Background: The KRAS oncogene is a driver mutation and is present in greater than 90% of pancreatic ductal adenocarcinomas (PDAC). A subset of these tumors, however, do not harbor mutations in KRAS (wild type KRAS). Studies have shown that patients with mutated KRAS have a poorer survival on first-line gemcitabine-based chemotherapy compared to wild type KRAS. In this study, we examined a cohort of patients with PDAC at our institution who were either wild type or mutant for the KRAS gene and assessed for differences in survival and response to different chemotherapeutic regimens. Methods: We examined clinical records of patients treated at the Abramson Cancer Center of the University of Pennsylvania from 2013 to 2017. Patients with a pancreatic mass and a histologic diagnosis of pancreatic or pancreaticobiliary adenocarcinoma were identified. Thirty-nine patients with PDAC who underwent tumor sequencing at Penn Medicine’s Center for Personalized Diagnostics (CPD) were selected for further study. Twelve patients were identified whose tumors were KRAS wild type. Twenty-seven patients with PDAC whose tumors harbored KRAS mutations were selected as controls (KRAS mutant). Results: We noted a longer overall survival (OS) among KRAS wild type patients compared to KRAS mutant patients (P=0.026). This was independent of the age at diagnosis, patient gender, stage of diagnosis, tumor morphology, mismatch repair (MMR) status, and chemotherapeutic regimen. Conclusions: Similar to previously reported studies, PDAC with a KRAS wild type mutational profile has a better prognosis with a longer OS. This improved prognosis is independent of the protocol utilized in therapy for these patients. Our findings suggest that future clinical trials in pancreatic cancer should take into consideration the presence of KRAS mutations in their pre-planned analysis when assessing the efficacy of a novel therapeutic approach. This may be a crucial factor in trial concepts and outcomes.

Cold agglutinins are autoantibodies against RBC antigens, leading to hemolysis at less-than-physiological temperatures through complement fixation. Production can be triggered by infections, resulting in secondary cold agglutinin syndrome (CAS). This syndrome has been classically described in the setting of Mycoplasma pneumoniae infection, as well as with several viral pathogens. Here, we present two cases of cold agglutinins identified in the context of Covid-19 in critically ill patients treated at our institution. Each case was characterized by little in-vivo hemolysis, but these antibodies complicated laboratory assessment and renal replacement therapy. Management included anticoagulation and warming of dialysis circuit. Despite minimal in-vivo hemolysis, these antibodies are of clinical significance given their implications for laboratory assessment and renal replacement therapy, particularly with the frequency of multi-organ system dysfunction associated with severe Covid-19.

Background: Prior reports have demonstrated inferior outcomes for patients with right-sided colorectal cancer (CRC) compared to patients with left-sided disease, as well as differences in treatment response based on disease sidedness. Differences in prognosis remain even among patients with metastatic disease, indicating that anatomy or stage at diagnosis alone cannot explain all of these findings. While genetic differences between right- and left-sided CRC have long been described, the genetic and molecular drivers underlying differences in prognosis and treatment response remain incompletely understood. Methods: We compared mutation prevalence between right- (cecum to splenic flexure) and left-sided (descending colon to rectum) CRC among 38 genes in a retrospective review of next-generation sequencing data of CRC samples obtained in routine clinical practice at a single academic medical center. Results: Among 288 cases (167 left-sided, 103 right-sided, 18 synchronous or without clear primary), patients with left-sided primaries had a longer overall survival from pathologic diagnosis (median 1,823 days vs. 1,006 days for right-sided cases, P=0.004). Among the assessed genes, BRAF and CTNNB1 mutations were more prevalent in right-sided CRC. BRAF was mutated in 15.5% of right-sided CRC (95% CI: 8.5–22.5%) compared to 4.8% (95% CI: 1.6–8.0%) (P=0.003). CTNNB1 was mutated in 3.9% of right-sided CRC (95% CI: 0.2–7.6%) compared to no instances of CTNNB1 mutations in left-sided disease (P=0.01). Conclusions: This difference in mutation prevalence may implicate these genetic pathways in the mechanisms underlying the discrepant outcomes and treatment responses between right- and left-sided CRC described in this and prior studies.

This is the case of an 84-year-old woman diagnosed with Stage IVb colon adenocarcinoma (CRC) metastatic to the liver, retroperitoneum, anastomotic site, and distal rectal sigmoid colon. She experienced intolerable side effects to systemic chemotherapy with 5-fluorouracil and bevacizumab, as well as disease progression. Next generation sequencing of her tumor was ordered, and further discussion of her malignancy’s genomic information took place at a multidisciplinary molecular tumor board. The patient had mutations in KRAS (Kirsten rat sarcoma viral oncogene homolog) which made her ineligible for epidermal growth factor receptor (EGFR) inhibitors; however, a KDR p.R961W c.2881C>T mutation was noted as a variant of unknown significance (VUS). KDR (kinase insert domain receptor) is the human gene encoding for vascular endothelial growth factor receptor 2 (VEGFR-2). She was then considered a suitable candidate for regorafenib, which she could only tolerate at a low dose of 40 mg daily, with the intent of prolonging her survival and to optimize her quality of life. We report her excellent tolerance and exceptional response to low dose regorafenib, including symptomatic, tumor marker, and sustained partial metabolic radiological improvement. In the largest Phase III trial of regorafenib in CRC, only five patients (1%) of 760 experienced a partial response (versus one patient, 0.4%, receiving placebo). KDR R961W mutation has been described but no functional data has been reported. This mutation occurs in the tyrosine kinase domain of the VEGFR-2. Regorafenib targets VEGFR-2 (KDR). Hereby we hypothesize KDR mutation as a novel predictive biomarker to exceptional response to regorafenib in metastatic colorectal cancer. To our knowledge, this is the first reported case of the potential correlation between KDR mutation and regorafenib use for the successful management of a patient with advanced CRC, leading to what is considered an exceptional response. Further studies based on this preliminary data are warranted.

Introduction: In January of 2010, North Carolina (NC) USA implemented state-wide Trauma Triage Destination Plans (TTDPs) to provide standardized guidelines for Emergency Medical Services (EMS) decision making. No study exists to evaluate whether triage behavior has changed for geriatric trauma patients.Hypothesis/Problem: The impact of the NC TTDPs was investigated on EMS triage of geriatric trauma patients meeting physiologic criteria of serious injury, primarily based on whether these patients were transported to a trauma center.Methods: This is a retrospective cohort study of geriatric trauma patients transported by EMS from March 1, 2009 through September 30, 2009 (pre-TTDP) and March 1, 2010 through September 30, 2010 (post-TTDP) meeting the following inclusion criteria: (1) age 50 years or older; (2) transported to a hospital by NC EMS; (3) experienced an injury; and (4) meeting one or more of the NC TTDP’s physiologic criteria for trauma (n = 5,345). Data were obtained from the Prehospital Medical Information System (PreMIS). Data collected included proportions of patients transported to a trauma center categorized by specific physiologic criteria, age category, and distance from a trauma center.Results: The proportion of patients transported to a trauma center pre-TTDP (24.4% [95% CI 22.7%-26.1%]; n = 604) was similar to the proportion post-TTDP (24.4% [95% CI 22.9%-26.0%]; n = 700). For patients meeting specific physiologic triage criteria, the proportions of patients transported to a trauma center were also similar pre- and post-TTDP: systolic blood pressure <90 mmHg (22.5% versus 23.5%); respiratory rate 29 (23.2% versus 22.6%); and Glascow Coma Scale (GCS) score <13 (26.0% versus 26.4%). Patients aged 80 years or older were less likely to be transported to a trauma center than younger patients in both the pre- and post-TTDP periods.Conclusions: State-wide implementation of a TTDP had no discernible effect on the proportion of patients 50 years and older transported to a trauma center. Under-triage remained common and became increasingly prevalent among the oldest adults. Research to understand the uptake of guidelines and protocols into EMS practice is critical to improving care for older adults in the prehospital environment.