Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Surgical resection of LAPC after neoadjuvant therapy is feasible in a highly selected cohort of patients (20%) and is associated with significantly longer median overall survival.

The NCCN Guidelines for Pancreatic Adenocarcinoma discuss the diagnosis and management of adenocarcinomas of the exocrine pancreas and are intended to assist with clinical decision-making. These NCCN Guidelines Insights discuss important updates to the 2019 version of the guidelines, focusing on postoperative adjuvant treatment of patients with pancreatic cancers.

PURPOSE.To characterize the genetic basis and phenotype of inherited Fuchs corneal dystrophy (FCD). METHODS.DNA from blood was used for genome-wide linkage scans with tandem repeat polymorphisms. Mutation detection involved sequencing PCR-amplified exons. Families with FCD were clinically evaluated and graded on the Krachmer severity scale. Confocal specular microscopy visualized the morphology of endothelial guttae, small protrusions of Descemet's membrane that are characteristic of FCD. RESULTS.Linkage was obtained to 1p34.3-p32 for the autosomal dominant kindred originally reported by Magovern in 1979. All 21 cases with FCD and one with posterior polymorphous dystrophy were heterozygous for L450W, a novel point mutation in the COL8A2 gene. Of 62 independent cases of familial FCD, none had the previously reported mutations in COL8A2. Corneal guttae in COL8A2 patients were small, rounded, and associated with the endothelial cell center. This contrasts with common FCD, in which guttae were larger, sharply peaked, and initially positioned at edges of endothelial cells. The profile of age and disease severity for the L450W FCD kindred suggested that disease onset occurred in infancy, compared with an average age of onset of 50 years estimated for 201 familial FCD patients in 62 other families. CONCLUSIONS.A novel pathogenic L450W COL8A2 mutation was identified and its highly distinctive pathology characterized. This indicates that COL8A2 mutations give rise to a rare subtype of FCD. This study also provides the first direct evidence that COL8A2-FCD progresses from early to late stages in 25 years, a rate similar to that estimated for late-onset FCD. (Invest Ophthalmol Vis Sci. 2005;46:1934 -1939) DOI: 10.1167/iovs.04-0937 F uchs corneal dystrophy (FCD) is a primary disorder of the endothelium that leads to progressive edema of the corneal stroma (OMIM 136800; Online Mendelian Inheritance in Man; http://www.ncbi.nlm.nih.gov/Omim/ provided in the public domain by the National Center for Biotechnology Information, Bethesda, MD). Visual disability from this disease is currently the major reason for corneal transplantation.1 The initial stages of FCD typically begin in the fifth through seventh decades of life and are characterized by localized thickening of Descemet's membrane and the development of nodular excrescences called guttae. This early phase is followed by long-term decreases in the density and ion transport functions of the overlying corneal endothelial cells, which allows excess water to accumulate in the cornea.2-8 Several reports, including the original description by Fuchs, have indicated that two to three times as many females as males are affected by the disease. 2,7,9 As many as 50% of clinical cases of FCD may show familial clustering, 9 and the disease generally follows an autosomal dominant pattern of inheritance. 10 -15 Nearly all these families show inheritance of late-onset FCD, whereas rare cases 12,14 show disease onset as early as the first decade, with extensive corneal edema by the third ...

Importance Medicare beneficiaries with cancer are at risk for financial hardship given increasingly expensive cancer care and significant beneficiary cost-sharing. Objective To measure out-of-pocket (OOP) costs incurred by Medicare beneficiaries with cancer and to identify which factors and services contribute to high OOP costs. Design Prospectively collected survey data from the 2002-12 waves of the Health and Retirement Study (HRS). Setting A nationally representative panel study of U.S. residents over age 50. Participants We studied 18,166 community-dwelling Medicare beneficiaries who participated in HRS, including 1,409 participants who were diagnosed with cancer over the study period. Main Outcome and Measures OOP medical spending and financial burden (OOP expenditures/household income). Results Type of supplementary insurance was significantly associated with mean annual OOP costs incurred following a cancer diagnosis (Medicaid: $2,116; VA: $2,367; Medicare HMO: $5,976; employer-sponsored: $5,492; Medigap: $5,670; none: $8,115). Beneficiaries with a new cancer diagnosis and Medicare alone incurred OOP expenditures that on average were 24% of their household income; 10% of these beneficiaries incurred OOP expenditures that were at least 63% of their household income. Among the 10% of beneficiaries with cancer who incurred the highest OOP costs, hospitalization contributed to 42% of total OOP costs. Conclusions and Relevance Medicare beneficiaries without supplemental insurance incur significant OOP costs following a diagnosis of cancer. Costs related to hospitalization may be a primary contributor to high OOP costs. Medicare reform proposals that restructure the benefit design for hospital-based services and that incorporate an OOP maximum may help alleviate financial burden, as can interventions that reduce hospitalization in this population.

Objectives Lymphopenia is a common consequence of chemoradiation therapy yet is seldom addressed clinically. This study was conducted to determine if patients with locally advanced pancreatic cancer (LAPC) treated with definitive chemoradiation develop significant lymphopenia and if this affects clinical outcomes. Methods A retrospective analysis of patients with LAPC treated with chemoradiation at a single institution from 1997 to 2011 was performed. Total lymphocyte counts (TLCs) were recorded at baseline and then monthly during and after chemoradiation. The correlation between treatment-induced lymphopenia, established prognostic factors, and overall survival was analyzed using univariate Cox regression analysis. Important factors identified by univariate analysis were selected as covariates to construct a multivariate proportional hazards model for survival. Results A total of 101 patients met eligibility criteria. TLCs were normal in 86% before chemoradiation. The mean reduction in TLC per patient was 50.6% (SD, 40.6%) 2 months after starting chemoradiation (P< 0.00001), and 46% had TLC< 500 cells/mm3. Patients with TLC < 500 cells/mm3 2 months after starting chemoradiation had inferior median survival (8.7 vs. 13.3mo, P= 0.03) and PFS (4.9 vs. 9.0mo, P = 0.15). Multivariate analysis revealed TLC< 500 cells/mm3 to be an independent predictor of inferior survival (HR= 2.879, P= 0.001) along with baseline serum albumin (HR= 3.584, P = 0.0002), BUN (HR = 1.060, P= 0.02), platelet count (HR= 1.004, P = 0.005), and radiation planning target volume (HR= 1.003, P= 0.0006). Conclusions Severe treatment-related lymphopenia occurs frequently after chemoradiation for LAPC and is an independent predictor of inferior survival.

Purpose: In research settings, circulating tumor DNA (ctDNA) shows promise as a tumor-specific biomarker for pancreatic ductal adenocarcinoma (PDAC). This study aims to perform analytical and clinical validation of a KRAS ctDNA assay in a Clinical Laboratory Improvement Amendments (CLIA) and College of American Pathology-certified clinical laboratory. Experimental Design: Digital-droplet PCR was used to detect the major PDAC-associated somatic KRAS mutations (G12D, G12V, G12R, and Q61H) in liquid biopsies. For clinical validation, 290 preoperative and longitudinal postoperative plasma samples were collected from 59 patients with PDAC. The utility of ctDNA status to predict PDAC recurrence during follow-up was assessed. Results: ctDNA was detected preoperatively in 29 (49%) patients and was an independent predictor of decreased recurrence-free survival (RFS) and overall survival (OS). Patients who had neoadjuvant chemotherapy were less likely to have preoperative ctDNA than were chemo-na€ ve patients (21% vs. 69%; P < 0.001). ctDNA levels dropped significantly after tumor resection. Persistence of ctDNA in the immediate postoperative period was associated with a high rate of recurrence and poor median RFS (5 months). ctDNA detected during follow-up predicted clinical recurrence [sensitivity 90% (95% confidence interval (CI), 74%-98%), specificity 88% (95% CI, 62%-98%)] with a median lead time of 84 days (interquartile range, 25-146). Detection of ctDNA during postpancreatectomy follow-up was associated with a median OS of 17 months, while median OS was not yet reached at 30 months for patients without ctDNA (P ¼ 0.011). Conclusions: Measurement of KRAS ctDNA in a CLIA laboratory setting can be used to predict recurrence and survival in patients with PDAC.

Importance Advance care planning (ACP) may prevent end-of-life (EOL) care that is non-beneficial and discordant with patient wishes. Despite long-standing recognition of the merits of ACP in oncology, it is unclear whether cancer patients’ participation in ACP has increased over time. Objective To characterize trends in durable power of attorney (DPOA) assignment, living will creation, and participation in discussions of EOL care preferences, and to explore associations between ACP subtypes and EOL treatment intensity, as reflected in EOL care decisions and terminal hospitalizations. Design Prospectively collected survey data from the Health and Retirement Study (HRS), including data from in-depth “exit” interviews conducted with next-of-kin surrogates following the death of an HRS participant. Trends in ACP subtypes were tested, and multivariable logistic regression models examined associations between ACP subtypes and measures of treatment intensity. Setting HRS, a nationally representative, biennial, longitudinal panel study of U.S. residents over age 50. Participants 1,985 next-of-kin surrogates of HRS participants with cancer who died between 2000 and 2012. Main Outcome and Measures Trends in the surrogate-reported frequency of DPOA assignment, living will creation, and participation in discussions of EOL care preferences, as well as associations between ACP subtypes and surrogate-reported EOL care decisions/terminal hospitalizations. Results From 2000-2012, there was an increase in DPOA assignment (52% to 74%, p=0.03), without change in use of living wills (49% to 40%, p=0.63) or EOL discussions (68% to 60%, p=0.62). Surrogates increasingly reported that patients received “all care possible” at EOL (7% to 58%, p=0.004), and rates of terminal hospitalizations were unchanged (29% to 27%, p=0.70). Both living wills and EOL discussions were associated with limiting/withholding treatment [living will: adjusted odds ratio (AOR)=2.51, 95% confidence interval (CI)=1.53-4.11, p<0.001; EOL discussions: AOR=1.93, 95% CI=1.53-3.14, p=0.002], while DPOA assignment was not. Conclusions and Relevance Use of DPOA increased significantly between 2000 and 2012, but was not associated with EOL care decisions. Importantly, there was no growth in key ACP domains such as discussions of care preferences. Efforts that bolster communication of EOL care preferences and also incorporate surrogate decision-makers are critically needed to ensure receipt of goal-concordant care.