Moreover, poorly differentiated adenocarcinoma or adenosquamous carcinoma had more entotic-CIC than well or moderately differentiated adenocarcinoma. With respect to genetic features TP53 mutations, KRAS amplification, and MYC amplification were significantly associated with entosis in PDAC tissues. From a clinical standpoint entotic CICs were independently associated with a poor prognosis by multivariate Cox regression analysis when considering all cases or primary PDACs specifically. These results provide a contextual basis for understanding entosis in PDAC, a highly aggressive cancer for which molecular insights are needed to improve survival.
We sought to comprehensively profile tissue and cyst fluid in patients with benign, precancerous, and cancerous conditions of the pancreas to characterize the intrinsic pancreatic microbiome.
Small ...studies in pancreatic ductal adenocarcinoma (PDAC) and intraductal papillary mucinous neoplasm (IPMN) have suggested that intra-pancreatic microbial dysbiosis may drive malignant transformation.
Pancreatic samples were collected at the time of resection from 109 patients. Samples included tumor tissue (control, n=20; IPMN, n=20; PDAC, n=19) and pancreatic cyst fluid (IPMN, n=30; SCA, n=10; MCN, n=10). Assessment of bacterial DNA by quantitative PCR and 16S ribosomal RNA gene sequencing was performed. Downstream analyses determined the relative abundances of individual taxa between groups and compared intergroup diversity. Whole-genome sequencing data from 140 patients with PDAC in the National Cancer Institute's Clinical Proteomic Tumor Analysis Consortium (CPTAC) were analyzed to validate findings.
Sequencing of pancreatic tissue yielded few microbial reads regardless of diagnosis, and analysis of pancreatic tissue showed no difference in the abundance and composition of bacterial taxa between normal pancreas, IPMN, or PDAC groups. Low-grade dysplasia (LGD) and high-grade dysplasia (HGD) IPMN were characterized by low bacterial abundances with no difference in tissue composition and a slight increase in Pseudomonas and Sediminibacterium in HGD cyst fluid. Decontamination analysis using the CPTAC database confirmed a low-biomass, low-diversity intrinsic pancreatic microbiome that did not differ by pathology.
Our analysis of the pancreatic microbiome demonstrated very low intrinsic biomass that is relatively conserved across diverse neoplastic conditions and thus unlikely to drive malignant transformation.
Background
KRAS, TP53, CDKN2A, and SMAD4 are established driver genes in pancreatic ductal adenocarcinoma (PDAC). This study was aimed at determining whether the mutational status of driver genes and ...those involved in DNA repair pathways are associated with clinical outcomes for individuals who undergo resection.
Methods
Eligible individuals were those who underwent resection of PDAC and consented to targeted sequencing of their primary tumor via Memorial Sloan Kettering–Integrated Mutation Profiling of Actionable Cancer Targets (MSK‐IMPACT). Genomic alterations were determined on the basis of MSK‐IMPACT results from formalin‐fixed, paraffin‐embedded samples. Associations between genomic alterations and clinical outcomes were assessed.
Results
Targeted sequencing was performed on 283 primary tumors resected between 2004 and 2017. The median follow‐up was 23 months among survivors. Alterations in KRAS and TP53 were associated with worse overall survival (OS) in comparison to wild type (median for KRAS, 38.8 months 95% CI, 33.0‐45.5 months vs 91.0 months 95% CI, 34.8 months to not available (NA); P = .043; median for TP53, 37.4 months 95% CI, 32.1‐42.8 months vs 65.0 months 95% CI, 33.0 months to NA; P = .035). KRAS G12D mutations were associated with worse OS (median, 31.6 months 95% CI, 25.3‐45.5 months vs 39.2 months 95% CI, 37.4‐75.2 months; P = .012). TP53 truncating mutations (median, 39.6 months 95% CI, 32.4‐75.2 months vs 33.9 months 95% CI, 24.0‐39.0 months; P = .020) and those associated with loss of heterozygosity (median, 26.6 months 95% CI, 21.6‐44.2 months vs 39.2 months 95% CI, 34.5‐49.1 months; P = .048) had decreased OS. TP53 alterations were independently associated with OS in a multivariate analysis (hazard ratio, 1.54; 95% CI, 1.01‐2.33; P = .042). Individuals with germline alterations in homologous recombination deficiency (HRD) genes had improved OS in comparison with those without them (median, not reached vs 37.0 months; 95% CI, 33.0‐49.8 months; P = .035).
Conclusions
In patients with resected PDAC, genomic alterations in KRAS and TP53 are associated with worse outcomes, whereas alterations in HRD genes are associated with a favorable prognosis. Further studies are needed to better define these alterations as biomarkers in resected PDAC.
Results from a routinely used, clinically actionable targeted sequencing panel demonstrate that alterations in KRAS and TP53 are associated with worse outcomes in patients undergoing resection for pancreatic ductal adenocarcinoma. Specifically, KRAS G12D mutations, TP53 alterations resulting in truncations, and TP53 alterations in areas with loss of heterozygosity are associated with a poorer prognosis; in addition, germline homologous repair deficiency mutations are associated with improved overall survival.
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