Predicting Dysplasia and Invasive Carcinoma in Intraductal Papillary Mucinous Neoplasms of the Pancreas: Development of a Preoperative Nomogram

Background

Clinical decision making for patients with intraductal papillary mucinous neoplasms (IPMN) of the pancreas is challenging. Even with strict criteria for resection, most resected lesions lack high-grade dysplasia (HGD) or invasive carcinoma.

Methods

We evaluated patients who underwent resection of histologically confirmed IPMN and had preoperative imaging available for review. A hepatobiliary radiologist blinded to histopathologic subtype reviewed preoperative imaging and recorded cyst characteristics. Patients with mixed-type IPMN were grouped with main-duct lesions for this analysis. Based on an ordinal logistic regression model, we devised two independent nomograms to predict the findings of adenoma, high-grade dysplasia (HGD–CIS), and invasive carcinoma, separately in both main and branch-duct IPMN. Bootstrap validation was used to evaluate the performance of these models, and a concordance index was derived from this internal validation.

Results

There were 219 patients who met criteria for this study. Branch-duct IPMN (bdIPMN) comprised 56 % of the resected lesions. The proportion of HGD–CIS was 15 % for bdIPMN and 33 % for main-duct lesions (mdIPMN); P = 0.003. Invasive carcinoma was identified in 15 % of bdIPMN and 41 % of main-duct lesions (P < 0.001). On multivariate regression, patient gender, history of prior malignancy, presence of solid component, and weight loss were found to be significantly associated with the ordinal outcome for patients with mdIPMN and built into the nomogram (concordance index 0.74). For patients with bdIPMN weight loss, solid component, and lesion diameter were associated with the outcome; (concordance index 0.74).

Conclusion

Based on the analysis of patients selected for resection, two nomograms were created that predict a patient’s individual likelihood of harboring HGD or invasive malignancy in radiologically diagnosed IPMN. External validation is ongoing.     

Elevated Galectin-3 Precedes the Development of CKD

Galectin-3, a profibrotic mediator, is linked to the development of renal fibrosis in animal models and inversely correlates with GFR in humans, but whether galectin-3 predicts incident kidney disease is unknown. Here, we assessed renal outcomes for 2450 Framingham Offspring participants who attended examination 6 (1995–1998) and had follow-up data at examination 8 (2005–2008). Renal outcomes of interest included rapid decline in renal function (≥3 ml/min per 1.73 m² per year decline in estimated GFR [eGFR]), CKD (eGFR < 60 ml/min per 1.73 m²), and albuminuria (albumin-to-creatinine ratio ≥17 mg/g in men or ≥25 mg/g in women). We used multivariable logistic regression models to evaluate associations between galectin-3 with incident renal outcomes at examination 8. During a mean follow-up of 10.1 years, GFR declined rapidly in 241 (9.2%) participants, incident CKD developed in 277 (11.3%), and albuminuria developed in 194 (10.1%). Higher plasma levels of galectin-3 were associated with rapid decline in eGFR (per 1-SD log-galectin-3; adjusted odds ratio [OR], 1.49; 95% confidence interval [CI], 1.28 to 1.73]) and a higher risk of incident CKD (OR, 1.47; 95% CI, 1.27 to 1.71), but not with the risk of incident albuminuria. The addition of galectin-3 to clinical predictors improved the C-statistic (0.837–0.845; P=0.02) but did not reach predefined thresholds for clinically significant improvements to risk prediction based on reclassification indices. In conclusion, elevated levels of plasma galectin-3 are associated with increased risks of rapid GFR decline and of incident CKD in the community, which calls for further study in higher-risk groups.CKD is a major worldwide public health problem^1–6 that may result in progressive deterioration in kidney function,⁷ substantial morbidity,^8–10 and increased mortality from both cardiovascular¹¹ and noncardiovascular causes.¹² Because of the lack of early clinical signs or symptoms and the poor sensitivity of currently available biomarkers (serum creatinine and urinary protein), CKD is typically detected at an advanced stage. However, when detected early, kidney function decline may be slowed or even reversed and these secondary complications averted.^13–15 Hence, there is a pressing clinical need for novel biomarkers that identify at-risk individuals at the earliest possible stage.Galectin-3 is a β-galactoside–binding lectin that has emerged as a key regulator of inflammation and fibrosis.¹⁶ Galectin-3 is strongly linked to the development of organ fibrosis in rodent models: Galectin-3 knockout mice are resistant to the development of fibrosis, whereas infusion of recombinant galectin-3 induces TGF-β−dependent tissue fibroblast proliferation and collagen deposition.^17,18 In addition, upregulation of galectin-3 has been implicated in fibrosis of multiple organs, including the liver,^19,20 lung,²¹ and heart.¹⁷ Galectin-3 has also been linked to the development of renal fibrosis,^22,23 as well as fibrosis attenuation via matrix remodeling,²⁴ indicating a context-dependent role.Progressive CKD is characterized by the development of tubulointerstitial fibrosis.²⁵ Galectin-3 expression and secretion by macrophages have previously been shown to promote the development of tubulointerstitial fibrosis in mouse models.²³ We believe galectin-3 merits study as a renal biomarker on the basis of this association with renal fibrosis, as well as strong cross-sectional correlations with GFR identified in studies of patients with heart failure and in the general population.^26–30 We hypothesized that higher plasma galectin-3 levels would be associated with an increased risk of incident CKD in the general population, defined as estimated GFR (eGFR) < 60 ml/min per 1.73 m² or incident albuminuria. We also considered whether galectin-3 is associated with rapid decline in kidney function, as assessed by decline in eGFR during the follow-up period. To address these questions, we assessed prospective relations of galectin-3 and these outcomes in unselected participants from the Framingham Heart Study (FHS).     

How Long Will I Be Blue? Prolonged Skin Staining Following Sentinel Lymph Node Biopsy Using Intradermal Patent Blue Dye

Zusammenfassung

Hintergrund: Der für die Sentinel-Knoten-Biopsie bei Mammakarzinom-Patientinnen verwendete blaue Farbstoff kann längerfristige Hautverfärbungen im Injektionsbereich verursachen. Ziel dieser Studie war es, die Dauer derartiger Hautverfärbungen zu bestimmen. Patientinnen und Methoden: 236 aufeinanderfolgende Mammakarzinom-Patientinnen, bei denen eine brusterhaltende Operation und Sentinel-Knoten-Biopsie durchgeführt worden waren, wurden von Januar 2007 bis Dezember 2009 prospektiv untersucht. Ergebnisse: Bei 2 der 236 Patientinnen war eine bilaterale chirurgische Behandlung erfolgt, und 41 wurden im Rahmen jährlicher Nachuntersuchungen beurteilt. Blaue Verfärbungen im Injektionsbereich waren nach 12, 24 bzw. > 36 Monaten bei 36,5, 23,6 bzw. 8,6% der Patientinnen weiterhin sichtbar. Schlussfolgerung: Die Anwendung von Patentblau zur Identifikation des Sentinellymphknotens bei chirurgisch behandelten Mammakarzinom-Patientinnen kann zur längerfristigen Verfärbung der Haut im Injektionsbereich führen.     

Addition of Algenpantucel-L Immunotherapy to Standard Adjuvant Therapy for Pancreatic Cancer: a Phase 2 Study

Background

Despite continued investigation, limited progress has been made in the adjuvant treatment of resected pancreatic cancer. Novel or targeted therapies are needed.

Methods

Multi-institutional, open-label, dose-finding, phase 2 trial evaluating the use of algenpantucel-L (NewLink Genetics Corporation, Ames, IA) immunotherapy in addition to chemotherapy and chemoradiotherapy in the adjuvant setting for resected pancreatic cancer (ClinicalTrials.gov identifier, NCT00569387). The primary outcome was 12-month disease-free survival. Secondary outcomes included overall survival and toxicity.

Results

Seventy patients were treated with gemcitabine and 5-fluorouracil-based chemoradiotherapy as well as algenpantucel-L (mean 12 doses, range 1–14). After a median follow-up of 21 months, the 12-month disease-free survival was 62 %, and the 12-month overall survival was 86 %. The most common adverse events were injection site pain and induration.

Conclusions

The addition of algenpantucel-L to standard adjuvant therapy for resected pancreatic cancer may improve survival. A multi-institutional, phase 3 study is ongoing (ClinicalTrials.gov identifier, NCT01072981).